Volume 16 • Number 3 Suppl.

1
September 2022
São Paulo • Brazil

OFFICIAL JOURNAL OF THE SCIENTIFIC DEPARTMENT OF COGNITIVE NEUROLOGY AND AGING OF THE BRAZILIAN ACADEMY OF NEUROLOGY

Consensus

1 Subjective cognitive decline, mild cognitive impairment,

and dementia - syndromic approach

21 Diagnosis of Alzheimer’s disease

36 Diagnosis of frontotemporal dementia

49 Diagnosis of vascular cognitive impairment

69 Diagnosis and management of Parkinson’s disease dementia

and dementia with Lewy bodies

83 Treatment of dementia

96 Management in severe dementia

 Volume 16 • Number 03
September 2022
São Paulo • Brazil

OFFICIAL JOURNAL OF THE SCIENTIFIC DEPARTMENT OF COGNITIVE NEUROLOGY AND AGING OF THE BRAZILIAN ACADEMY OF NEUROLOGY

EDITORIALEditors
BOARD
Ricardo Nitrini Sonia Maria Dozzi Brucki
Editor-in-Chief
University of São Paulo, São Paulo SP, Brazil University of São Paulo, São Paulo SP, Brazil

Ricardo Nitrini Associate Editors Sonia Maria Dozzi Brucki

Universidade de São Paulo, São Paulo, São Paulo, Brazil Universidade de São Paulo, São Paulo, São Paulo, Brazil
Eliane Correa Miotto Mônica Sanches Yassuda
University of São Paulo, São Paulo SP, Brazil University of São Paulo, São Paulo SP, Brazil
Co-Editors
Section Editors
Eliane Correa Miotto Mônica Sanches Yassuda
Universidade deHistory
São Paulo,Note
São Paulo, São Paulo, Brazil Neuroimaging through
Universidade clinical
de São Paulo, Sãocases
Paulo, São Paulo, Brazil
http://lattes.cnpq.br/6923820631915917
Eliasz Engelhardt Marcio Luiz Figueredo Balthazar http://lattes.cnpq.br/0754786947169577
Leandro Tavares Lucato
https://orcid.org/0000-0003-2711-1627 https://orcid.org/0000-0002-9182-2450
Federal University of Rio de Janeiro, Rio de Janeiro RJ, Brazil University of Campinas, Campinas SP, Brazil University of São Paulo, São Paulo SP, Brazil

Advisory Editorial Board José Luiz Consultive Board

Sá Cavalcanti Renato Anghinah
Alexandre Castro-Caldas Jerusa Federal
Smid University of Rio de Janeiro, Rio de Janeiro RJ, Brazil UniversityVicente
Orestes of São Paulo, São Paulo SP, Brazil
Forlenza
André
Universidade Católica Palmini
Portuguesa, Lisboa, Portugal Márcia
Universidade Lorena
de São Paulo, Fagundes
São Paulo, São Paulo,Chaves
Brazil Wilson Jacob
Universidade Filho
de São Paulo, São Paulo, São Paulo, Brazil
Catholic University
André Luis Fernandes of Rio Grande do Sul, Porto Alegre RS, Brazil
Palmini João Carlos
FederalBarbosa
University Machado
of Rio Grande do Sul, Porto Alegre RS, Brazil Patricio
UniversityFuentes
of São Paulo, São Paulo SP, Brazil
Claudia Sellitto Porto Paulo
Universidade Caramelli
Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil Universidad de Chile, Santiago, Chile
Andrea Camaz Deslandes
University of São Paulo, São Paulo SP, Brazil John R.Federal
HodgesUniversity of Minas Gerais, Belo Horizonte MG, Brazil Paulo Caramelli
Universidade Federal
Jersondo Rio Laks
de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil University of New South Wales, Sydney, Australia
Paulo Henrique Ferreira Bertolucci
Andrew J. Lees
Federal University of Rio de Janeiro, Rio de Janeiro RJ, Brazil John C.Federal
MorrisUniversity of São Paulo, São Paulo SP, Brazil Paulo Henrique Ferreira Bertolucci
University College London, London, United Kingdom Washington University School of Medicine, Saint Louis, United States of America
Benito Pereira Damasceno
Paulo Roberto de Brito Marques
Editorial
Universidade de Campinas, Board
Campinas, São Paulo, Brazil Unidade deJamary Oliveira
Neurociência Filho e Cognitiva, Rio de Janeiro, Rio de
Comportamental Moyses Chaves
Universidade Estadual de Pernambuco, Recife, Pernambuco, Brazil
Breno Satler de Oliveira Diniz Janeiro, Brazil
Federal University of Bahia, Salvador BA, Brazil Federal University of Goiás, Goiânia GO, Brazil
Alexandre
University of Texas Health ScienceCastro-Caldas
Center at Houston, Houston, TX, United José Luiz Sá Calvalcanti
Jerusa Smid Orestes Vicente Forlenza
States of AmericaPortuguese Catholic University, Lisbon, Portugal
University of São Paulo, São Paulo SP, Brazil University of São Paulo, São Paulo SP, Brazil
Cláudia da Costa LeiteCamaz Deslandes Kenichi Meguro Ricardo F. Allegri
Andrea
Universidade de São Paulo, São Paulo, São Paulo, Brazil João Carlos
Tohoku University, Barbosa Machado
Sendai, Japan PatriciodeFuentes
Universidad Buenos Aires, Buenos Aires, Argentina
Federal University of Rio de Janeiro, Rio de Janeiro RJ, Brazil Faculty of Medical Sciences of Minas Gerais, Belo Horizonte MG, Brazil University of Chile, Santiago, Chile
Claudia Sellitto Porto Leila Maria Cardao Chimelli Ricardo de Oliveira Souza
Andrew Lees John
Universidade R. doHodges
Federal Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil PaulodeR.
Unidade de BritoComportamental
Neurociência Marques de Cognitiva, Rio de Janeiro, Rio
University
Dora Selma Fix VenturaCollege London, London, UK Leonardo Ferreira
University Caixeta
of New South Wales, Sydney, Australia deState
Janeiro, Brazil of Pernambuco, Recife PE, Brazil
University
Benito
Universidade de São Paulo, Pereira Damasceno
São Paulo, São Paulo, Brazil John
Universidade C. deMorris
Federal Goiás, Goiânia, GO, Brazil Sandra Weintraub
Ricardo F. Allegri
Facundo F. Manes Leonel Tadao Takada Northwestern University, Chicago, United States of America
Instituto de Neurología, Buenos Aires, Argentina Universidade de São Paulo, São Paulo, São Paulo, Brazil Sérgio Luís Blay
Francisco de Assis Carvalho do Vale Márcia Lorena Fagundes Chaves Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
Universidade Federal de São Carlos, São Carlos, São Paulo, Brazil Sergio Teixeira Ferreira
Francisco Javier Lopera Restrepo Marcia Radanovic Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil
University of Antioquia, Medelín, Colombia Universidade de São Paulo, São Paulo, São Paulo, Brazil
Tânia Marcourakis
Giacomo Rizzolatti Maria Alice de Mattos Pimenta Parente Universidade de São Paulo, São Paulo, São Paulo, Brazil
Università degli Studi di Parma, Parma, Italy Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
Tales Alexandre Aversi-Ferreira
Helenice Charchat-Fichman Maria Rita dos Santos e Passos Bueno Universidade Federal de Goiás, Catalão, GO, Brazil
Universidade Estácio de Sá, Rio de Janeiro, Rio de Janeiro, Brazil Universidade de São Paulo, São Paulo, São Paulo, Brazil
Henrique Cerqueira Guimarães Mayana Zatz Thomas H. Bak
Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil Universidade de São Paulo, São Paulo, São Paulo, Brazil University of Edinburgh, Edinburgh, United Kingdom
Howard Chertkow Michael D. Geschwind Vilma Regina Martins
McGill University, Montreal, Quebec, Canada University of California, San Francisco, United States of America Instituto de Pesquisa Ludwig, São Paulo, São Paulo, Brazil
Jamary Oliveira Filho M.-Marsel Mesulam Wilson Jacob Filho
Universidade Federal da Bahia, Salvador, Bahia, Brazil Northwestern University, Chicago, United States of America
Jerson Laks Moyses de Paul a Rodrigues Chaves Yves Joanette
Universidade Federal de Goiás, Goiânia, GO, Brazil University of Montreal, Quebec, Canada

Denise Ieiri de Moraes

Executive Editor Editorial Assistant
fabiana.montanari@abneuro.org.br dementia@abneuro.org.br
Associate editors
• Behavioral disorders in dementia Karolina Gouveia César Freitas
Analuiza Camozzatto de Pádua Universidade de Taubaté, Taubaté, São Paulo, Brazil
Universidade Federal de Ciências de Saúde de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil Nilton Santos Custodio Capuñay
Peruvian Institute of Neurosciences, Lima, Peru
Antonio Lucio Teixeira Junior
University of Houston, Texas, United States of America
• Clinical Trials
Florindo Stella Pablo Miguel Bagnati
Universidade Estadual Paulista, Rio Claro, São Paulo, Brazil Universidad de Buenos Aires, Buenos Aires, Argentina

• Biomarkers in dementia diagnosis • Genetics

Ezequiel Surace Leonel Tadao Takada
University of Buenos Aires, Buenos Aires, Argentina Universidade de São Paulo, São Paulo, Brazil
Breno Satler de Oliveira Diniz Mauricio Arcos-Burgos
University of Texas Health Science Center at Houston, Houston, TX, United States of America Universidad de Antioquia, Medellín, Colombia
Maria Niures Pimentel dos Santos Matioli
Centro Universitário Lusíada, Santos, São Paulo, Brazil • Neuroimaging
Artur Martins Novaes Coutinho
• Mild cognitive impairment Universidade de São Paulo, São Paulo, São Paulo, Brazil
Renata Kochhann Douglas Mendes Nunes
Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil Universidade de São Paulo, São Paulo, São Paulo, Brazil

• Caregiver: stress and orientation • Neuroimaging through Clinical cases

Marcia Cristina Nascimento Dourado Marcio Luiz Figueredo Balthazar
Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil Universidade de Campinas, Campinas, São Paulo, Brazil
Thaís Bento Lima da Silva Leandro Tavares Lucato
Universidade de São Paulo, São Paulo, São Paulo, Brazil Universidade de São Paulo, São Paulo, São Paulo, Brazil

• Cognition and Aging • Language and Aphasia

Lilian Schafirovits Morillo Marcela Lima Silagi de Siqueira
Universidade de São Paulo, São Paulo, São Paulo, Brazil Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil

Maira Tonidandel Barbosa Mirna Li Hosogi

Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil Universidade de São Paulo, São Paulo, São Paulo, Brazil

• Dementia costs • Neuropathology

Ceres Eloah de Lucena Ferretti Lea Tenenholz Grinberg
Universidade de São Paulo, São Paulo, SP Brazil University of California, San Francisco, United States of America
Roberta Diehl-Rodriguez
• Lewy Body Dementia/ Parkinson Disease/Atypical parkinsonism Universidade de São Paulo, São Paulo, São Paulo, Brazil
Jacy Bezerra Parmera
Universidade de São Paulo, São Paulo, São Paulo, Brazil • Developmental Neuropsychology
Rubens Gisbert Cury Claudia Berlin de Mello
Universidade de São Paulo, São Paulo, São Paulo, Brazil Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil

Vitor Tumas Maria Joana Mader Joaquim

Universidade de São Paulo, Ribeirão Preto, S]ao Paulo, Brazil Universidade Federal do Paraná, Curitiba, Paraná, Brazil
Vitor Geraldi Haase
• Frontotemporal Dementia Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
Leonardo Cruz de Souza
Universidade Federal de Belo Horizonte, Belo Horizonte, Minas Gerais, Brazil • Neuropsychology: diagnostic tests
Valéria Santoro Bahia Mario Amore Cecchini
University of Edinburgh, Edinburgh, United Kingdom
Universidade de São Paulo, São Paulo, São Paulo, Brazil
Valeska Marinho Rodrigues • History Note
Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil, Eliasz Engelhardt
Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil
• Vascular Dementia
Claudia Kimie Suemoto • Rehabilitation
Universidade de São Paulo, São Paulo São Paulo, Brazil Cláudia Maia Memória
Universidade de São Paulo, São Paulo, São Paulo, Brazil
Lucas Porcello Schilling
Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
• Subjective cognitive decline
• Diagnosis in indigenous and low education populations Adalberto Studart-Neto
Universidade de São Paulo, São Paulo São Paulo, Brazil
Elisa de Paula França Resende
Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil Wyllians Jose Vendramini Borelli
Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
Juliana Nery de Souza-Talarico
Universidade de São Paulo, São Paulo, São Paulo, Brazil Eduardo Sturzeneker Trés
Universidade de São Paulo, São Paulo, São Paulo, Brazil
Maíra Okada de Oliveira
Universidade de São Paulo, São Paulo, São Paulo, Brazil
• Translation and Transcultural Validation
• Epidemiology Marcia Maria Pires Camargo Novelli
Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
Alessandro Ferrari Jacinto
Universidade Estadual Paulista, Botucatu, São Paulo, Brazil • Social Media and Visual Abstract Editors
Cleusa Pinheiro Ferri Raphael Machado de Castilhos
Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
Déborah Oliveira Ricardo Pires Alvim
Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
 Volume 16 • Number 3 Suppl.1
September 2022
São Paulo • Brazil

OFFICIAL JOURNAL OF THE SCIENTIFIC DEPARTMENT OF COGNITIVE NEUROLOGY AND AGING OF THE BRAZILIAN ACADEMY OF NEUROLOGY

EDITORIALEditors
BOARD
Ricardo Nitrini Sonia Maria Dozzi Brucki
University of São Paulo, São Paulo SP, Brazil University of São Paulo, São Paulo SP, Brazil

Jerusa Smid Breno José Alencar Pires Barbosa

Associate Editors Lucas Porcello Schilling
Universidade de São Paulo, São Paulo SP, Brazil Universidade Federal de Pernambuco, Recife PE, Brazil Pontifícia Universidade do Rio Grande do Sul, Porto Alegre RS, Brazil
Eliane Correa Miotto Mônica Sanches Yassuda
University of São Paulo, São Paulo SP, Brazil University of São Paulo, São Paulo SP, Brazil
CONSULTIVE BOARD
Section Editors
History Note Neuroimaging through clinical cases
Adalberto Studart-Neto Eliasz Engelhardt Marcio
Jerson LaksLuiz Figueredo Balthazar Leandro Tavares
Mônica Lucato
Sanches Yassuda
Federal University of Rio de Janeiro, Rio de Janeiro RJ, Brazil
Benito Pereira Damasceno José University
IbiapinaofSiqueira
Campinas, Campinas SP, Brazil
Neto University of São Paulo, São Paulo SP, Brazil
Norberto Anízio Ferreira Frota
Ceres Eloah de Lucena Ferretti Karolina Gouveia César-Freitas Orestes Vicente Forlenza
Advisory Editorial Board José Luiz Sá Cavalcanti Renato Anghinah
Claudia Kimie Suemoto Leonardo Cruz de Souza
Federal University of Rio de Janeiro, Rio de Janeiro RJ, Brazil
Paulo Caramelli
University of São Paulo, São Paulo SP, Brazil
AndréCamargos
Einstein Francisco Palmini MárciaLeonel TadaoFagundes
Lorena Takada Chaves Wilson Jacob FilhoPaulo Henrique Ferreira Bertolucci
Catholic University of Rio Grande do Sul, Porto Alegre RS, Brazil
Eliasz Engelhardt FederalLilian Schafirovits
University of Rio GrandeMorillo
do Sul, Porto Alegre RS, Brazil University of São Paulo, SãoRaphael Machado Castilhos
Paulo SP, Brazil
Claudia
Elisa de Paula França Sellitto
ResendePorto Paulo Caramelli
Maira Tonidandel Barbosa Renata Kochhann
University of São Paulo, São Paulo SP, Brazil Federal University of Minas Gerais, Belo Horizonte MG, Brazil
Felipe Kenji Sudo Marcela Lima Silagi Ricardo Nitrini
Jerson Laks Paulo Henrique Ferreira Bertolucci
Fernanda Tovar-Moll
Federal University of Rio de Janeiro, Rio de Janeiro RJ, Brazil Marcia Cristina Nascimento Dourado
Federal University of São Paulo, São Paulo SP, Brazil
Rodrigo Rizek Schultz
Florindo Stella Márcia Lorena Fagundes Chaves Sonia Maria Dozzi Brucki
Francisco Assis Carvalho
Editorial Vale
Board JamaryMárcia Radanovic
Oliveira Filho Moyses Chaves Thais Helena Machado
Gilberto Sousa Alves FederalMárcio
UniversityLuiz Figueiredo
of Bahia, Balthazar
Salvador BA, Brazil Federal University of Goiás,Valéria Santoro
Goiânia GO, Brazil Bahia
Alexandre
Helen Bedinoto DurganteCastro-Caldas JerusaMarcusSmidVinicius Della Coletta Orestes Vicente Forlenza Valeska Marinho
Portuguese Catholic University, Lisbon, Portugal University of São Paulo, São Paulo SP, Brazil University of São Paulo, SãoVictor
Paulo SP, Brazil
Henrique Ballalai Ferraz Maria Teresa Carthery-Goulart Calil da Silveira
Andrea Camaz Deslandes JoãoMariana
Carlos Spitz
Barbosa Machado Patricio Fuentes Vitor Tumas
Ivan Aprahamian
Federal University of Rio de Janeiro, Rio de Janeiro RJ, Brazil Faculty of Medical Sciences of Minas Gerais, Belo Horizonte MG, Brazil University of Chile, Santiago, Chile
Jacy BezerraAndrew
ParmeraLees JohnMirna Lie Hosogi
R. Hodges Wyllians Vendramini Borelli
Paulo R. de Brito Marques
University College London, London, UK University of New South Wales, Sydney, Australia State University of Pernambuco, Recife PE, Brazil
 Consensus
CONTENTS
1 Subjective cognitive decline, mild cognitive impairment, and dementia - syndromic approach: recommendations
of the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology
Jerusa Smid, Adalberto Studart-Neto, Karolina Gouveia César-Freitas, Marcia Cristina Nascimento Dourado,
Renata Kochhann, Breno José Alencar Pires Barbosa, Lucas Porcello Schilling, Márcio Luiz Figueiredo Balthazar,
Norberto Anízio Ferreira Frota, Leonardo Cruz de Souza, Paulo Caramelli, Paulo Henrique Ferreira Bertolucci,
Márcia Lorena Fagundes Chaves, Sonia Maria Dozzi Brucki, Ricardo Nitrini, Elisa de Paula França Resende, Francisco Assis Carvalho Vale

21 Diagnosis of Alzheimer’s disease: recommendations of the Scientific Department of Cognitive Neurology and
Aging of the Brazilian Academy of Neurology
Lucas Porcello Schilling, Marcio Luiz Figueredo Balthazar, Márcia Radanovic,
Orestes Vicente Forlenza, Marcela Lima Silagi, Jerusa Smid, Breno José Alencar Pires Barbosa, Norberto Anízio
Ferreira Frota, Leonardo Cruz de Souza, Francisco Assis Carvalho Vale, Paulo Caramelli, Paulo Henrique Ferreira
Bertolucci, Márcia Lorena Fagundes Chaves,Sonia Maria Dozzi Brucki, Benito Pereira Damasceno, Ricardo Nitrini

36 Diagnosis of frontotemporal dementia: recommendations of the Scientific Department of Cognitive Neurology and
Aging of the Brazilian Academy of Neurology
Leonardo Cruz de Souza, Mirna Lie Hosogi, Thais Helena Machado, Maria Teresa Carthery-Goulart, Mônica Sanches
Yassuda, Jerusa Smid,Breno José Alencar Pires Barbosa, Lucas Porcello Schilling, Marcio Luiz Figueredo Balthazar,
Norberto Anízio Ferreira Frota, Francisco Assis Carvalho Vale, Paulo Caramelli, Paulo Henrique Ferreira Bertolucci,
Márcia Lorena Fagundes Chaves, Sonia Maria Dozzi Brucki, Ricardo Nitrini,Valéria Santoro Bahia, Leonel Tadao Takada

49 Diagnosis of vascular cognitive impairment: recommendations of the scientific department of cognitive neurology and
aging of the Brazilian Academy of Neurology
Breno José Alencar Pires Barbosa, José Ibiapina Siqueira Neto, Gilberto Sousa Alves, Felipe Kenji Sudo, Claudia Kimie Suemoto,
Fernanda Tovar-Moll, Jerusa Smid, Lucas Porcello Schilling, Marcio Luiz Figueredo Balthazar, Norberto Anízio Ferreira Frota,
Leonardo Cruz de Souza, Francisco Assis Carvalho Vale, Paulo Caramelli, Paulo Henrique Ferreira Bertolucci,
Sonia Maria Dozzi Brucki, Ricardo Nitrini, Eliasz Engelhardt, Márcia Lorena Fagundes Chaves

69 Diagnosis and management of Parkinson’s disease dementia and dementia with Lewy bodies: recommendations
of the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology
Jacy Bezerra Parmera, Vitor Tumas, Henrique Ballalai Ferraz, Mariana Spitz, Maira Tonidandel Barbosa, Jerusa Smid,
Breno José Alencar Pires Barbosa, Lucas Porcello Schilling, Márcio Luiz Figueiredo Balthazar, Leonardo Cruz de Souza,
Francisco Assis Carvalho Vale, Paulo Caramelli, Paulo Henrique Ferreira Bertolucci, Márcia Lorena Fagundes Chaves,
Sonia Maria Dozzi Brucki, Ricardo Nitrini, Raphael Machado Castilhos, Norberto Anízio Ferreira Frota

83 Treatment of dementia: recommendations of the Scientific Department of Cognitive

Neurology and Aging of the Brazilian Academy of Neurology
Paulo Caramelli, Valeska Marinho, Jerson Laks, Marcus Vinicius Della Coletta, Florindo Stella, Einstein Francisco Camargos,
Jerusa Smid, Breno José Alencar Pires Barbosa, Lucas Porcello Schilling, Marcio Luiz Figueredo Balthazar,
Norberto Anízio Ferreira Frota, Leonardo Cruz de Souza, Francisco Assis Carvalho Vale, Márcia Lorena Fagundes Chaves,
Sonia Maria Dozzi Brucki, Ricardo Nitrini,Helen Bedinoto Durgante, Paulo Henrique Ferreira Bertolucci

96 Management in severe dementia: recommendations of the Scientific Department of Cognitive Neurology and
Aging of the Brazilian Academy of Neurology
Sonia Maria Dozzi Brucki, Ivan Aprahamian, Wyllians Vendramini Borelli, Victor Calil da Silveira, Ceres Eloah de Lucena Ferretti,
Jerusa Smid, Breno José Alencar Pires Barbosa, Lucas Porcello Schilling,Márcio Luiz Figueiredo Balthazar, Norberto Anízio Ferreira Frota,
Leonardo Cruz de Souza, Francisco Assis Carvalho Vale, Paulo Caramelli, Paulo Henrique Ferreira Bertolucci,
Márcia Lorena Fagundes Chaves, Ricardo Nitrini, Rodrigo Rizek Schultz, Lilian Schafirovits Morillo
Dement Neuropsychol 2022 September;16(3 Suppl. 1):1-17 Consensus
https://doi.org/10.1590/1980-5764-DN-2022-S101EN

Subjective cognitive decline,

mild cognitive impairment,
and dementia - syndromic approach:
recommendations of the Scientific
Department of Cognitive Neurology
and Aging of the Brazilian Academy of Neurology
Jerusa Smid1 , Adalberto Studart-Neto1 , Karolina Gouveia César-Freitas1 ,
Marcia Cristina Nascimento Dourado2 ,Renata Kochhann3 , Breno José Alencar Pires Barbosa1,4,5 ,
Lucas Porcello Schilling6,7,8 , Márcio Luiz Figueiredo Balthazar9 , Norberto Anízio Ferreira Frota10,11 ,
Leonardo Cruz de Souza12 , Paulo Caramelli12 , Paulo Henrique Ferreira Bertolucci13 ,
Márcia Lorena Fagundes Chaves14,15 , Sonia Maria Dozzi Brucki1 , Ricardo Nitrini1 ,
Elisa de Paula França Resende16 , Francisco Assis Carvalho Vale17

1
Universidade de São Paulo, Faculdade de Medicina, Departamento de Neurologia, Grupo de Neurologia Cognitiva e do Comportamento, São Paulo SP, Brazil.
2
Universidade Federal do Rio de Janeiro,Instituto de Psiquiatria, Rio de Janeiro RJ, Brazil.
3
Hospital Moinhos de Vento, Porto Alegre RS, Brazil.
4
Universidade Federal de Pernambuco, Centro de Ciências Médicas, Área Acadêmica de Neuropsiquiatria, Recife PE, Brazil.
5
Instituto de Medicina Integral Prof. Fernando Figueira, Recife PE, Brazil.
6
Pontifícia Universidade do Rio Grande do Sul, Escola de Medicina, Serviço de Neurologia, Porto Alegre RS, Brazil.
7
Pontifícia Universidade do Rio Grande do Sul, Instituto do Cérebro do Rio Grande do Sul, Porto Alegre RS, Brazil.
8
Pontifícia Universidade do Rio Grande do Sul, Programa de Pós-Graduação em Gerontologia Biomédica, Porto Alegre RS, Brazil.
9
Universidade Estadual de Campinas, Faculdade de Ciências Médicas, Departamento de Neurologia, Campinas SP, Brazil.
10
Hospital Geral de Fortaleza, Serviço de Neurologia, Fortaleza CE, Brazil.
11
Universidade de Fortaleza, Fortaleza CE, Brazil.
12
Universidade Federal de Minas Gerais, Departamento de Clínica Médica, Belo Horizonte MG, Brazil.
13
Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Neurologia e Neurocirurgia, São Paulo SP, Brazil.
14
Hospital de Clínicas de Porto Alegre, Serviço de Neurologia, Porto Alegre RS, Brazil.
15
Universidade Federal do Rio Grande do Sul, Faculdade de Medicina,Departamento de Medicina Interna, Porto Alegre RS, Brazil.
16
Universidade Federal de Minas Gerais, Hospital das Clínicas, Belo Horizonte MG, Brazil.
17
Universidade Federal de São Carlos, Departamento de Medicina, Centro de Ciências Biológicas da Saúde, São Carlos SP, Brazil.
Correspondence: Jerusa Smid; Email: jsmid77@hotmail.com.
Conflict of interest: JS: Participation as speaker in symposia sponsored by Roche laboratory; LPS: Participation in advisory boards for Biogen. Participation as
speaker in symposia sponsored by Aché, Apsen, and Biogen laboratories; MLFB: Participation in advisory boards for Biogen. Development of material for continuous
medical education and participation as speaker in symposia sponsored by EMS and Torrent laboratories; PC: Participation as principal investigator in clinical trials
for the Novo Nordisk and Roche laboratories. Participation in advisory boards for the Aché, Biogen, EMS, Nutricia, and Roche laboratories. Development of material
for continuous medical education and participation as speaker in symposia sponsored by the Aché, Nutricia, Libbs, Roche, Sandoz, Torrent, and Zodiac laboratories;
PHFB: Participation in advisory boards for the Biogen and Novo Nordisk laboratories. Supervision of training activities for Biogen, Janssen-Cilag, and Novo Nordisk
laboratories and for Quintiles. Participation as speaker in symposia sponsored by the Apsen, Nutricia, Roche, and Sandoz laboratories; EPFR: funding by the
Alzheimer’s Association, the World Federation of Neurology, and the National Institute of Health (grant number R21AG069252); LCS: Participation in advisory board
for Biogen. Participation as speaker in symposia sponsored by Biogen; RN: Participation in advisory board for Biogen; KGCF, MCND, RK, ASN, BJAPB, NAFF, MLFC,
SMDB, FACV: There is no conflict of interest to declare.
Received on July 18, 2021; Received in its final form on January 03, 2022; Accepted on April 27, 2022.

Smid J, et al.   Syndromic approach to SCD, MCI, and dementia.   1

 Dement Neuropsychol 2022 September;16(3 Suppl. 1):1-17

ABSTRACT. This consensus, performed by the Brazilian Academy of Neurology (BAN) will approach practically how to evaluate patients with cognitive complaints
and how to clinically and etiologically diagnose the three clinical syndromes associated with the different stages of cognitive decline: subjective cognitive
decline (SCD), mild cognitive impairment (MCI), and dementia. This BAN consensus discusses SCD diagnosis for the first time, updates MCI and dementia
diagnoses, recommends the adequate cognitive tests and the relevant etiological work-up and care of patients with cognitive decline at different levels of
care within the Brazilian Unified Health System. We also review the main assessment instruments used in Brazil and Latin America.
Keywords: Dementia; Cognitive Dysfunction; Neuropsychological Tests.

DECLÍNIO COGNITIVO SUBJETIVO, COMPROMETIMENTO COGNITIVO LEVE E DEMÊNCIA: DIAGNÓSTICO SINDRÔMICO: RECOMENDAÇÕES DO DEPARTAMENTO
CIENTÍFICO DE NEUROLOGIA COGNITIVA E DO ENVELHECIMENTO DA ACADEMIA BRASILEIRA DE NEUROLOGIA
RESUMO. Este consenso realizado pela Academia Brasileira de Neurologia (ABN) abordará de maneira prática como avaliar pacientes com queixas cognitivas
e como realizar o diagnóstico clínico e etiológico das três síndromes clínicas associadas aos estágios de declínio cognitivo: declínio cognitivo subjetivo (DCS),
comprometimento cognitivo leve (CCL) e demência. O diagnóstico de DCS é discutido pela primeira vez em consenso da ABN e as atualizações para
o diagnóstico de CCL e demência são abordadas, bem como a recomendação para o uso de testes cognitivos apropriados, investigação etiológica pertinente
e cuidados aos pacientes com declínio cognitivo nos diferentes níveis de atenção do Sistema Único de Saúde. Foi realizada pesquisa dos principais
instrumentos de avaliação utilizados em nosso meio e na América Latina.
Palavras-chave: Demência; Disfunção Cognitiva; Testes Neuropsicológicos.

INTRODUCTION APPROACH TO PATIENTS WITH COGNITIVE AND

W hen we evaluate persons with cognitive complaints

(self-reported or referred by an informant),
the first question we must answer is whether they
BEHAVIORAL COMPLAINTS

have dementia. Dementia is defined as a syndrome
characterized by cognitive and/or behavioral decline in
which symptoms interfere with activities of daily living
(ADL) causing functional impairment when compared
with previous functionality and that is not explained
by delirium or major psychiatric1.
Mild cognitive impairment (MCI) is a condition in
which the individual has a cognitive impairment that does
not interfere with their autonomy in ADL performance.
They may experience slight difficulties performing complex
tasks that used to be trivial but still can maintain their
independence with minimal assistance2. More recently,
research has described a new syndrome for a group
of individuals who have cognitive complaints (mainly
memory) but who, when tested, show normal performance
in neuropsychological tests. This situation is called
subjective cognitive decline (SCD)3.
Therefore, dementia, MCI, and SCD are mainly
clinical diagnoses. Physicians should be able to diagnose
cognitive-behavioral syndromes during clinical
appointments after taking patients’ medical history and
performing cognition and functionality assessment.
Laboratory testing and neuroimaging are helpful to
define the etiology of the syndrome. Figure 1 illustrates
the continuum of cognitive decline. This study aims
1) to propose a standardized assessment of patients
with cognitive complaints; 2) to present the diagnostic
criteria for dementia, MCI, and SCD; and 3) to propose
a flowchart for investigating cognitive decline within
the Brazilian Unified Health System (SUS).
Medical history
Clinical evaluation begins with patients’ medical history.
The medical history should also be taken with a family
member or other close informants because anosognosia
(the inability to the recognize cognitive impairment)
is relatively common. Interviews with patients and their
informants should be carried out separately whenever
possible to address all complaints without embarrassing
patients and their informant. Physicians should ask specific
questions to identify which cognitive domains are affected,
whether patients show behavioral symptoms, and how
their cognitive decline impacts patients’ functionality.
Investigable cognitive domains by medical history include
memory, attention, visual-spatial functions, praxis,
executive functions, and language (Table 1).
During medical history, physicians should also
assess conditions that can cause a false impression
of cognitive impairment, such as untreated hearing
or visual impairment. Furthermore, symptoms that may
suggest delirium, such as fluctuation of the arousal and
attention levels should be observed. Clinicians should
ask patients about their use of medications, including
over-the-counter drugs since many medications with
anticholinergic or sedative effects can cause or worsen
cognitive impairment. Moreover, clinicians should enquire
about patients’ sleep pattern in search for symptoms
of obstructive apnea, REM sleep behavior disorder,
and daytime sleepiness. Dysautonomia symptoms such
as urinary or, bowel dysfunction, erectile dysfunction
and postural hypotension should also be investigated.
Motor symptoms, such as changes in gait and balance,
and sensory symptoms should be investigated.

2   Syndromic approach to SCD, MCI, and dementia.   Smid J, et al.

 Dement Neuropsychol 2022 September;16(3 Suppl. 1):1-17

Self-perception of cognitive decline

Normal aging
Cognitive performance

Independence in activities of daily living

Pathological aging

Normal Subjective Cognitive Decline Mild Cognitive Impairment Dementia

Age (years)
Figure 1. Continuum of cognitive decline in normal and pathological aging.

Table 1. Targeted medical history of patients with cognitive and behavioral complaints
Does the patient get more confused or disoriented sometimes?
Attention Is the patient easily distracted?
Is the patient missing objects?

Does the patient have more difficulties remembering recent facts than remote ones?
Has the patient shown temporal disorientation?
Memory Is the patient more repetitive and asking the same questions many times?
Does the patient need more annotations to remember appointments?
Has the patient forgotten appointments?

Does the patient have difficulties finding words?

Is the patient having difficulties naming objects?
Cognitive Language
Is the patient having difficulties articulating words?
symptoms Is the patient having difficulties understanding what you say to them?

Has the patient got lost in previously known routes?

Spatial orientation Is the patient having difficulties learning new routes?
Is the patient having difficulties locating themselves inside the house?

Is the patient having difficulties using utensils?

Praxies
Is the patient having difficulties dressing themselves?

Is the patient having difficulties planning or organizing activities and travels?

Is the patient having difficulties multitasking?
Executive functions
Is the patient having difficulties solving daily problems?
Is the patient having difficulties making decisions?

Is the patient having difficulties managing their own finances?

Instrumental activities of Is the patient having difficulties shopping?
daily living (IADLs) Is the patient having problems at work?
Functionality Is the patient having cooking problems?

Basic activities of daily Is the patient capable of doing the activities below independently?
living (BADLs) Dressing/Bathing/Hygiene/Feeding/Transference/Continence
Continue...

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Table 1. Continuation.
Does the patient look sad, dejected or cry easily?
Does the patient not see pleasure in life or says they have no future?
Humor
Is the patient more irritable or impatient?
Is the patient isolating themself, not getting along with others?

Is the patient worried about planned events?

Anxiety Is the patient unable to relax or is excessively tense?
Does the patient worry excessively about even trivial things?

Does the patient have no interest in the world around them?

Apathy Does the patient have more difficulty engaging in conversations or tasks?
Is the patient more indifferent?

Does the patient act impulsively, without thinking?

Has the patient been saying things that should not be said in public?
Disinhibition
Has the patient acted in an embarrassing way?
Did the patient suffer personality changes? Is the patient more socially isolated?

Is the patient uncooperative?

Behavior and Does the patient not allow to be helped?
neuropsychiatric Agitation Is the patient verbally or physically aggressive?
symptoms Does the patient repeatedly move objects around them?
Does the patient have ritualistic or compulsive behavior?

Does the patient believe in things that are not real?

Does the patient think someone is trying to harm or rob him?
Delusions
Does the patient claim that their relatives are not who they say they are?
Does the patient claim that the house they live in is not theirs?

Does the patient report hearing voices or act as if they heard voices that are not heard by others?
Does the patient speak to themself?
Hallucinations
Does the patient see people or animals that are not seen by others?
Does the patient behave as if they saw something that others do not see?

Did the patient have any change in eating habits?

Appetite
Has the patient changed food preference (e.g., they started to prefer sweets)?

Does the patient have difficulty initiating or maintaining sleep?

Does the patient speak or move in sleep as if they were awake?
Sleep
Does the patient often have vivid dreams or nightmares?
Does the patient snore, wake up fatigued, or have daytime sleepiness?

Cognitive screening tests
Cognitive screening tests consist of brief structured
instruments which enable physicians to globally assess
individuals’ cognition. There are several standardized
instruments, of which the Mini Mental State Examination
(MMSE) is the best known and most used4,5. MMSE is
simple and easy to apply; the whole assessment takes
from about five to seven minutes. It evaluates temporal
and spatial orientation, memory, attention, calculation,
language, and constructive skills. MMSE has many
advantages. It is easy to apply, general practitioners
know it well, and it can possibly stage disease progression.
Healthy older adults keep similar MMSE scores over
time, whereas patients with Alzheimer’s disease (AD),
for example, lose an average of two to four points per year6.
Other cognitive screening tests that have been
validated in Brazil are: The Blessed Information-Memory-
Concentration Test 7, Cognitive Abilities Screening
Instrument – Short (CASI-S) 8, the Addenbrooke’s
Cognitive Examination revised version (ACE-R, which
also includes the MMSE)9,10, the Montreal Cognitive
Assessment (MoCA) 11,12 and the CERAD ’s words
list13. Among those, MoCA stands out as it evaluates
executive function with the trails and clock drawing;
test the visual-constructive abilities with the cube
copying and clock drawing test; the episodic memory
with the five words delayed recall; attention with the
digit span, serials A’s and serial subtractions; language
with naming, repetition, and phonemic verbal fluency;
abstraction; and orientation. Therefore, the MoCA

4   Syndromic approach to SCD, MCI, and dementia.   Smid J, et al.

 Dement Neuropsychol 2022 September;16(3 Suppl. 1):1-17

assesses a broader number of cognitive domains than
the MMSE, especially the executive functions.
The MMSE and the MoCA scores are strongly
affected by the level of education. We suggest using the
cutoff points in Table 2 considering the several studies
conducted in different Brazilian populations5,12,14-21.
Considering the challenge of having a test to assess
populations with lower educational level, Nitrini and
collaborators developed the Brief Cognitive Screening
Battery (BCSB)22-24. This test consists of naming and
learning a list of 10 drawings to be freely recalled five
min later, after an interference activity consisting of
semantic verbal fluency (animals/1 min) and the clock
drawing test22-24.It is an easy-to-apply instrument useful
for diagnosing episodic memory impairment in patients
with low and high educational levels25.

Table 2. Tests suggested for cognitive screening and their respective cutoff scores.

Cognitive Test Cognitive domains Suggested cut-off scores for the Brazilian population

According to education level:

Temporal and spatial orientation
Illiterate: ≤19
Verbal episodic memory
Mini Mental State 1-4 years: ≤24
Attention and calculation
Examination (MMSE)5 5-8 years: ≤26
Language
9-11 years: ≤27
Visual constructive skills
≥ 12 years: ≤28

Figure Memory Subtest:

Incidental memory: ≤4
Immediate memory: ≤6
Learning: ≤6
Visual and verbal episodic memory Delayed recall: ≤5
Brief Cognitive Screening
Executive functions Recognition: ≤7
Battery (BCSB)24
Visual constructive skills
Semantic Verbal Fluency (animals) by education level26
Illiterate: ≤8
1-7 years: ≤11
≥ 8 years: ≤12

For Dementia (by education level):

Illiterate: ≤8
1-4 years: ≤15
Executive functions
5-8 years: ≤16
Visual constructive skills
9-11 years: ≤19
Verbal episodic memory
Montreal Cognitive ≥ 12 years: ≤21
Attention
Assessment (MoCA)12 For cognitive impairment no dementia [CIND] (by education level):
Language
Illiterate: ≤11
Abstraction
1-4 years: ≤17
Temporal and spatial orientation
5-8 years: ≤19
9-11 years: ≤19
≥ 12 years: ≤21

The authors recommend using the MMSE and
the BCSB for cognitive screening (supplementary
materials). Clinicians may instead use MoCA in
patients with high educational level (>12 completed
years of study) and MCI or mild dementia or due to
the need of better executive function assessment.
Table 2 shows our suggested cut-off scores for MMSE5,
MoCA12, figure delayed recall from the BCSB24-26, and the
semantic fluency27. Eventually, dementia specialists may
include other cognitive tests to assess specific cognitive
domains, such as language, praxis, visuospatial
skills, episodic memory, attention, and executive
functions assessment batteries. Clinicians may require
neuropsychological tests when cognitive screening
tests are insufficiently sensitive to detect cognitive
impairment, especially in individuals with MCI.

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 Dement Neuropsychol 2022 September;16(3 Suppl. 1):1-17
Neurological examination
In addition to cognitive assessment, the neurological
physical exam of patients with cognitive complaints
must evaluate neurological signs that may point
to a possible etiology. Some findings may have
particular relevance, such as brisk reflexes, signs of
parkinsonism, gait changes, and ocular motricity.
Primitive reflexes are often seen in patients with frontal
involvement (hence the term “frontalization” signs) and
severe dementia. Primitive reflexes include the grasp
(handgrip), rooting (searching), snout (lips protrusion),
and palmomental ones.
Functional evaluation
Daily function evaluation is a core feature in assessing
patients with cognitive decline because the level
of functional impairment will determine patients’
syndromes. Most instruments used for functional
assessment, which are validated for Brazilian
populations, are based on informants’ responses28.
In Brazil, one of the most used instruments is Pfeffer
Functional Activities Questionnaire (FAQ), which
includes 10 questions especially focused on instrumental
activities (supplementary material)29. It consists of
a simple questionnaire that is easy to understand and
quick to apply (average of seven minutes). FAQ scores
range from 0 to 30 and scores above four points indicate
functional impairment. This test avoids the influence
of age or education level30,31. Another scale which also
has a Portuguese version and proved to be useful for
diagnosing dementia in a Brazilian study is the Bayer
activities of daily living scale (B-ADL)32. The Informant
Questionnaire on Cognitive Decline in the Elderly
(IQCODE) is a structured interview administered
to informants which combines questions related
to cognitive functioning and functional performance.
It was translated and adapted for Brazilian populations
and can be helpful to screen dementia in individuals
with varying educational level 33,34. The Katz scale,
which has been translated and adapted for Brazilian
populations, can be used to assess basic activities
of daily living (BADLs)28,35.
Cognitive impairment staging
When a person is diagnosed with cognitive decline,
clinicians need to stage this condition. The Clinical
Dementia Rating (CDR) scale has been used worldwide
for staging cognitive decline and has been validated for
Brazil36. CDR rates six domains: memory, orientation,
judgment and problem solving, community affairs,
home and hobbies, and personal care37. Clinicians can
use a semi-structured interview to assist with scoring.
6   Syndromic approach to SCD, MCI, and dementia.   Smid J, et al.
The first three domains are assessed with patients and
informants and the last three domains, with informants
only. The CDR global score ranges between 0 (normal),
0.5 (MCI), 1 (mild dementia), 2 (moderate dementia),
and 3 (severe dementia).
A brief cognitive assessment using the MMSE and
dementia staging by the CDR are needed to request
the Brazilian Unified Health System (SUS) to provide
the symptomatic pharmacological treatment for
dementia due to AD. SUS provides acetylcholinesterase
inhibitors for mild to moderate AD and memantine
to moderate to severe AD 38. This consensus will
comprehensively discuss dementia treatment39.
SUBJECTIVE COGNITIVE DECLINE (SCD)
Concept and diagnostic criteria
Subjective cognitive decline (SCD) is defined as self-
perceived cognitive decline with neither objective
impairment on cognitive tests nor functional
impairment on ADLs 40,41. The literature has used
several expressions to define self-perceived cognitive
impairment, such as “subjective memory complaint,”
“subjective cognitive impairment,” and “subjective
cognitive complaint”3,42. In 2014, an international
working group (the Subjective Cognitive Decline
Initiative, SCD-I) proposed diagnostic criteria for SCD
focused on standardizing terminology for research in
preclinical AD (Table 3). This group recommends to use
the term “cognitive,” instead of “memory,” because the
first symptoms may not be limited only to amnestic and
“decline” instead of a “complaint,” as it refers to the idea
of progressive deterioration and not only an isolated
and non-progressive complaint.
Table 3. Approaches to Classifying SCD among a sample of Subjective
Cognitive Decline Initiative (SCD-I) Working Group studies3,42.
Criteria 1 and 2 must be present:
1. Self-experienced persistent decline in cognitive capacity in comparison
with a previously normal status, unrelated to an acute event.
2. Normal performance on standardized cognitive tests, which are
used to classify mild cognitive impairment (MCI) (adjusted for age,
gender, and education level).
Exclusion criteria:
1. Diagnosis of mild cognitive impairment or dementia.
2. Cannot be explained by a psychiatric* or neurologic disease
(apart from AD), medical disorder, medication, or substance use.
*Symptoms of depression or anxiety that fail to meet criteria for a psychiatric disorder are
not considered exclusion criteria.

Epidemiology
A Mayo Clinic study showed an SCD prevalence between
12.3% and 57% among cognitively healthy participants
aged between 70 and 95 years. Overall, 24% of the total
population reported memory concerns43. Similarly,
a Brazilian study, conducted in the municipality
of Tremembé, reported an SCD prevalence of 27.6% among
all participants over 60 years old, which represented 45.2%
of individuals with normal cognitive tests44. Longitudinal
epidemiological studies have associated SCD with an
increased risk for progression to MCI and dementia3,43,45,46.
In a meta-analysis of 29 studies, the annual conversion
rate from SCD to MCI and dementia was around 6.7%
and 2.3%, respectively, compared with a conversion to
dementia of only 1% among older adults without SCD.
Among studies which conducted follow-ups for longer
than four years, the evolution to MCI and dementia
reached 26.7% and 14.1%, respectively47. Furthermore,
older adults with SCD showed a higher prevalence of
positive AD biomarkers48-51.
SCD etiologies
Many people with SCD remain stable or even improve.
This is because not only neurodegenerative diseases
(such as AD) are among the causes of SCD. Several
other conditions can be associated with SCD, such as
normal aging, personality traits, psychiatric disorders
(especially depression and anxiety), sleep disorders
(like obstructive sleep apnea syndrome), and the use
of psychoactive medications with anticholinergic
or GABAergic effects42,52.
Therefore, several questions arise: How to identify
which individuals within this heterogeneous group
will progress to MCI or dementia? What are the SCD
characteristics which increase the risk for progression?
In other words, how can we determine whether
an individual with SCD has an underlying preclinical AD?
Therefore, some authors have proposed the term
“SCD plus.” Patients with SCD plus have a higher
probability of showing a neurodegenerative pathology.
Individuals at increased risk of conversion to Alzheimer-
type dementia are older adults (≥ 60 years) with
progressive amnestic cognitive complaints within the
last five years who worry about this decline and has
family members confirming this decline3,40.
It is important to identify people with SCD at
higher risk of developing AD mainly in the context of
therapeutic clinical trials. In clinical practice, patients
with SCD must be followed up, especially those who
meet the SCD plus criteria. Although there are no
pharmacological treatments, non-pharmacological
interventions, should be encouraged such as aerobic
Dement Neuropsychol 2022 September;16(3 Suppl. 1):1-17
exercise and control of cardiovascular risk factors.
Patients with SCD should be screened for psychiatric
disorders, such as depression, sleep disorders like
sleep apnea, as well as for the use of anticholinergic
medications and other clinical disorders associated
with cognitive impairment, such as hypothyroidism.
MILD COGNITIVE IMPAIRMENT (MCI)
Concept and diagnostic criteria
MCI consists of an intermediate clinical condition
between normal aging and dementia, which SCD
may precede. The MCI criteria initially defined by
Petersen emphasized the presence of complaints
and memory impairment with performance on tests
usually 1.5 standard deviations below the mean for age
and education, during basic activities of daily living53.
The literature has described the risk of progression
to AD as 10 to 12% per year53. Thereafter, research
has recognized MCI as a more heterogeneous and
comprehensive entity regarding its clinical presentation,
etiology, and prognosis, considering deficits in other
cognitive domains besides memory 54,55. The MCI
definition includes the following criteria: (1) cognitive
complaints reported by the patient and/or informant;
(2) report of cognitive decline during the past year;
(3) changes in cognition (memory and/or other
domains) evinced at the clinical objective evaluation
when compared with normal adults of the same age
and educational level; (4) no difficulty with daily
activities, preserved general cognitive functioning;
and (5) absence of dementia56,57.
Over the years, these clinical criteria received
updates since the MCI definition initially proposed in
1999 (known as the Mayo Clinic criteria53) had gaps,
such as involvement of other cognitive domains,
the possibility that cognitive complaints could come
from informants, and acceptance of minimally impaired
complex instrumental functions. These updates were
included in the 2004 Key Symposium consensus 55.
From then on, MCI includes four subtypes: single-domain
amnestic MCI, multiple-domain amnestic MCI,
single-domain non-amnestic MCI, and multiple-domain
non-amnestic MCI (Figure 2). The several MCI subtypes
are due to possible degenerative, vascular, metabolic,
and psychiatric etiologies, among others55.
In 2011, the National Institute on Aging and
Alzheimer’s Association (NIA-AA) again updated the
consensus for the clinical diagnosis of MCI, establishing
diagnostic criteria for the symptomatic stage of AD
pre-dementia58, thus creating the AD-due MCI terminology
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for cases with the clinical characteristics, as per Table 4.
Moreover, it included the presence of biomarkers into the
criteria for research, specialized centers, and clinical trials,
allowing for different degrees of AD etiology probability58.
Finally, in 2013, the MCI consensus underwent yet
another terminology increments during the establishment
of the Diagnostic and Statistical Manual of Mental
Disorders, Fifth Edition (DSM-5), which recognized it as
a mild neurocognitive disorder59. In 2022, the 11th edition
of the International Statistical Classification of Diseases
and Related Health Problems (ICD 11) proposed the term
mild neurocognitive disorder60.

Cognitive complaint

Not normal for age

No dementia
Cognitive decline
Essentially normal functional activities

MCI

Yes Memory impaired? No

Amnestic MCI Non-amnestic MCI

Yes Memory impairment only? No Yes Single impaired non-memory cognitive domain? No

Amnestic MCI Amnestic MCI Non-amnestic MCI Non-amnestic MCI

Single domain Multiple domain Single domain Multiple domain

Etiology

FTD DLB
Degenerative AD AD
AD AD

Vascular VCI VCI

Psychiatric Depression Depression

MCI: Mild Cognitive Impairment; AD: Alzheimer’s disease; VCI: vascular cognitive impairment; FTD: frontotemporal dementia; DLB: dementia with Lewy bodies.
Figure 2. Diagnostic classification of MCI after the Key Symposium criteria.

Table 4. Diagnostic criteria for Mild Cognitive Impairment due to Alzheimer’s disease by the National Institute on Aging and Alzheimer’s Association (NIA-AA)58.
Clinical and cognitive characteristics
Cognitive worries reflecting a change in cognition reported by patients, informants or clinicians (i.e., historical or observed evidence
of decline over time)

Objective evidence of impairment in one or more cognitive domains, typically including memory (i.e., formal, or bedside testing
to establish level of cognitive function in multiple domains)

Preservation of independence in functional abilities. They may show slight problems performing complex tasks, such as taking longer
to complete the task or making some mistakes
Not demented

Etiology of MCI consistent with AD pathophysiological process

Rule out vascular, traumatic, medical causes of cognitive decline, where possible
Provide evidence of longitudinal decline in cognition, when feasible
Report history consistent with AD genetic factors
MCI: Mild Cognitive Impairment; AD: Alzheimer’s disease.

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For the clinical diagnosis, in addition to a detailed
medical history, it is important to question about the
presence of systemic diseases, use of medications and
have the evidence of objective cognitive assessment with
a mild decline in relation to the individuals’ previous
cognitive level in one or more cognitive domains (complex
attention, executive function, learning and memory,
language, perceptuomotor, or social cognition), besides
not meeting the diagnostic criteria for dementia58.
Therefore, cognitive deficits in MCI do not interfere with
the ability to be independent in ADLs, thus complex
instrumental activities of daily life are preserved,
such as paying bills or controlling medications,
but there may be need for more effort or compensatory
strategies 58. Independence in instrumental ADLs
distinguishes MCI from dementia. Nevertheless,
when compared to normal aging, individuals with MCI
perform more poorly59.
Epidemiology
Epidemiological studies of MCI, although scarce and
heterogeneous regarding their adopted criteria (used
tests and educational level of the studied population),
are important since longitudinal studies have shown
that people with MCI are at increased risk of developing
dementia, up to five times as high annually than the
general population62-65. The estimated prevalence of MCI
in most international population studies ranges from 10
to 22% in people aged 65 years or older62,64-68. A meta-
analysis found a wide range of definitions and concepts
to estimate MCI prevalence and incidence, representing
a challenge for researchers’ understanding of the
burden of this disease; MCI prevalence and incidence
rates ranged, respectively, from 3 to 42% and from 21.5
to 71.3 per 1000 person-years, and the prevalence of
cognitive impairment with no dementia (CIND) ranged
from 5.1 to 35.9%69.
We find varying terminology in the few population
studies conducted in Brazil. Overall, two studies,
conducted in the municipality of Porto Alegre
(Rio Grande do Sul State), found an MCI prevalence
of 6.1%70 and a 13.2 per 1000 person-years incidence71,
whereas the study conducted in the municipality of
Tremembé, in São Paulo State, found a CIND prevalence
of 19.5% for the population aged 60 years and older72.
DEMENTIA: A SYNDROMIC APPROACH
Concept and diagnostic criteria
The criteria for dementia proposed in 2011 by the
NIA-AA and the Brazilian Academy of Neurology pare
shown in Table 51,71. In 2014, the American Psychiatric
Association through the DSM-5, proposed the use of
the term major neurocognitive disorder and expanded
the diagnosis of dementia to situations where there is
only one cognitive domain affected58.
For the most recent edition of the International
Statistical Classification of Diseases and Related Health
Problems (ICD-11), published in 2019 and which
will come into force in 2022, there is still a need for
cognitive decline in at least two cognitive domains for
the diagnosis of dementia , not allowing the diagnosis
of cognitive decline in a single domain72,73.

Table 5. Diagnostic criteria for dementia according to the National Institute on Aging and Alzheimer’s Association (NIA-AA) and the Brazilian Academy of Neurology1,73.
1. Dementia is diagnosed when there are cognitive or behavioral (neuropsychiatric) symptoms that:
1.1. Interfere with the ability to work or to carry out usual activities
1.2. Represent a decline from previous levels of functioning and performance;
1.3. Cannot be explained by delirium or major psychiatric disorder.
2. Cognitive impairment is detected and diagnosed by a combination of:
2.1. Medical history with the patient and a reliable informant; and
2.2. An objective cognitive assessment, either a “bedside” mental status examination or neuropsychological testing. Neuropsychological testing should
be performed when medical history and bedside mental status examination cannot provide a confident diagnosis.
3. Cognitive or behavioral impairment involves a minimum of two of the following domains:
3.1. Memory: impaired ability to acquire and remember new information — symptoms include repetitive questions or conversations, misplacing personal
belongings, forgetting events or appointments, getting lost on a familiar route;
3.2. Executive functions: impaired reasoning and carrying out complex tasks and judging — symptoms include poor understanding of safety risks,
inability to manage finances, poor decision-making ability, inability to plan complex or sequential activities;
3.3. Visuospatial abilities: symptoms include inability to recognize faces or common objects or to find objects in the visual field, inability to handle utensils
and dressing oneself for reasons other than visual or motor deficiency.
3.4. Language (speaking, reading, writing): symptoms include difficulty in finding common words while speaking, hesitations; speech, spelling, and
writing errors and exchange of words or phonemes, unexplicable by a sensory or motor deficit.
3.5. Behavior or personality: symptoms include uncharacteristic mood fluctuations such as agitation, impaired motivation, initiative, apathy, loss of drive,
social withdrawal, decreased interest in previous activities, loss of empathy, compulsive or obsessive behaviors, and socially unacceptable behaviors.

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 Dement Neuropsychol 2022 September;16(3 Suppl. 1):1-17

Epidemiology reduce the prevalence of dementia in 2050 by 8.7

The prevalence of dementia in Brazil ranges from
5.1 to 17.5%, var ying according to the studied
reg ion a nd st udy desig n75 . T he preva lence of
dementia in the world population aged ≥60 years
is 5 to 7% in most regions, with the highest prevalence
in Latin America, at 8.5%76 . In a Brazilian study,
the prevalence of dementia is even higher, reaching
23% in illiterate individuals aged 60 years or older
living at the municipality of Tremembé72.
In Brazil, a study suggests that 32.3% of dementia
cases are due to seven modifiable risk factors: diabetes
mellitus, systemic arterial hypertension, middle-age
obesity, physical inactivity, depression, smoking,
and poor education77. Reducing the prevalence of each
risk factor by 10% or 20% per decade could potentially
or 16.2% in Brazil77.
Etiologies of MCI and dementia
The literature divides the etiologies of dementias into
primary (or neurodegenerative) and secondary ones
(Figure 3). The altered accumulation of misfolded proteins
(misfolded proteins diseases) in the central nervous
system (CNS)78 pathologically characterizes degenerative
dementias. AD, Lewy body (LBD), and frontotemporal
dementias (FTD) are the most frequent ty pes
of primary dementias. Other various neurological
diseases, usually associated with movement disorders
(such as parkinsonism or chorea), can develop dementia
throughout its evolution, such as Parkinson’s disease,
progressive supranuclear palsy, corticobasal syndrome,
and Huntington’s disease.

Cognitive complaint brought by the patient and/or companion

Demonstration of cognitive impairment in assessment

Yes No
Subjective Cognitve Decline
Functional decline
No Yes
Mild cognitive impairment Dementia

Degenerative dementias Non-degenerative dementias

Amnestic predominance Alzheimer’s Disease (AD)

Disexecutive predominance Frontal variant of AD

Dementia with Lewy bodies With evidence of Without evidence
structural lesion of structural lesion
Behavioral Predominance Frontotemporal dementia

Aphasic predominance Primary progressive Aphasias

Encefalites Vascular dementia HAND
Posterior Cortical Atrophy (AD) Normal Pressure Hydrocephalus Neurosyphilis
Visuospatial predominance
Dementia with Lewy bodies Chronic Traumatic Encephalopathy Thyroid diseases
CNS Neoplasms Uremic
Parkinson’s Disease Dementia Autoimmune encephalitis Hypermonemia
Dementia with Lewy bodies Infectious Encephalitis Drugs
With Parkinsonism
Progressive Supranuclear Palsy B12 deficiency
Corticobasal Syndrome Thiamine Deficiency

Rapidly Progressive Creutzfeldt-Jakob Disease

Figure 3. Main etiological differential diagnoses of dementia.

10   Syndromic approach to SCD, MCI, and dementia.   Smid J, et al.

 Dement Neuropsychol 2022 September;16(3 Suppl. 1):1-17

Epidemiological and clinical studies found that
AD dementia is the most prevalent cause of dementia
in Brazil, followed by vascular dementia (VD) due to
cerebrovascular disease 75. A study conducted with
clinicopathological analysis also found the same
ordering of causes related to dementia 79. Another
study from a Brazilian brain bank with 480 participants
found that 50% of its sample met the neuropathological
criteria for AD, 35%, VD; 18%, LBD; 17% received other
diagnoses (e.g., frontotemporal lobar degeneration);
and 20% showed mixed pathology (most were AD
associated with VD)80.
Historically, neurodegenerative dementias were
described based on their clinical phenotypes (e.g.,
AD is described as amnestic dementia in most cases).
However, in the last two decades, studies searching
an early diagnosis based on biomarkers , that allow
the identification of pathological proteins in vivo
have been increasing 77 . Interestingly, the same
pathological protein can lead to different phenotypes,
while the same phenotype can be associated with
different proteins80. Figure 4 illustrates this broad
spectrum of proteinopathies and clinical phenotypes.

FTD: Frontotemporal dementia; ALS: Amyotrophic lateral sclerosis; MND: Motor neuron disease; svPPA: Semantic variant of primary progressive aphasia; nfvPPA: Nonfluent (or agrammatic)
variant of primary progressive aphasia; CBS: Corticobasal syndrome; PSP: Progressive supranuclear palsy; AD: Alzheimer’s disease; lvPPA: Logopenic variant of primary progressive aphasia;
DLB: Dementia with Lewy bodies; PD: Parkinson’s disease; MSA: Multiple systems atrophy.
Figure 4. Spectrum of proteinopathies causing neurodegenerative dementias and their respective clinical phenotypes.
Pathological proteins: TDP-43, FUS, Tau, beta-amyloid and alpha-synuclein.

Secondary causes are potentially treatable and
should be investigated for early treatment. The most
frequent cause of secondary dementia is VD, which
is the second leading cause of dementia in Brazil.
The investigation of risk factors and mechanisms
of cerebral vascular involvement is essential for
adequate treatment of VD patients78. Vitamin B12
deficiency, neurosyphilis, and normal pressure
hydrocephalus are causes of secondary dementia that
should be initially ruled out.
Rarer causes, shown as rapidly progressive conditions
(evolving to dementia within one to two years of the
onset of the first symptoms, usually within weeks
to months) are prion, autoimmune, and infectious
dementias, among others 82 . Rapidly progressive
dementia (RPD) requires extensive investigation,
which must be carried out early to avoid cognitive
sequelae in cases of potentially reversible etiology.
Depression is one of the main differential diagnoses
of dementia. Major depressive disorder courses
with cognitive decline, executive dysfunction,
and attention deficit83. The relation between dementia
and depression is complex because depressive
symptoms can be the initial manifestation of dementia.
Therefore, depression is a risk factor for dementia
and severe depression can cause potentially reversible
dementia84. Depression is one of the 12 modifiable
risk factors responsible for 40% of dementia cases
worldwide85. Accordingly, every patient with depressive
symptoms should receive adequate treatment for
depression. However, if cognitive deficits remain after
optimized treatment, clinical practice should suspect
of a degenerative etiology.

Smid J, et al.   Syndromic approach to SCD, MCI, and dementia.   11

 Dement Neuropsychol 2022 September;16(3 Suppl. 1):1-17

Cognitive decline associated with HIV infection, Etiological investigation of MCI and dementia
called HAND (HIV-associated neurocognitive disorder), The current recommendation for investigating MCI
shows an increasing prevalence after the use of highly and dementia in the Brazilian population involves
effective antiretroviral treatment for people living with a neuroimaging study (computed tomography
HIV86. HAND prevalence in Brazil ranges from 52.4% to scan - CT - or, ideally, brain magnetic resonance
73.6%, with a higher percentage of asymptomatic cases, imaging - MRI) and laboratory tests which investigate
named asymptomatic neurocognitive impairment87,88. non-neurodegenerative etiologies. These tests include
Research should investigate the use of psychoactive complete blood count, serum concentrations of
medications, especially benzodiazepines, antipsychotics, creatinine, TSH, albumin, liver enzymes, vitamin B12,
non-benzodiazepine hypnotics, and anticholinergic ionized calcium, serological reactions for syphilis;
medications, as possible etiologies of dementia. Table 6 and HIV serology for those with atypical clinical
shows some anticholinergic medications associated presentations or suggestive symptoms 90. Clinical
with cognitive decline89. practice should also request cerebrospinal fluid (CSF)
examination for patients with early-onset dementia
(before 65 years of age), atypical presentations,
Table 6. List of drugs with centrally acting strong anticholinergic properties*. and suspected inflammatory, prion, or infectious
Antiarrhythmic Antimuscarinics (urinary incontinence) diseases 90 . Clinicians should always assess RPD
Disopyramide Darifenacin with brain MRIs (with diffusion-weighted imaging),
Fesoterodine electroencephalogram, CSF, and broader laboratory
Antidepressants
Flavoxate
Amitriptyline investigation, depending on the clinical hypotheses.
Oxybutynin
Amoxapine
Solifenacin
This MRI recommendation is especially due to the
Clomipramine possibility of finding atrophy in the hippocampal region,
Tolterodine
Desipramine which is impossible by CT scan in the early stages of the
Trospium
Doxepin (>6mg)
disease. The finding of atrophy in the mesial temporal
Imipramine
Nortriptyline regions is suggestive of the diagnosis of MCI due to AD,
Paroxetine however, it is not exclusive to this pathology, since
Protriptyline a considerable proportion of cases of amnestic MCI with
Trimipramine hippocampal atrophy may have different causes other
Antiemetics Antiparkinsonian agents than AD, denominated SNAP (suspected non-Alzheimer
Prochlorperazine Biperiden pathophysiology)91. Another advantage of brain MRI
Promethazine Trihexyphenidyl is its better identification of cerebrovascular disease,
Benztropine especially of small vessel disease.
Antihistamines (first generation)
Brompheniramine Antipsychotics The clinical indications for biomarkers include
Carbinoxamine Chlorpromazine 1) identification of individuals with MCI and mild
Chlorpheniramine Clozapine dementia due to AD pathology and 2) diagnostic
Clemastine Loxapine uncertainty about the dementia etiology. Biomarkers
Cyproheptadine Olanzapine
Dexbrompheniramine available for clinical use can be divided into specific AD
Perphenazine
Dexchlorpheniramine Thioridazine pathology or neurodegeneration biomarkers. Specific
Dimenhydrinate Trifluoperazine AD pathology biomarkers include 1) measurement
Diphenhydramine (oral) of the beta-amyloid peptide and phosphorylated tau
Doxylamine Antispasmodics
Atropine (excludes ophthalmic)
(phospho-tau) in the CSF and 2) positron emission
Hydroxyzine
Meclizine Belladonna alkaloids computed tomography (PET) with amyloid peptide
Clidinium-chlordiazepoxide Scopolamine (excludes ophthalmic) marker and PET with marker for tau protein.
Dicyclomine Until now, PET-amyloid is offered in few centers
Skeletal muscle relaxants
Homatropine (excludes ophthalmic) in Brazil and PET-tau is still unavailable in Brazil.
Cyclobenzaprine
Hyoscyamine Neurodegeneration biomarkers consist of PET with
Orphenadrine
Methscopolamine
18F-fluorodeoxyglucose (PET-FDG), measurement
Propantheline
Promethazine of total tau protein in the CSF, and light chain
Pyrilamine neurofilament. More recently, plasma biomarkers
Triprolidine have been developed but they still lack validation for
* Adapted from Beers Criteria89. clinical use (tau-181, tau-217)92-94.

12   Syndromic approach to SCD, MCI, and dementia.   Smid J, et al.


Confirmation of the AD in vivo requires amyloid
and tau pathology. CSF measurement or PET-amyloid
uptake can confirm the amyloid pathology, whereas
measuring CSF phospho-tau or PET-tau uptake
can conf ir m the Tau patholo g y. PE T-F DG is
a neurodegeneration biomarker whose metabolic
pattern may suggest the pathology of degenerative
dementias with good sensitivity and specificity
(e.g., the pattern of hypometabolism in the areas
of temporoparietal association, posterior cingulate,
and precuneus has a sensitivity and specificity >90%
for AD diagnosis)95. Furthermore, PET FDG is used
in the diagnostic criteria of LBD, primary progressive
aphasias, and FTD.
PROPOSAL FOR THE MANAGEMENT OF PATIENTS
WITH COGNITIVE DECLINE AT DIFFERENT
LEVELS OF CARE IN THE BRAZILIAN PUBLIC
HEALTH SERVICE - SUS
Primary healthcare
Identification of modifiable risk factors for dementia
prevention should be done at primary health care.
Recently, a study described 12 important modifiable
risk factors to prevent or delay the onset of 40% of
dementia in the world and 56% in low- and middle-
income countries84. They are diagnosed at different
stages of life, with the possibility of involvement by
the health system in all of them. Risk factors include:
1) age up to 45 years: low educational level; 2) age from
45 to 65 years old: systemic arterial hypertension, obesity,
hearing loss, traumatic brain injury, and alcohol abuse;
and 3) age above 65 years old: smoking, depression,
sedentary lifestyle, diabetes, social isolation, and air
pollution. Clinical practice must consider preventive
and educational actions to identify, promote treatment,
and combat these different factors84.
Primary care physicians should actively seek out
complaints of cognitive decline in patients, especially
after 60 years of age. Clinicians should perform
screening tests for cognitive and functional decline
in patients with cognitive complaints (or reported
by caregivers). In case of a clinical diagnosis of MCI
or dementia, physicians should request etiological
work-up. When ruling out potentially reversible causes,
patients should be referred to secondary healthcare,
to neurology, geriatrics, or psychiatry specialists,
with a hypothesis of degenerative or vascular etiology.
The RPD cases must be promptly referred to secondary
or tertiary care, as a matter of urgency.
Dement Neuropsychol 2022 September;16(3 Suppl. 1):1-17
Primar y care physicians must receive back
patients referred to secondary or tertiary care
for long-term follow-up of AD and VD dementia.
Primar y care physicians should request a new
specialist evaluation in case of any doubt regarding
the follow-up of the case.
Secondary healthcare
Physicians in secondary care emergencies must
be able to identify cases of RPD, because patients
often seek emergenc y units due to the rapid
progression of symptoms. W hen recognizing
a case of RPD, physicians must urgently conduct
an initial investigation and, preferably, refer patients
to tertiary care for extensive work-up.
Specialists (neurologists, geriatricians, and
psychiatrists) who receive patients referred for
dementia, whose secondary etiologies were excluded
at the primary level, should confirm the diagnosis
and establish treatment. For cases in which there is
no greater complexity in managing neuropsychiatric
symptoms, recommendations on how to treat
dementia should be explained to the primary care
physician who will follow up the patient.
Secondary care should request biomarker tests
when necessary. Physicians should request biomarker
tests in atypical cases (initial non-amnestic clinical
presentation or early-onset dementia) and interpreting
them requires trained secondary care professionals.
If it is impossible to assess biomarkers or the
professional is unfamiliar with result interpretation,
patients must be referred to tertiary centers.
In cases of early-onset dementia in which the
specialist demands further etiological investigation,
patients should be referred to tertiary services
for diagnosis elucidation.
Tertiary healthcare
Cases which maybe referred to tertiary care include
RPD, early-onset dementia, suspected genetic form
of cognitive decline, cases of unclear diagnosis,
cases of difficult management of neuropsychiatric
symptoms, and cases for biomarker investigation
which secondary care is unable to assess.
In cases of clinical stability or advanced stage
of dementia, patients can be counter-referred
to primary or secondary care. Figure 5 summarizes
the competences of each level of healthcare in caring
for patients with cognitive decline.
Smid J, et al.   Syndromic approach to SCD, MCI, and dementia.   13
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):1-17

Primary Healthcare

Identify modifiable
risk factors for
dementia prevention.
Ask about cognitive
complaints, especially
in older adults.
Perform complementary
Perform clinical
Apply cognitive exams (neuroimaging To receive patients
diagnosis of cognitive
and functional and laboratory tests) with AD or VD against
syndrome (SCD, MCI
screening tests. to exclude potentially referenced for follow-up.
or dementia).
reversible causes.

Referral to Secondary Healthcare in the following situations:

1. Degenerative or vascular dementia.
2. If the hypothesis of MCI due to AD (amnestic MCI).
3. RPD (urgently).
4. When there are a diagnostic doubts about the cause of the dementia.

Secondary Healthcare

Evaluate patients
with a hypothesis
of degenerative
dementia for
diagnostic confirmation.
Against referring less
Initiate treatment
complex AD and DV
for degenerative
cases to physician of
or vascular dementia.
Primary Healthcare.
Carry out an initial Receive patients
Request biomarkers
investigation in with AD or DV
in atypical cases.
patients with against referenced
RPD urgently. for follow-up.

Referral to Tertiary Healthcare in the following situations

1. Biomarkers are not accessible and are needed.
2. Early-onset dementia or atypical dementias requiring further etiological investigation.
3. RPD urgently after initial investigation.

Tertiary Healthcare

Evaluation of patients with:

1. Diagnostic doubt about the etiology of the dementia
2. RPD
3. Early onset dementias
4. Suspected genetic form of dementia

When there is clinical stability or in an advanced stage of dementia, patients can be counter-referred to primary or secondary healthcare

AD: Alzheimer’s Disease, VD: Vascular Dementia, MCI: Mild cognitive impairment; SCD: Subjective cognitive decline; RPD: Rapidly progressive dementia.
Figure 5. Hierarchy of care for patients with cognitive syndromes according to the levels of care in the Brazilian Unified Health System (SUS).

ACKNOWLEDGEMENTS
PC, LCS and RN are funded by CNPq, Brazil (bolsa de RK, EPFR, FACV: drafting of the manuscript; BJAPB,
produtividade em pesquisa). FACV, JS, LCS, LPS, MLFB, MLFC, NAFF, PC, PHFB, RN,
Authors’ contributions. JS, ASN, KGCF, MCND, RK, EPFR, SMDB: critical revision of the manuscript for important
FACV, BJAPB, LPS: concept; JS, ASN, KGCF, MCND, intellectual content.

REFERENCES
1. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR,
Kawas CH, et al. The diagnosis of dementia due to Alzheimer’s
disease: recommendations from the National Institute on Aging-Al- 2.
zheimer’s Association workgroups on diagnostic guidelines for Alzhei-
mer’s disease. Alzheimers Dement. 2011;7(3):263-9. doi:10.1016/j.
jalz.2011.03.005.
Petersen RC. Clinical practice. Mild cognitive impairment. N Engl J Med.
2011;364(23):2227-34. doi:10.1056/NEJMcp0910237.

14   Syndromic approach to SCD, MCI, and dementia.   Smid J, et al.


3. Jessen F, Amariglio RE, Van Boxtel M, Breteler M, Ceccaldi M, Chételat G,
et al. A conceptual framework for research on subjective cognitive decline
in preclinical Alzheimer’s disease. Alzheimers Dement. 2014;10(6):844-52.
doi:10.1016/j.jalz.2014.01.001.
4. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical
method for grading the cognitive state of patients for the clinician.
J Psychiatr Res. 1975;12(3):189-98. doi:10.1016/0022-3956(75)90026-6.
5. Brucki SMD, Nitrini R, Caramelli P, Bertolucci PHF, Okamoto IH. Sugestões
para o uso do mini-exame do estado mental no Brasil. Arq Neuropsiquiatr.
2003;61(3B):777-81. doi:10.1590/S0004-282X2003000500014.
6. Barocco F, Spallazzi M, Concari L, Gardini S, Pelosi A, Caffarra P.
The Progression of Alzheimer’s Disease: Are Fast Decliners Really
Fast? A Four-Year Follow-Up. J Alzheimers Dis. 2017;57(3):775-86.
doi:10.3233/JAD-161264.
7. Viana GS, Rouquayrol MZ, Bruin VM, Albuquerque JJ. Use of the
Information, Memory and Concentration (IMC) Test in the epidemiological
study of senile dementia in Fortaleza,Ceará (Brazil). Cad Saude Publica.
1991;7(3):396-408. doi:10.1590/s0102-311x1991000300008.
8. Damasceno A, Delicio AM, Mazo DFC, Zullo JFD, Scherer P, Ng RTY, et al.
Validation of the Brazilian version of mini-test CASI-S. Arq Neuropsiquiatr.
2005;63(2B):416-21. doi:10.1590/s0004-282x2005000300010.
9. Carvalho VA, Caramelli P. Brazilian adaptation of the Addenbrooke’s
Cognitive Examination-Revised (ACE-R). Dement Neuropsychol.
2007;1(2):212-6. doi:10.1590/S1980-57642008DN10200015
10. César KG, Yassuda MS, Porto FHG, Brucki SMD, Nitrini R. Addenbrooke’s
cognitive examination-revised: Normative and accuracy data for seniors
with heterogeneous educational level in Brazil. Int Psychogeriatrics.
2017;29(8):1345-53. doi:10.1017/S1041610217000734.
11. Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V,
Collin I, et al. The Montreal Cognitive Assessment, MoCA: a brief screening
tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695-9.
doi:10.1111/j.1532-5415.2005.53221.x.
12. Cesar KG, Yassuda MS, Porto FHG, Brucki SMD, Nitrini R. MoCA Test:
normative and diagnostic accuracy data for seniors with heterogeneous
educational levels in Brazil. Arq Neuropsiquiatr. 2019;77(11):775-81.
doi:10.1590/0004-282X20190130.
13. Bertolucci PH, Okamoto IH, Brucki SM, Siviero MO, Toniolo Neto J,
Ramos LR. Applicability of the CERAD neuropsychological battery to
Brazilian elderly. Arq Neuropsiquiatr. 2001;59(3-A):532-6. doi:10.1590/
s0004-282x2001000400009.
14. Bertolucci PH, Brucki SM, Campacci SR, Juliano Y. The Mini-Mental State
Examination in a general population: impact of educational status. Arq
Neuropsiquiatr. 1994;52(1):1-7.
15. Almeida OP. Mini mental state examination and the diagnosis of dementia
in Brazil. Arq Neuropsiquiatr. 1998;56(3B):605-12. doi:10.1590/
S0004-282X1998000400014.
16. Laks J, Batista EMR, Guilherme ERL, Contino ALB, Faria MEV,
Figueira I, et al. Mini-mental state examination in community-
dwelling elderly: preliminary data from Santo Antônio de Pádua,
Rio de Janeiro, Brazil. Arq Neuropsiquiatr. 2003;61(3B):782-5. doi:10.1590/
S0004-282X2003000500015.
17. Castro-Costa E, Fuzikawa C, Uchoa E, Firmo JOA, Lima-Costa MF.
Norms for the mini-mental state examination: adjustment of the cut-off
point in population-based studies (evidences from the Bambuí health
aging study). Arq Neuropsiquiatr. 2008;66(3A):524-8. doi:10.1590/
s0004-282x2008000400016.
18. Kochhann R, Varela JS, Lisboa CSM, Chaves MLF. The Mini Mental State
Examination: Review of cutoff points adjusted for schooling in a large
Southern Brazilian sample. Dement Neuropsychol. 2010;4(1):35-41.
doi:10.1590/S1980-57642010DN40100006.
19. Memória CM, Yassuda MS, Nakano EY, Forlenza OV. Brief screening
for mild cognitive impairment: validation of the Brazilian version of the
Montreal cognitive assessment. Int J Geriatr Psychiatry. 2013;28(1):34-40.
doi:10.1002/gps.3787.
20. Apolinario D, Santos MF, Sassaki E, Pegoraro F, Pedrini AVA, Cestari B,
et al. Normative data for the Montreal Cognitive Assessment (MoCA) and
the Memory Index Score (MoCA-MIS) in Brazil: Adjusting the nonlinear
effects of education with fractional polynomials. Int J Geriatr Psychiatry.
2018;33(7):893-9. doi:10.1002/gps.4866.
21. Lourenço RA, Veras RP. Mini-Mental State Examination: psychometric
characteristics in elderly outpatients. Rev Saude Publica. 2006;40(4):712-9.
doi:10.1590/S0034-89102006000500023.
22. Nitrini R, Lefèvre BH, Mathias SC, Caramelli P, Carrilho PE, Sauaia N,
et al. Neuropsychological tests of simple application for diagnosing
dementia. Arq Neuropsiquiatr. 1994;52(4):457-65. doi:10.1590/
s0004-282x1994000400001.
23. Nitrini R, Caramelli P, Porto CS, Charchat-Fichman H, Formigoni AP,
Carthery-Goulart MT, et al. Brief cognitive battery in the diagnosis
of mild Alzheimer ’ s disease in subjects with medium and high levels
Dement Neuropsychol 2022 September;16(3 Suppl. 1):1-17
of education. Dement Neuropsychol. 2007;1:32-6. doi:10.1590/
S1980-57642008DN10100006.
24. Nitrini R, Bucki SMD, Yassuda MS, Fichman HC, Caramelli P. The Figure
Memory Test: diagnosis of memory impairment in populations with
heterogeneous educational background. Dement Neuropsychol.
2021;15(2):173-85. doi:10.1590/1980-57642021dn15-020004.
25. Nitrini R, Caramelli P, Herrera Júnior E, Porto CS, Charchat-Fichman H,
Carthery MT, et al. Performance of illiterate and literate nondemented
elderly subjects in two tests of long-term memory. J Int Neuropsychol
Soc. 2004;10(4):634-8. doi:10.1017/S1355617704104062.
26. Yassuda MS, Silva HS, Lima-Silva TB, Cachioni M, Falcão DVS, Lopes A, et al.
Normative data for the Brief Cognitive Screening Battery stratified by age
and education. Dement Neuropsychol. 2017;11(1):48-53. doi:10.1590/
1980-57642016dn11-010008.
27. Caramelli P, Carthery-Goulart MT, Porto CS, Charchat-Fichman H,
Nitrini R. Category fluency as a screening test for Alzheimer disease in
illiterate and literate patients. Alzheimer Dis Assoc Disord. 2007;21(1):65-7.
doi:10.1097/WAD.0b013e31802f244f.
28. Chaves MLF, Godinho CC, Porto CS, Mansur L, Carthery-Goulart MT,
Yassuda MS, et al. Cognitive, functional and behavioral assessment:
Alzheimer’s disease. Dement Neuropsychol. 2011;5(3):153-66.
doi:10.1590/S1980-57642011DN05030003.
29. Pfeffer RI, Kurosaki TT, Harrah CH Jr, Chance JM, Filos S. Measurement
of functional activities in older adults in the community. J Gerontol.
1982;37(3):323-9. doi:10.1093/geronj/37.3.323.
30. Sanchez MADS, Correa PCR, Lourenço RA. Cross-cultural
Adaptation of the “Functional Activities Questionnaire – FAQ” for
use in Brazil. Dement Neuropsychol. 2011;5(4):322-7. doi:10.1590/
S1980-57642011DN05040010.
31. Assis LO, Paula JJ, Assis MG, Moraes EN, Malloy-Diniz LF.
Psychometric properties of the Brazilian version of Pfeffer’s Functional
Activities Questionnaire. Front Aging Neurosci. 2014;6:255. doi:10.3389/
fnagi.2014.00255.
32. Bustamante SEZ, Bottino CMC, Lopes MA, Azevedo D, Hototian SR,
Litvoc J, et al. Combined instruments on the evaluation of dementia in
the elderly: preliminary results. Arq Neuropsiquiatr. 2003;61(3A):601-6.
doi:10.1590/s0004-282x2003000400014.
33. Sanchez MAS, Lourenço RA. Informant Questionnaire on Cognitive
Decline in the Elderly (IQCODE): cross-cultural adaptation for use
in Brazil. Cad Saude Publica. 2009;25(7):1455-65. doi:10.1590/
S0102-311X2009000700003.
34. Perroco TR, Bustamante SEZ, Moreno MPQ, Hototian SR, Lopes MA,
Azevedo D, et al. Performance of Brazilian long and short IQCODE
on the screening of dementia in elderly people with low education.
Int Psychogeriatr. 2009;21(3):531-8. doi:10.1017/S1041610209008849.
35. Lino VTS, Pereira SRM, Camacho LAB, Ribeiro Filho ST, Buksman S.
Cross-cultural adaptation of the Independence in Activities of Daily Living
Index (Katz Index). Cad Saude Publica. 2008;24(1):103-12. doi:10.1590/
s0102-311x2008000100010.
36. Chaves MLF, Camozzato AL, Godinho C, Kochhann R, Schuh A,
Almeida VL, et al. Validity of the clinical dementia rating scale for the
detection and staging of dementia in Brazilian patients. Alzheimer Dis
Assoc Disord. 2007;21(3):210-7. doi:10.1097/WAD.0b013e31811ff2b4.
37. Morris JC. The Clinical Dementia Rating (CDR): current version and scoring
rules. Neurology. 1993;43(11):2412-4. doi:10.1212/wnl.43.11.2412-a.
38. Ministério da Saúde (BR). Portaria nº 1.298, de 21 de novembro de
2013. Aprova o Protocolo Clínico e Diretrizes Terapêuticas da Doença
de Alzheimer. Diário Oficial da União. 2013 Out 24.
39. Caramelli P, Marinho V, Laks J, Coletta MVD, Stella F, Camargos EF et al.
Treatment of Dementia. Arq Neuropsiquiatr. 2022; submitted.
40. Jessen F, Amariglio RE, Buckley RF, Flier WM, Han Y, Molinuevo JL,
et al. The characterisation of subjective cognitive decline. Lancet Neurol.
2020;19(3):271-8. doi:10.1016/S1474-4422(19)30368-0.
41. Rabin LA, Smart CM, Amariglio RE. Subjective Cognitive Decline in
Preclinical Alzheimer’s Disease. Annu Rev Clin Psychol. 2017;13:369-96.
doi:10.1146/annurev-clinpsy-032816-045136.
42. Molinuevo JL, Rabin LA, Amariglio R, Buckley R, Dubois B, Ellis KA, et al.
Implementation of subjective cognitive decline criteria in research studies.
Alzheimers Dement. 2017;13(3):296-311. doi:10.1016/j.jalz.2016.09.012.
43. Harten AC, Mielke MM, Swenson-Dravis DM, Hagen CE, Edwards KK,
Roberts RO, et al. Subjective cognitive decline and risk of MCI: The Mayo
Clinic Study of Aging. Neurology. 2018;91(4):e300-12. doi:10.1212/
WNL.0000000000005863.
44. César-Freitas KG, Suemoto CK, Power MC, Brucki SMD, Nitrini R. Incidence
of dementia in a Brazilian population: The Tremembé Epidemiologic
Study. Alzheimers Dement. 2022;18(4):581-90. doi:10.1002/alz.12423.
45. Reisberg B, Shulman MB, Torossian C, Leng L, Zhu W. Outcome over seven
years of healthy adults with and without subjective cognitive impairment.
Alzheimers Dement. 2010;6(1):11-24. doi:10.1016/j.jalz.2009.10.002.
Smid J, et al.   Syndromic approach to SCD, MCI, and dementia.   15
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):1-17
46. Rönnlund M, Sundström A, Adolfsson R, Nilsson L-G. Subjective memory
impairment in older adults predicts future dementia independent of baseline
memory performance: Evidence from the Betula prospective cohort study.
Alzheimers Dement. 2015;11(11):1385-92. doi:10.1016/j.jalz.2014.11.006.
47. Mitchell AJ, Beaumont H, Ferguson D, Yadegarfar M, Stubbs B.
Risk of dementia and mild cognitive impairment in older people with
subjective memory complaints: meta-analysis. Acta Psychiatr Scand.
2014;130(6):439-51. doi:10.1111/acps.12336.
48. Snitz BE, Lopez OL, McDade E, Becker JT, Cohen AD, Price JC, et al.
Amyloid-β Imaging in Older Adults Presenting to a Memory Clinic
with Subjective Cognitive Decline: A Pilot Study. J Alzheimers Dis.
2015;48(Suppl 1):S151-9. doi:10.3233/JAD-150113.
49. Perrotin A, Mormino EC, Madison CM, Hayenga AO, Jagust WJ. Subjective
cognition and amyloid deposition imaging: a Pittsburgh Compound
B positron emission tomography study in normal elderly individuals.
Arch Neurol. 2012;69(2):223-9. doi:10.1001/archneurol.2011.666.
50. Amariglio RE, Mormino EC, Pietras AC, Marshall GA, Vannini P, Johnson KA,
et al. Subjective cognitive concerns, amyloid-β, and neurodegeneration
in clinically normal elderly. Neurology. 2015;85(1):56-62. doi:10.1212/
WNL.0000000000001712.
51. Buckley RF, Maruff P, Ames D, Bourgeat P, Martins RN, Masters CL, et al.
Subjective memory decline predicts greater rates of clinical progression in
preclinical Alzheimer’s disease. Alzheimers Dement. 2016;12(7):796-804.
doi:10.1016/j.jalz.2015.12.013.
52. Studart A, Nitrini R. Subjective cognitive decline: The first clinical manifestation
of Alzheimer’s disease? Dement Neuropsychol. 2016;10(3):170-7.
doi:10.1590/S1980-5764-2016DN1003002.
53. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E.
Mild cognitive impairment: clinical characterization and outcome.
Arch Neurol. 1999;56(3):303-8. doi:10.1001/archneur.56.3.303.
54. Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern
Med. 2004;256(3):183-94. doi:10.1111/j.1365-2796.2004.01388.x.
55. Winblad B, Palmer K, Kivipelto M, Jelic V, Fratiglioni L, Wahlund LO, et al.
Mild cognitive impairment--beyond controversies, towards a consensus:
report of the International Working Group on Mild Cognitive Impairment. J
Intern Med. 2004;256(3):240-6. doi:10.1111/j.1365-2796.2004.01380.x.
56. Morris JC. Revised criteria for mild cognitive impairment may
compromise the diagnosis of Alzheimer disease dementia. Arch Neurol.
2012;69(6):700-8. doi:10.1001/archneurol.2011.3152.
57. Portet F, Ousset PJ, Visser PJ, Frisoni GB, Nobili F, Scheltens P, et al.
Mild cognitive impairment (MCI) in medical practice: a critical review of the
concept and new diagnostic procedure. Report of the MCI Working Group
of the European Consortium on Alzheimer’s Disease. J Neurol Neurosurg
Psychiatry. 2006;77(6):714-8. doi:10.1136/jnnp.2005.085332.
58. Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al.
The diagnosis of mild cognitive impairment due to Alzheimer’s disease:
recommendations from the National Institute on Aging-Alzheimer’s
Association workgroups on diagnostic guidelines for Alzheimer’s disease.
Alzheimers Dement. 2011;7(3):270-9. doi:10.1016/j.jalz.2011.03.008.
59. American Psychiatric Association. Diagnostic and statistical manual of
mental disorders. 5th ed. Washington (DC): APA, 2013.
60. World Health Organization. International Classification of Diseases
11th Revision (ICD-11). Version: 2019 April. Geneva: WHO; 2019 [Accessed
20 dez 2021]. Available at: https://icd.who.int/browse11/l-m/en
61. Gold DA. An examination of instrumental activities of daily living
assessment in older adults and mild cognitive impairment. J Clin Exp
Neuropsychol. 2012;34(1):11-34. doi:10.1080/13803395.2011.614598.
62. Busse A, Hensel A, Gühne U, Angermeyer MC, Riedel-Heller SG. Mild
cognitive impairment: Long-term course of four clinical subtypes. Neurology.
2006;67(12):2176-85. doi:10.1212/01.wnl.0000249117.23318.e1.
63. Farias ST, Mungas D, Reed BR, Harvey D, DeCarli C. Progression of mild
cognitive impairment to dementia in clinic- vs community-based cohorts.
Arch Neurol. 2009;66(9):1151-7. doi:10.1001/archneurol.2009.106.
64. Manly JJ, Tang M, Schupf N, Stern Y, Vonsattel JPG, Mayeux R. Frequency
and course of mild cognitive impairment in a multiethnic community.
Ann Neurol. 2008;63(4):494-506. doi:10.1002/ana.21326.
65. Plassman BL, Langa KM, Fisher GG, Heeringa SG, Weir DR, Ofstedal MB,
et al. Prevalence of cognitive impairment without dementia in the United
States. Ann Intern Med. 2008;148(6):427-34. doi:10.7326/0003-4819-
148-6-200803180-00005.
66. Di Carlo A, Lamassa M, Baldereschi M, Inzitari M, Scafato E, Farchi G,
et al. CIND and MCI in the Italian elderly: frequency, vascular risk factors,
progression to dementia. Neurology. 2007;68(22):1909-16. doi:10.1212/
01.wnl.0000263132.99055.0d.
67. Overton M, Pihlsgard M, Elmstahl S. Prevalence and Incidence of Mild
Cognitive Impairment across Subtypes, Age, and Sex. Dement Geriatr
Cogn Disord. 2019;47(4-6):219-32. doi:10.1159/000499763.
16   Syndromic approach to SCD, MCI, and dementia.   Smid J, et al.
68. Petersen RC, Roberts RO, Knopman DS, Geda YE, Cha RH, Pankratz
VS, et al. Prevalence of mild cognitive impairment is higher in men. The
Mayo Clinic Study of Aging. Neurology. 2010;75(10):889-97. doi:10.1212/
WNL.0b013e3181f11d85.
69. Ward A, Arrighi HM, Michels S, Cedarbaum JM. Mild cognitive impairment:
disparity of incidence and prevalence estimates. Alzheimers Dement.
2012;8(1):14-21. doi:10.1016/j.jalz.2011.01.002.
70. Godinho C, Camozzato AL, Onyszko D, Chaves ML. Estimation of the
risk of conversion of mild cognitive impairment of Alzheimer type to
Alzheimer’s disease in a south Brazilian population-based elderly cohort:
the PALA study. Int Psychogeriatr. 2012;24(4):674-81. doi:10.1017/
S1041610211002043.
71. Chaves ML, Camozzato AL, Godinho C, Piazenski I, Kaye J.
Incidence of mild cognitive impairment and Alzheimer disease in
Southern Brazil. J Geriatr Psychiatry Neurol. 2009;22(3):181-7.
doi:10.1177/0891988709332942.
72. César KG, Brucki SMD, Takada LT, Nascimento LFC, Gomes CMS,
Almeida MCS, et al. Prevalence of Cognitive Impairment Without
Dementia and Dementia in Tremembé, Brazil. Alzheimer Dis Assoc Disord.
2016;30(3):264-71. doi:10.1097/WAD.0000000000000122.
73. Frota NAF, Nitrini R, Damasceno BP, Forlenza O, Dias-Tosta E,
Silva AB, et al. Critérios para o diagnóstico de doença de Alzheimer.
Dement Neuropsychol. 2011;5(Suppl 1):5-10.
74. World Health Organization. International Classification of Diseases
10th Revision (ICD-10) . Version 2019. Geneva: WHO; 2019 [Accessed
20 dez 2021]. Available at: https://icd.who.int/browse10/2019/en#/VI
75. Boff MS, Sekyia FS, Bottino CMC. Prevalence of dementia among
brazilian population: systematic review. Rev Med. 2015;94(3):154-61.
doi:10.11606/issn.1679-9836.v.94i3p154-161.
76. Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global
prevalence of dementia: a systematic review and metaanalysis. Alzheimers
Dement. 2013;9(1):63-75.e2. doi:10.1016/j.jalz.2012.11.007.
77. Oliveira D, Jun Otuyama L, Mabunda D, Mandlate F, Gonçalves-Pereira M,
Xavier M, et al. Reducing the Number of People with Dementia Through
Primary Prevention in Mozambique, Brazil, and Portugal: An Analysis
of Population-Based Data. J Alzheimers Dis. 2019;70(s1):S283-91.
doi:10.3233/JAD-180636.
78. Allegri RF. Moving from neurodegenerative dementias, to cognitive
proteinopathies, replacing “where” by “what”… Dement Neuropsychol.
2020;14(3):237-42. doi:10.1590/1980-57642020dn14-030005.
79. Grinberg LT, Nitrini R, Suemoto CK, Ferretti-Rebustini REL, Leite REP,
Farfel JM, et al. Prevalence of dementia subtypes in a developing country:
a clinicopathological study. Clinics. 2013;68(8):1140-5. doi:10.6061/
clinics/2013(08)13.
80. Suemoto CK, Ferretti-Rebustini REL, Rodriguez RD, Leite REP,
Soterio L, Brucki SMD, et al. Neuropathological diagnoses and clinical
correlates in older adults in Brazil: A cross-sectional study. PLoS Med.
2017;14(3):e1002267. doi:10.1371/journal.pmed.1002267.
81. Elahi FM, Miller BL. A clinicopathological approach to the diagnosis of
dementia. Nat Rev Neurol. 2017;13(8):457-76. doi:10.1038/nrneurol.2017.96.
82. Geschwind MD. Rapidly Progressive Dementia. Continuum (Minneap Minn).
2016;22(2 Dementia):510-37. doi:10.1212/CON.0000000000000319.
83. Dias NS, Barbosa IG, Kuang W, Teixeira AL. Depressive disorders in the
elderly and dementia: An update. Dement Neuropsychol. 2020;14(1):1-6.
doi:10.1590/1980-57642020dn14-010001.
84. B e n n e t t S , T h o m a s A J . D e p re s s i o n a n d d e m e n t i a : c a u s e ,
consequence or coincidence? Maturitas. 2014;79(2):184-90.
doi:10.1016/j.maturitas.2014.05.009.
85. Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S,
et al. Dementia prevention, intervention, and care: 2020 report of the
Lancet Commission. Lancet. 2020;396(10248):413-46. doi:10.1016/
S0140-6736(20)30367-6.
86. Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, et al. Updated
research nosology for HIV-associated neurocognitive disorders. Neurology.
2007;69(18):1789-99. doi:10.1212/01.WNL.0000287431.88658.8b.
87. Rodrigues RA, Oliveira RL, Grinsztejn B, Silva MTT. Validity of
the International HIV dementia scale in Brazil. Arq Neuropsiquiatr.
2013;71(6):376-9. doi:10.1590/0004-282X20130042
88. Gascón MRP, Vidal JE, Mazzaro YM, Smid J, Marcusso RMN, Capitão CG,
et al. Neuropsychological Assessment of 412 HIV-Infected Individuals in
São Paulo, Brazil. AIDS Patient Care STDS. 2018;32(1):1-8. doi:10.1089/
apc.2017.0202
89. 2019 American Geriatrics Society Beers Criteria® Update Expert Panel.
American Geriatrics Society 2019 Updated AGS Beers Criteria® for
Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr
Soc. 2019;67(4):674-94. doi:10.1111/jgs.15767.

90. Caramelli P, Teixeira AL, Buchpiguel CA, Lee HW, Livramento JA,
Fernandez LL, et al. Diagnosis of Alzheimer’s disease in Brazil:
Supplementary exams. Dement Neuropsychol. 2011;5(3):167-77.
doi:10.1590/S1980-57642011DN05030004.
91. Petersen RC, Aisen P, Boeve BF, Geda YE, Ivnik RJ, Knopman DS, et al.
Mild cognitive impairment due to Alzheimer disease in the community.
Ann Neurol. 2013;74(2):199-208. doi:10.1002/ana.23931.
92. Thijssen EH, La Joie R, Wolf A, Strom A, Wang P, Iaccarino L, et al.
Diagnostic value of plasma phosphorylated tau181 in Alzheimer’s disease
and frontotemporal lobar degeneration. Nat Med. 2020;26(3):387-97.
doi:10.1038/s41591-020-0762-2.
Dement Neuropsychol 2022 September;16(3 Suppl. 1):1-17
93. Loeffler T, Schilcher I, Flunkert S, Hutter-Paier B. Neurofilament-Light Chain as
Biomarker of Neurodegenerative and Rare Diseases With High Translational
Value. Front Neurosci. 2020;14:579. doi:10.3389/fnins.2020.00579.
94. Palmqvist S, Janelidze S, Quiroz YT, Zetterberg H, Lopera F,
Stomrud E, et al. Discriminative Accuracy of Plasma Phospho-tau217
for Alzheimer Disease vs Other Neurodegenerative Disorders. JAMA.
2020;324(8):772-81. doi:10.1001/jama.2020.
95. Lesman-Segev OH, La Joie R, Iaccarino L, Lobach I, Rosen HJ, Seo SW,
et al. Diagnostic Accuracy of Amyloid versus 18F-Fluorodeoxyglucose
Positron Emission Tomography in Autopsy-Confirmed Dementia.
Ann Neurol. 2021;89(2):389-401. doi:10.1002/ana.25968.
Smid J, et al.   Syndromic approach to SCD, MCI, and dementia.   17
Dement Neuropsychol 2022 September;16(3 Suppl. 1):18-20

https://doi.org/10.1590/1980-5764-DN-2022-S101EN

Supplementary Material I
BRIEF COGNITIVE SCREENING BATTERY1

Available at:
https://www.demneuropsy.com.br/imageBank/suplementar/Brief_Cognitive_Screening_Battery.pdf

REFERENCES
1. Nitrini R, Brucki SMD, Yassuda MS, Fichman HC, Caramelli P. The Figure Memory Test: diagnosis of memory impairment in
populations with heterogeneous educational background. Dement Neuropsychol. 2021 Apr-Jun;15(2):173-185. doi: 10.1590/
1980-57642021dn15-020004.

Supplementary Material II
FUNCTIONAL ACTIVITIES QUESTIONNAIRE3

This test, created by Pfeffer et al.1, was modified to be applied in people with heterogeneous
educational attainment by Amaducci et al2. in 1991 for a worldwide epidemiological study
organized by the WHO and then by Nitrini et al., in 1997 3 for an epidemiological
study in Brazil4 so it could be answered directly by the informant. However, if necessary,
the examiner can apply the questionnaire. Answers always follow the same criteria. Ask the
informant to circle the correct answer.

Patient Name:
Date: / /
Informant(s): (degree of kinship or function):

1) Do they handle their own money?

0 = Normal 0 = Never did, but could do it now
1 = Does, with difficulty 1 = Never did it and now would have difficulty
2 = Needs help
3 = Unable

2) Can they buy clothes, food, objects for their home by themselves?
0 = Normal 0 = Never did, but could do it now
1 = Does, with difficulty 1 = Never did it and now would have difficulty
2 = Needs help
3 = Unable

18  
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):18-20

3) Can they heat water to make coffee and turn off the stove?
0 = Normal 0 = Never did, but could do it now
1 = Does, with difficulty 1 = Never did it and now would have difficulty
2 = Needs help
3 = Unable

4) Can they prepare a meal?

0 = Normal 0 = Never did, but could do it now
1 = Does, with difficulty 1 = Never did it and now would have difficulty
2 = Needs help
3 = Unable

5) Can they keep up with current events or community or neighborhood ones?

0 = Normal 0 = Never did, but could do it now
1 = Does, with difficulty 1 = Never did it and now would have difficulty
2 = Needs help
3 = Unable

6) Can they pay attention, understand, and discuss a radio or television show or newspaper and magazine news?
0 = Normal 0 = Never did, but could do it now
1 = Does, with difficulty 1 = Never did it and now would have difficulty
2 = Needs help
3 = Unable

7) Can they remember commitments, family events, and holidays?

0 = Normal 0 = Never did, but could do it now
1 = Does, with difficulty 1 = Never did it and now would have difficulty
2 = Needs help
3 = Unable

8) Can they handle their own medications?

0 = Normal 0 = Never did, but could do it now
1 = Does, with difficulty 1 = Never did it and now would have difficulty
2 = Needs help
3 = Unable

9) Can they walk around the neighborhood and find their way back home?
0 = Normal 0 = Never did, but could do it now
1 = Does, with difficulty 1 = Never did it and now would have difficulty
2 = Needs help
3 = Unable

  19
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):18-20

10) Can they be safely left at home alone?

0 = Normal 0 = Never stayed, but could stay now
1 = Yes, but with precautions 1 = Never stayed and now would have difficulty
2 = Yes, for short periods
3 = No

Score (0 to 30) = ____

Scores higher than 5 indicate functional impairment

REFERENCES
1. Pfeffer RI, Kurosaki TT, Harrah CH, Chance JM, Filos S. Measurement
of functional activities in older adults in the community. J Gerontol.
1982;37(3):323-9. doi:10.1093/geronj/37.3.323.
2. Amaducci L, Baldereschi M, Amato MP, Lippi A, Nencini P, Maggi S,
Litvak J. The World Health Organization cross-national research program
on age-associated dementias. Aging (Milano). 1991;3(1):89-96.
doi:10.1007/BF03323983.
3. Herrera E Jr, Caramelli P, Nitrini R. Estudo epidemiológico populacional
de demência na cidade de Catanduva, estado de São Paulo, Brasil.
Rev Psiquiatr Clín. 1997;25(2),70-3.
4. Herrera E Jr, Caramelli P, Silveira AS, Nitrini R. Epidemiologic
survey of dementia in a community-dwelling Brazilian population.
A lzheimer Dis Assoc Disord. 20 02;16(2):103-8. doi:10.1097/
00002093-200204000-00007.

20  
Dement Neuropsychol 2022 September;16(3 Suppl. 1):21-35 Consensus
https://doi.org/10.1590/1980-5764-DN-2022-S102EN

Diagnosis of Alzheimer’s disease:

recommendations of the Scientific Department
of Cognitive Neurology and Aging of
the Brazilian Academy of Neurology
Lucas Porcello Schilling1,2,3 , Marcio Luiz Figueredo Balthazar4 , Márcia Radanovic5 ,
Orestes Vicente Forlenza5,6 , Marcela Lima Silagi7,8 , Jerusa Smid8 , Breno José Alencar Pires Barbosa8,9,10 ,
Norberto Anízio Ferreira Frota11,12 , Leonardo Cruz de Souza13 , Francisco Assis Carvalho Vale14 ,
Paulo Caramelli13 , Paulo Henrique Ferreira Bertolucci15 , Márcia Lorena Fagundes Chaves16,17 ,
Sonia Maria Dozzi Brucki8 , Benito Pereira Damasceno4 , Ricardo Nitrini8

ABSTRACT. This paper presents the consensus of the Scientific Department of Cognitive Neurology and Aging from the Brazilian
Academy of Neurology on the diagnostic criteria for Alzheimer’s disease (AD) in Brazil. The authors conducted a literature review
regarding clinical and research criteria for AD diagnosis and proposed protocols for use at primary, secondary, and tertiary care
levels. Within this clinical scenario, the diagnostic criteria for typical and atypical AD are presented as well as clinical, cognitive,
and functional assessment tools and complementary propaedeutics with laboratory and neuroimaging tests. The use of biomarkers
is also discussed for both clinical diagnosis (in specific conditions) and research.
Keywords: Alzheimer Disease; Dementia; Diagnosis.

1
Pontifícia Universidade do Rio Grande do Sul, Escola de Medicina, Serviço de Neurologia, Porto Alegre RS, Brazil.
2
Pontifícia Universidade do Rio Grande do Sul, Instituto do Cérebro do Rio Grande do Sul, Porto Alegre RS, Brazil.
3
Pontifícia Universidade do Rio Grande do Sul, Programa de Pós-Graduação em Gerontologia Biomédica, Porto Alegre RS, Brazil.
4
Universidade Estadual de Campinas, Faculdade de Ciências Médicas, Departamento de Neurologia, Campinas SP, Brazil.
5
Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, Instituto de Psiquiatria, Laboratório de Neurociências, São Paulo SP, Brazil.
6
Universidade de São Paulo, Faculdade de Medicina, Departamento de Psiquiatria, São Paulo SP, Brazil.
7
Universidade Federal de São Paulo, Departamento de Fonoaudiologia, São Paulo SP, Brazil.
8
Universidade de São Paulo, Faculdade de Medicina, Departamento de Neurologia, Grupo de Neurologia Cognitiva e do Comportamento, São Paulo SP, Brazil.
9
Universidade Federal de Pernambuco, Centro de Ciências Médicas, Área Acadêmica de Neuropsiquiatria, Recife PE, Brazil.
10
Instituto de Medicina Integral Prof. Fernando Figueira, Recife PE, Brazil.
11
Hospital Geral de Fortaleza, Serviço de Neurologia, Fortaleza CE, Brazil.
12
Universidade de Fortaleza, Fortaleza CE, Brazil.
13
Universidade Federal de Minas Gerais, Departamento de Clínica Médica, Belo Horizonte MG, Brazil.
14
Universidade Federal de São Carlos, Centro de Ciências Biológicas e da Saúde, Departamento de Medicina, São Carlos SP, Brazil.
15
Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Neurologia e Neurocirurgia, São Paulo SP, Brazil.
16
Hospital de Clínicas de Porto Alegre, Serviço de Neurologia, Porto Alegre RS, Brazil.
17
Universidade Federal do Rio Grande do Sul, Faculdade de Medicina, Departamento de Medicina Interna, Porto Alegre RS, Brazil.
Corresponding Author: Lucas Porcello Schilling; Email: lucas.schilling@pucrs.br.
Conflict of interest: LPS: Participation in advisory boards for Biogen. Participation as speaker in symposia sponsored by Aché, Apsen, and Biogen laboratories;
MLFB: Participation in advisory boards for Biogen. Development of material for continuous medical education and participation as speaker in symposia sponsored
by EMS and Torrent laboratories; JS: Participation as speaker in symposia sponsored by Roche; PC: Participation as principal investigator in clinical trials for Novo
Nordisk and Roche laboratories. Participation in advisory boards for Aché, Biogen, EMS, Nutricia, and Roche laboratories. Development of material for continuous
medical education and participation as speaker in symposia sponsored by Aché, Nutricia, Libbs, Roche, Sandoz, Torrent, and Zodiac laboratories; PHFB: Participation
in advisory boards for Biogen and Novo Nordisk laboratories. Supervision of training activities for Biogen, Janssen-Cilag, and Novo Nordisk laboratories and for
Quintiles. Participation as speaker in symposia sponsored by Apsen, Nutricia, Roche, and Sandoz laboratories; RN: Participation in advisory board for Biogen;
LCS: Participation in advisory board for Biogen. Participation as speaker in symposia sponsored by Biogen. MR, OVF, MLS, BJAPB, NAFF, FACV, MLFC, SMDB, BPD:
There is no conflict of interest to declare.
Received on August 13, 2021; Received in its final version on November 22, 2021; Accepted on April 27, 2022.

Schilling LP, et al.   Diagnostic Criteria for AD in Brazil.   21

 Dement Neuropsychol 2022 September;16(3 Suppl. 1):21-35

DIAGNÓSTICO DA DOENÇA DE ALZHEIMER: RECOMENDAÇÕES DO DEPARTAMENTO CIENTÍFICO DE NEUROLOGIA COGNITIVA E DO ENVELHECIMENTO

DA ACADEMIA BRASILEIRA DE NEUROLOGIA
RESUMO. Este artigo apresenta o consenso realizado pelo Departamento Científico de Neurologia Cognitiva e do Envelhecimento da Academia Brasileira
de Neurologia sobre os critérios diagnósticos da Doença de Alzheimer (DA) no Brasil. Foi realizada uma revisão da literatura e dos critérios clínicos
e de pesquisa para DA, sendo propostos protocolos para o diagnóstico de DA em níveis de atenção primária, secundária e terciária. Dentro deste cenário
clínico, são apresentados os critérios diagnósticos para DA típica e atípica, além de instrumentos de avaliação clínica, cognitiva e funcional; bem como
propedêutica complementar com exames laboratoriais e de neuroimagem. A utilização de biomarcadores é também apresentada, tanto para o diagnóstico
clínico em situações específicas quanto para pesquisa.
Palavras-chave: Doença de Alzheimer; Demência; Diagnóstico.

INTRODUCTION Pathophysiology
The main hypothesis in AD pathophysiology establishes
Epidemiology and relevance that the degenerative process is triggered by a hyper-

T he continuous aging of the world population

increases the prevalence and incidence of chronic
and neurodegenerative diseases. Currently, dementia
affects an estimated 50 million people worldwide and
has 10 million new diagnoses per year, of which about
60% are due to Alzheimer’s disease (AD). Projections
indicate an estimated 150 million people with dementia
due to AD by 20501. In Brazil, an estimated 1.7 million
people have dementia, with a prevalence of approximately
1,036/100,000 inhabitants2.
Risk factors
Risk factors for AD can be divided into environmental
and genetic. Environmental factors are more related
to the sporadic form of the disease (late-onset or se-
nile AD), whose main risk factor is aging3. Other risk
factors include low schooling level, systemic arterial
hypertension, diabetes, obesity, sedentary lifestyle,
head trauma, depression, smoking, hearing loss, and so-
cial isolation4, which can all be prevented and modified.
From the genetic point of view, mutations
responsible for the autosomal dominant forms
of AD stand out. Unlike the multifactorial etiology of
late-onset sporadic AD, autosomal dominant forms
(which are relatively rare) have early onset, occurring
before 65 years (presenile AD), and are strongly
associated with mutations of the amyloid precursor
protein (APP), presenilin 1, or presenilin 2 genes, which
are identified in 70% of cases, and with a dominant,
autosomal inheritance pattern5.
Though late-onset forms of AD are rarely associated
with dominant inheritance, they can be related
to genetic risk factors such as the ε4 allele of the
apolipoprotein E (APOE) gene, which increases the
risk for AD development and anticipates its onset in
a few years. Homozygosis for the APOEε4 allele increases
this risk in five times compared to heterozygotes6.
production and/or decreased clearance and consequent
accumulation of amyloid-beta peptide (Aβ) and tau
protein in the affected brain tissues, accompanied by ho-
meostatic changes that lead to a collapse of the neuronal
cytoskeleton. The APP is usually cleaved by the enzyme
α-secretase (ADAM10), generating soluble peptides
(APPs); in AD, an alternative and sequential cleavage of
APP occurs by secretases β (BACE-1) and y, generating
insoluble Aβ peptides that aggregate and deposit in
the extracellular space, triggering several pathological
events that cause neuronal death and formation of se-
nile or neuritic plaques (NPs). Neurofibrillary tangles
(NFTs) are intracellular deposits composed of hyper-
phosphorylated tau protein. The tau protein maintains
the integrity of intraneuronal microtubules, a function
that is lost after the hyperphosphorylation process.
The initial clinical symptoms of amnestic AD
are related to the increased density of NFTs in
the hippocampal formation, nucleus basalis of
Meynert, and paralimbic regions (fusiform gyrus and
inferior and middle temporal gyri), corresponding to
stages III and IV of Braak’s neuropathological staging7.
In preclinical stages of AD (Braak stages I and II), NFTs
occur almost exclusively in limbic system structures
(entorhinal cortex, subiculum, and hippocampus,
in addition to the amygdala, nucleus basalis of Meynert,
and temporopolar cortex). In mild AD (Braak stage V),
the density of NFTs increases in the limbic system
and they emerge at the associative neocortical regions
of the middle and superior temporal gyri (related
to language symptoms) as well as at the prefrontal,
retrosplenial, and posterior parietal cortices (related
to executive dysfunction and spatial disorientation).
NPs also deposit in these areas, progressively increasing
the density of NFTs and NPs in the whole neocortex,
including unimodal (visual, auditory, and somestesic)
and multimodal association areas in the temporoparietal

22   Diagnostic Criteria for AD in Brazil.   Schilling LP, et al.


and dorsolateral frontal junction. Severe AD corresponds
to Braak advanced stage VI, in which all cortical
association areas and the basal ganglia are affected
by NFTs and NPs, with relative sparing of the motor
and sensory cortices.
Other pathophysiological mechanisms in AD
include synaptic dysfunction, neurotransmitters
(mainly acetylcholine) and neurotrophin depletion,
mitochondrial dysfunction and deficits in insulin
signaling pathways, increase in oxidative stress and
inflammation, vascular changes 8, and cholesterol
metabolism9. Recent studies suggest that the interaction
between different pathophysiological processes,
such as white matter involvement associated with Aβ
accumulation10 and soluble Aβ oligomers interaction
with other proteins (such as α-synuclein and tau),
destabilize microtubules, mitochondrial and synaptic
dysfunction, and neurodegeneration11,12.
CLINICAL CHARACTERIZATION
Clinical characterization
AD usually manifests in the typical amnestic presenta-
tion, with a predominant difficulty of episodic memory
associated with degenerative lesions of medial temporal
structures. This pattern occurs in about 85% of cases.
Atypical and less frequent presentations may begin
mainly with impairment in language, visual-spatial,
executive, or complex motor functions. The most com-
mon atypical (usually presenile) forms are the logopenic
variant of primary progressive aphasia (lvPPA) and
the visual-spatial-apraxic of posterior cortical atro-
phy (PCA), whereas the least common forms are the
corticobasal syndrome (CBS) and the behavioral and
dysexecutive variant (ADbdv).
Due to these non-amnestic variants, memory
impairment is no longer mandatory for AD diagnosis
according to the most recent diagnostic criteria
from the Brazilian Academy of Neurology 13 based
on the National Institute on Aging-Alzheimer’s
Association (NIA-AA)14. To help identify these initial
forms of AD presentation, we will detail their clinical
characteristics, evolution stages, and corresponding
neuropathological substrates.
AD amnestic presentation
The typical AD presentation starts with difficulties
remembering messages and recent news and repeat-
ing the same questions, comments, and narratives.
Initially mild and intermittent, the symptoms first
Dement Neuropsychol 2022 September;16(3 Suppl. 1):21-35
appear as subjective memory impairment (SCI) followed
by mild cognitive impairment (MCI) – usually of the
multiple-domain amnestic type (also impairing the
language and executive functions) –, later evolving to
full-blown dementia, when they begin to interfere in the
activities of daily living and in the patient’s autonomy14.
Logopenic variant of primary progressive aphasia (lvPPA)
The first and predominant symptoms in this variant are
language alterations with non-fluent speech, pauses due
to word-finding difficulty, and errors (also phonological)
when repeating long sentences and in spontaneous
speech, but preserving semantics, syntax (grammar),
comprehension of single words, and motor production
of speech15,16.
Posterior cortical atrophy (PCA) or posterior variant
PCA is a rare form of AD which usually starts between
the ages of 50 and 60 years. Its occipitotemporal variant
presents with impairment of the visual identification
of objects, faces, or symbols; its biparietal variant,
more common, is characterized by visual-spatial dys-
function, topographical disorientation, poor hand-eye
coordination, limb apraxia, visual neglect, and at clinical
evaluation, elements of Balint’s syndrome (optic atax-
ia, oculomotor apraxia, and simultanagnosia) and/or
Gerstmann syndrome (acalculia, agraphia, left-right
disorientation, and finger agnosia)17,18.
In the early stages of the disease, episodic memory,
language, and executive functions are still relatively
preserved. PCA presents with AD neuropathology
in 62 to 100% of cases19.
Behavioral and dysexecutive variant (ADbdv)
The AD dysexecutive variant (ADdv) affects mainly
planning, working memory, and multi-tasking, with loss
of inhibitory control and alternating attention, de-
pression, anxiety and neuropsychiatric symptons.
In turn, behavioural symptoms are rare.
Though the behavioral variant of AD is similar to
the behavioral variant of frontotemporal dementia
(bvFTD), it presents greater deficits in memory,
apathy, delusional ideas, and hallucinations, with less
disinhibition, compulsive or persevering behavior,
affective indifference, or personality change 20-23.
This presentation of AD is rare, occurring in about
2% of large samples of AD patients and with 7-20%
of patients clinically diagnosed as FTD19,24,25.
Schilling LP, et al.   Diagnostic Criteria for AD in Brazil.   23
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):21-35
Corticobasal syndrome (CBS)
CBS manifests with remarkably asymmetric or unilater-
al signs and symptoms of stiffness, dystonia, my-
oclonus, bradykinesia, and tremor. It is associated
with gait alteration, asymmetric apraxia, alien hand
phenomenon, sensory hemineglect, and visual-spa-
tial deficits, besides the more typical symptoms of
episodic and visual-spatial memory deficits and apha-
sia19,23. AD causes 15-50% of CBS cases, degenerating
cortical structures and basal ganglia, including the
substantia nigra, and manifesting clinically mainly
as motor symptoms.
Clinical stages of dementia
Mild dementia
The mild dementia stage is characterized by progres-
sive worsening of amnestic symptoms associated with
other cognitive disorders, such as impaired working
memory, attentional control (difficulty multitasking),
language alterations (anomia), executive dysfunction
(struggles with planning, problem-solving), and tem-
poral-spatial disorientation26.
Neuropsychiatric symptoms occur in all stages (in up
to 80% of cases) and worsen as dementia progresses,
especially apathy, depression, anxiety27,28, and a lack of
awareness regarding cognitive deficits (anosognosia),
which occurs in up to 50% of patients19,29.
Moderate dementia
In the moderate dementia stage, patients become
more dependent on others to perform instrumen-
tal activities of daily living (although still capable
of self-care) and have greater difficulty remembering
the name of relatives, remote events, or more signif-
icant recent events. Other cognitive symptoms may
worsen, such as temporal and spatial disorientation,
development of transcortical sensory aphasia, ideo-
motor apraxia, dyscalculia, visual agnosia, and neu-
ropsychiatric symptoms such as delusions (typically
of betrayal or theft), hallucinations, and agitation,
with or without aggressiveness.
Severe dementia
In the severe dementia stage, patients are entirely
dependent on a caregiver, with memory reduced
to fragments of information, temporal and personal
disorientation (maintaining only self-awareness),
and speech restricted to a few unintelligible words.
In more advanced stages, they can present urinary and
24   Diagnostic Criteria for AD in Brazil.   Schilling LP, et al.
fecal incontinence, parkinsonism, myoclonus, epileptic
seizures (in up to 20% of cases)30,31, and gait difficulties.
Later, patients have difficulty sitting and swallowing.
The average survival time is five to 12 years after
the onset of symptoms, but with significant variability
among patients32.
Diagnosis
Clinical diagnosis of AD
The clinical diagnosis of AD dementia is based on
a thorough evaluation, especially of the patient’s
affected cognitive domains and functional impair-
ment, as described in the diagnostic criteria and
neuropsychological assesment section 13,14 . AD is
a progressive pathological process with different clinical
stages, and dementia occurs when pathological changes
have already spread33.
Understanding this cognitive continuum is
essential for an appropriate clinical evaluation
of the patient and, with complementar y tests
(including biomarkers), an accurate diagnosis in
atypical or early-onset cases. Biomarkers also allow
identifying patients and indicating possible future
specific treatments for AD34.
Diagnosis of dementia due to Alzheimer’s disease (modified from
McKhann et al., 201113 and Frota et al., 201114)
• Probable Alzheimer’s disease dementia
If the patient meets the criteria for diagnosis
of dementia35 and has the following characteristics:
I. Insidious onset (months or years);
II. Clear history or observation of cognitive worsening;
III. Initial and more prominent cognitive deficits
in one of the following categories:
• Amnestic presentation (there must be another
affected domain).
• Non-amnestic presentation (there must be
another domain affected).
• Language (memory of words).
• Visual-spatial (spatial cognition or agnosia
for objects or faces, simultanagnosia,
and alexia).
• Executive functions (alterations of reasoning,
judgment, and problem-solving).
IV. Tomography or, preferably, magnetic resonance
imaging of the brain should be performed
to exclude other diagnostic possibilities or
comorbidities, especially cerebrovascular disease;

V. The diagnosis of probable AD dementia should
not be applied when there are:
• Evidence of significant cerebrovascular
disease defined by a history of stroke
temporally related to the onset or worsening
of cognitive impairment; presence of multiple
or extensive brain infarctions; or extensive
lesions in the white matter evidenced
by neuroimaging; or
• Central features of dementia with Lewy
bodies (visual hallucinations, parkinsonism,
REM sleep behavior disorder, and cognitive
fluctuation); or
• Prominent features of the behavioral
variant of FTD (hyperorality, hypersexuality,
perseveration); or
• Prominent characteristics of PPA manifesting
as semantic variant (with fluent speech,
anomia, and semantic memory difficulties)
or as non-fluent variant (with agrammatism
and/or marked speech apraxia); or
• Evidence of concomitant neurological or
non-neurological active disease, or medication
use that may substantially affect cognition.
Anamnesis
A detailed anamnesis focused on the most common
cognitive and neuropsychiatric alterations of AD al-
lows diagnosing the disease more safely, establishing
its subtype based on its initial presentation and stage,
and differentiating it from other neurodegenerative
diseases. Interrogation of patients and their relative/
caregiver should cover (1) neuropsychiatric disorders
such as depression, anxiety, apathy, delusional ideas,
hallucinations, and aberrant or uninhibited motor be-
haviors, which are socially inappropriate; and (2) cogni-
tive difficulties in the following domains, most affected
by the disease:
I. Episodic memory: Does the patient forget
recent facts and dates, items to purchase,
appointments, or places where he/she keeps
objects? Or does he/she keep repeating the same
questions or comments?
II. Executive functions: Does the patient have
difficulty staying focused, making decisions,
planning activities, solving everyday problems,
shopping, and dealing with small amounts
of money? Do they present loss of motivation
and initiative? Do they have impaired judgment?
Dement Neuropsychol 2022 September;16(3 Suppl. 1):21-35
III. Visual-spatial or praxic skills: Does the patient
have difficulty orienting themselves spatially
(outside and indoors), dressing, combing,
shaving, using everyday objects, recognizing
familiar faces? Have they lost dexterity in tasks
in which they used to do well?
IV. Language: Does the patient have difficulty
finding words in conversations or naming
objects and people? Or in understanding
words or sentences, explaining situations and
making themselves understood, presenting poor
vocabulary and reduced speech fluency?
Neuropsychological assessment
According to specific studies on the subject 36,37 ,
the diagnosis of AD in its initial stage (or MCI)
has greater reliability when using two tests for
each of the four cognitive domains most affected
by the disease and greater sensitivity when de-
fining deficit score as >1 standard deviation (SD),
and not >1.5 or >2SD), relative to normative values.
Thus, in addition to conducting a global cognitive test
(MMSE, Mini-Mental State Examination; or MoCA,
Montreal Cognitive Assessment), the evaluation must
include episodic memory, language, executive func-
tions, and visual-spatial functions, with two subtests
for each cognitive domain.
The main instruments recommended for cognitive
assessment in AD in Brazil are presented below.
Given the country’s socio-cultural and educational
heterogeneity, it is advisable to use instruments with
cutoff scores adjustable by level of education to avoid
false-positive results in the diagnostic process 38.
The instruments are subdivided into cognitive
screening tests, specific tests for evaluating different
cognitive domains, and instruments for assessing
functionality (Table 1).
More recently, the sum of boxes (CDR-Sum
of Boxes – CDR-SB) have replaced the Clinical Dementia
Rating (CDR) global scores. The first allows detecting
smaller differences within and between subsequent
global scores as well as within and between stages
of the disease, helping differentiate MCI from initial
dementia, as seen in O’Bryant et al.87, who described the
following ranges of CDR-SB corresponding to CDR-GS
scores: 0.5 to 4.0 for the CDR-GS of 0.5; 4.5 to 9.0
for CDR-GS of 1; 9.5 to 15.5 for CDR-GS of 2; and 16.0
to 18.0 for CDR-GS of 3.
Schilling LP, et al.   Diagnostic Criteria for AD in Brazil.   25
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):21-35

Table 1. Main instruments for cognitive assessment in AD.

Type of instrument Main tests and normative studies

Screening tests

Mini-Mental State Examination (MMSE)39,40, Montreal Cognitive Assessment (MoCA)41,42, Cognitive Abilities
Brief tests
Screening Instrument – Short Version (CASI-S)43,44, Brief Cognitive Screening Battery (BBRC)45,46

Addenbrooke’s Cognitive Examination – revised version (ACE-R)47,48, Cambridge Cognitive Examination

Multi-functional batteries (CAMCOG)49-51, Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-COG)52,53, Consortium
to Establish a Registry for Alzheimer’s Disease (CERAD)54,55, Mattis Dementia Rating Scale (MDRS)56,57

Evaluation of single cognitive domains

Verbal episodic memory Rey Auditory Verbal Learning Test (RAVLT)58,59, CERAD Battery Word List Learning Subtest

Subtest “figure recognition” (BBRC), Subtest “geometric figure recall” (CERAD Battery),
Nonverbal memory
Rey-Osterrieth Complex Figure60,61

Language Verbal Fluency Test (phonemic and semantic)62,63, Boston Naming Test (BNT)64,65

Attention control and executive function Digit Span Task in forward and inverse order66,67, Clock Drawing Test68,69, Verbal Fluency Test

Visual-spatial /
CERAD / MoCA Figure Copy Subtest, Clock Drawing Test
visual-constructive abilities

Functional assessment

Functional Activities Questionnaire (FAQ)70,71, Informant Questionnaire on Cognitive Decline in the Elderly
(IQCODE)72,73, Direct Assessment of Functional Status-Revised (DAFS-R)74,75, Disability Assessment
Instrumental activities of daily living
for Dementia (DAD)76,77, Activities of Daily Living Questionnaire (ADLQ)78,79, Bayer Activities of Daily
Living Scale (B-ADL)80,81, AD8 Dementia Screening Interview82

Basic activities of daily living Katz scale83,84, Functional Activities Questionnaire (FAQ)70,72

Dementia staging Clinical Dementia Rating scale (CDR)85,86

Note: The global CDR scores (CDR-GS: 0, 0.5, 1, 2, or 3) have the limitation of being based on the scores of the item Memory, considering the other items as secondary, and thus
underestimating relevant information from instrumental activities that may be primarily and early affected.

Laboratory tests in AD clinical propaedeutics
Several clinical conditions may cause cognitive impair-
ment, such as hypothyroidism, hypovitaminosis, and
neurosyphilis. An initial medical evaluation should
conduct a basic laboratory evaluation to rule out the
main secondary causes of cognitive decline. It should
also seek to identify systemic diseases and comorbid-
ities that could worsen the neurological condition,
such as dyslipidemia and diabetes88-91.
The list of recommended laboratory tests should
include hematological, renal, hepatic, lipid, and metabolic
profiles (serum sodium, potassium, and calcium),
fasting glucose, folic acid dosage, vitamin B12, TSH,
free T4, syphilis serology, and especially in atypical cases
or in case of clinical suspicion, HIV testing92.
Structural neuroimaging
Brain evaluation by structural neuroimaging such as
computed tomography (CT) or magnetic resonance im-
aging (MRI) is essential for properly diagnosing AD, both
to rule out secondary lesions and to identify patterns
of brain atrophy specific to the disease. MRI provides
better anatomical resolution and different acquisition
techniques that are more useful than CT for differen-
tial diagnoses with other dementias, such as those of
vascular or prion pathology.
As a neurodegenerative disease, AD invariably
occurs with cerebral atrophy. The most common pattern
of volumetric alteration is atrophy of mesial temporal
structures (MTS), in structures such as the hippocampus
and entorhinal cortex, which correlates with the clinical
findings of episodic memory deficit. However, atrophy
can also affect different regions, especially in atypical
presenile presentations, such as linguistic, dysexecutive
and/or behavioral (frontal), and visual-spatial variants,
among others, which will be discussed later93.
Computed tomography (CT) is a useful, more available,
and lower-cost effective study that can be used even in
primary health care. Similarly to MRI, CT can rule out
structural lesions such as subdural hematoma, tumors,

26   Diagnostic Criteria for AD in Brazil.   Schilling LP, et al.


and hydrocephalus94. It can also evaluate hippocampal
atrophy, especially via coronal plane reconstruction.
Although MRI has a higher anatomical resolution
than CT, the Medial Temporal Atrophy Scale (MTA or
Scheltens scale) can also be used in CT (Figure 1)95.
The MTA is sensitive to diagnose AD and specific to
Score Width of the choroidal fissure
0 Normal
1 ↑
2 ↑↑
3 ↑↑↑
4 ↑↑↑
Figure 1. Application of the MTA scale on MRI (above) and CT (below). Under 75 years old, ≥2 is abnormal; over 75 years old, ≥3 is abnormal95.
Figure 2. Structures evaluated in the MTA scale. A: temporal horn; B: choroidal fissure; C: hippocampus.
As aforementioned, MRI presents better anatomical
resolution and allows performing other imaging
techniques. Visual inspection of MTS using scales such
as the MTA is still the most widespread and available
method in the clinical diagnosis of AD, with sensitivity
Dement Neuropsychol 2022 September;16(3 Suppl. 1):21-35
differentiate AD from normal older adults, although
other dementias may also present hippocampal atrophy,
such as vascular dementia or dementia with Lewy
bodies. The Scheltens scale assesses the width of the
choroidal fissure and temporal horn as well as the height
of the hippocampus(Figure 2)94,96.
Length of the temporal horn Hippocampus height
Normal Normal
Normal Normal
↑ ↓
↑↑ ↓↓
↑↑↑ ↓↓↓
and specificity of 80 to 85% in differentiating individuals
with AD from cognitively normal individuals 97 .
Some radiological centers and software available on
the Internet measure hippocampal volume by MRI,
which may increase sensitivity/specificity for diagnosis.
Schilling LP, et al.   Diagnostic Criteria for AD in Brazil.   27
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):21-35
Although this information is essential, especially for
follow-up, it still lacks standardization for the Brazilian
population considering age and sex. Regarding MTS
in AD, the subregions of the hippocampus, such as CA1
and subiculum, can be quantified, but without widespread
clinical application98. A recent review of MCI due to
AD showed low sensitivity/specificity (73 and 71%,
respectively) of MTS measures to differentiate patients
whose condition evolved or not to dementia99.
Other MRI techniques do not yet have a consolidated
role in clinical practice for AD diagnosis. As an example,
although the MRI proton magnetic resonance spectroscopy
technique – which assesses brain metabolites such as
N-acetylaspartate (Naa), creatine (Cr), and myo-inositol
(mI) – shows differences between groups of patients with
and without AD, it still has many limitations and technique
heterogeneity as to be applied in clinical practice as
a marker of the disease. The main findings of the technique
are a decrease in NAA and NAA/Cr ratio and an increase
in mI and mI/Cr ratio100.
Several other techniques, such as diffusion tensor
imaging, texture analysis, MRI infusion, and functional
connectivity, are still restricted for research.
Structural neuroimaging in atypical AD
A common feature of atypical presentations of AD, is the
relative preservation of MTS in relation to atrophy
of other brain regions. Each variant has its imaging
characteristics, which generally correlate with clinical
symptoms. Some neuroimaging characteristics of
the three most common atypical presentations will
be briefly described: visual-spatial variant (part of the
PCA spectrum); linguistic variant, most commonly
lvPPA; and ADbdv.
• PCA: predominance of parietal and posterior
temporal atrophy. The Koedam’s parietal atrophy
scale ranges from 0 to 3 and assesses the
integrity of the precuneus and dilatation of the
posterior cingulate, parieto-occipital, and parietal
lobe sulci. It may be helpful in the diagnosis
of PCA, and scores ≥ 2 can be considered
abnormal, according to the author’s proposal101;
• lvPPA: asymmetric atrophy of temporoparietal
structures, predominantly in the left hemisphere
(dominant for language)16;
• ADbdv: is the most heterogeneous presentation
in terms of image. It presents greater atrophy
in the dorsolateral prefrontal cortex compared
to typical AD but may also present a pattern of
temporoparietal atrophy20.
28   Diagnostic Criteria for AD in Brazil.   Schilling LP, et al.
Biomarker-assisted diagnosis
Biomarkers in cerebrospinal fluid
The cerebrospinal fluid (CSF) biomarkers used for AD di-
agnosis are the 42-amino acid Aβ peptide (Aβ1-42) and
the tau protein in its total composition and as phos-
phorylated residue at threonine 181 (T-tau and P-tau,
respectively). The “AD pathological signature” in CSF
consists of a pattern determined by reduced Aβ1-42
concentration and increased concentrations of T-tau
and P-tau102-104.
In recent years, the use of CSF AD biomarkers
for diagnosis has significantly advanced. Ideally,
concentrations of Aβ1-42 should be normalized
in relation to those of Aβ1-40, which do not vary
significantly among dementias. The ratio Aβ1-42/Aβ1-40
can also better predict the PET measurement of amyloid
load than the concentration of Aβ1-42 alone105-107.
There is a correspondence between the pattern of
CSF biomarkers and the pathophysiological changes
underlying AD. The reduction of Aβ1-42 and the
increase of P-tau in CSF indicate cerebral amyloidosis
and tauopathy, mechanisms that form, respectively,
NPs and NFTs. The increase in T-tau signals the ongoing
neurodegenerative process, usually represented by structural
changes (atrophy) and regional metabolic impairment.
Molecular neuroimaging biomarkers
Pathophysiological processes related to AD can be
alternatively inferred in vivo by molecular imaging
methods based on positron emission tomography (PET)
by injecting different radiotracers.
The progressive degenerative process of AD causes
cerebral hypometabolism, which can be assessed
using [18F]Fluorodeoxyglucose (FDG) as a tracer.
Patients with AD present hypometabolism patterns
involving the posterior cingulate, precuneus,
temporoparietal, and medial temporal cortices108-111.
Several molecular agents can evaluate the cerebral
accumulation of Aβ from peptide Aβ affinity, such as the
[11C]Pittsburgh compound-B (PiB), the [18F]Flutemetamol,
the [18F]Florbetaben, and [18F]Florbetapir 112,113.
PiB presents a greater limitation to clinical use since it
has carbon in its molecular structure, with a half-life of
only 20 minutes. Compared to the measurement of Aβ
in CSF, molecular imaging by PET has the advantage
of topographically identifying Aβ accumulation in
the brain, involving the precuneus and bilateral
fronto-temporo-parietal cortices113.
PET-specific radiotracers, such as [18F]Flortaucipir,
can also assess the accumulation of tau protein,

an essential pathological characteristic of AD 114.
Tau accumulation observed in molecular neuroimaging
studies has significant clinical correlations: a greater
accumulation of tau is related to the increased severity
of cognitive decline115-117 and, in atypical AD, the regions
with higher radiotracer retention are associated
with symptoms related to these regions, such as
occipital lobes in PCA, and to the pattern of glycolytic
hypometabolism118. Aβ biomarkers have good sensitivity
to identify cases of incipient AD 119 whereas P-Tau
markers have greater specificity to diagnose AD120,121.
Currently, biomarkers are used mainly in research.
From the clinical point of view, biomarkers should
be used to assess conditions considered atypical,
either for an initial non-amnestic clinical presentation
or in patients with early-onset dementia, which will
be further addressed in the next section.
When to request CSF biomarkers in AD?
The indications for the CSF examination , in general,
did not change since the last Brazilian Academy
of Neurology consensus92. CSF examination is thus
indicated in the investigation of presenile dementia
(before 65 years) and in cases with atypical clinical pre-
sentation or course, communicating hydrocephalus,
and any evidence or suspicion of inflammatory, infec-
tious, or prion disease of the central nervous system.
I f the entire diagnostic process involving
anamnesis, cognitive assessment, general examination,
and neuroimaging studies, the etiology of the dementia
syndrome remains doubtful, CSF biomarkers may
be helpful. This uncertainty commonly arises in the
differential diagnosis of atypical AD presentations with
other dementias, such as the behavioral variant of FTD
or agrammatic and semantic PPA.
CSF biomarkers can also be used in the workup
for cognitive disorders to predict dementia in
oligosymptomatic cases, where the identification of the
AD ‘pathological signature’ in MCI allows inferring the
underlying etiology of the disease with high accuracy.
The development of potentially disease-modifying
drugs, such as anti-Aβ monoclonal antibodies,
will promote CSF biomarker assessment, which is
essential for indicating these medications.
Biological diagnosis of AD through biomarkers
Diagnosis assisted by biomarkers allowed formulating
recommendations for the biological diagnosis of AD
by the A/T(N) classification122. According to this pro-
posal, suspected cases of AD can be classified according
to the positivity of biomarkers that allow inferring
Dement Neuropsychol 2022 September;16(3 Suppl. 1):21-35
the underlying presence of one or more pathogenic
processes characteristic of AD, where: “A” is the infor-
mation obtained by biomarkers indicative of cerebral
Aβ accumulation (i.e., Aβ1-42 reduction in the CSF or
positivity in molecular imaging methods of amyloid
detection); “T” is the positivity of biomarkers indicative
of tau hyperphosphorylation (increased P-Tau in CSF or
positivity in molecular imaging methods with tau-PET);
and “N” indicates the occurrence of neurodegeneration
by the increase of T-Tau levels in the CSF, hippocampal
and/or temporoparietal atrophy in MRI, or loss of re-
gional cerebral metabolic integrity, according to glucose
uptake profile by [18F]FDG-PET122,123. According to
specific topographic patterns, such measurements are
further related to the presence of degenerative process
at an early stage, corresponding to the degree of cerebral
atrophy and cognitive decline115,124.
According to the 2018 NIA/AA recommendations,
which included the AT(N) classification, the AD
diagnostic spectrum requires evidence of accumulation
of Aβ peptide and AD is defined by the combination of
the positivity of this biomarker (A+) and biomarkers
indicative of phosphorylated tau protein (T+). Positivity
of biomarkers for cerebral amyloidosis (A+) and
neurodegeneration (e.g., increase in CSF total tau)
(N+) in the absence of P-tau increase (T-) markers
concomitantly reflects AD pathological alteration and
suspected non-AD pathological process. In short:
A -: not in the AD spectrum
A+: AD spectrum
A+/T+: AD
A+/T-/N+: AD + suspicion of another non-AD
pathological process
NIA/AA authors122 advise that these recommendations
apply only to research (observational and interventional)
and should not be understood as guidelines or diagnostic
criteria for clinical practice, considering that: (1) they do
not consider clinical symptoms, signs, and functional
impairment; and (2) 40% of cognitively normal older
adults may present AD biomarkers and neuropathological
alterations125, of which about 20% will never develop
dementia, even in their nineties126.
Pathological diagnosis of AD
The pathological diagnosis of AD is based on the pres-
ence of cortical atrophy, especially in the hippocam-
pus and frontoparietal regions (associative areas),
with marked neuronal loss and extracellular NPs and
intraneuronal NFTs, which are the histopathological
markers of AD that establish its definitive diagno-
sis. These markers are initially formed in the limbic
Schilling LP, et al.   Diagnostic Criteria for AD in Brazil.   29
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):21-35

system (hippocampus and entorhinal cortex), pro-
gressing to the association cortex, subcortical nuclei,
and brainstem structures. Other neuropathological
findings include neuronal loss in the pyramidal
layers of the cerebral cortex and synaptic degener-
ation affecting associative limbic and cortical areas,
starting from the hippocampus, with relative preser-
vation of the primary areas (motor, somatosensory,
and visual).
Diagnosis of AD at different levels of health care
In Brazil, economic realities and access to health ser-
vices are quite heterogeneous. This requires adapting
the instruments and diagnostic approaches within
the levels of care established in the Guidelines of the
Unified Health System (Sistema Único de Saúde – SUS)
(Primary, Secondary, and Tertiary Care).
Table 2 shows the suggested protocols for the
evaluation and diagnosis of AD at each level of care:

Table 2. Suggested protocol for the diagnosis of AD at each level of health care.
Diagnosis in Primary Care

Ask the patient and their relative/caregiver about cognitive, neuropsychiatric, and behavioral symptoms. The interviews
Anamnesis
should be preferably conducted separately.

Perform general physical examination looking for signs of systemic diseases and a complete neurological examination
Clinical examination
attentive to focal signs.

Laboratory tests Perform laboratory tests to detect causes of secondary dementias and comorbidities that may contribute to the clinical picture.

Cognitive assessment
Applying a brief cognitive screening test, such as MoCA, BBRC, or CASI-S is suggested. BBRC stands out due to its easy
application and high sensitivity, even for individuals with low schooling levels. Moreover, applying brief highly sensitive tasks,
such as semantic verbal fluency (animals) and a word-learning test, which are highly accurate to detect dysfunction of the
hippocampal system (amnesia), is recommended. Data on functionality can be addressed in the anamnesis or specific brief
questionnaires, such as the Functional Activities Questionnaire (FAQ).

A brain CT is essential to rule out other causes of dementia (such as tumors, hydrocephalus, or cerebral infarctions)
Structural neuroimaging
and to identify, within the limitations of the method, patterns of atrophy compatible with AD.

Diagnosis in Secondary Care

Anamnesis Ask the patient and their relative/caregiver about cognitive, neuropsychiatric, and behavioral symptoms.

Perform general physical examination looking for signs of systemic diseases and a complete neurological examination
Clinical examination
attentive to focal signs.

Perform laboratory tests to detect causes of secondary dementias and comorbidities that may contribute to the clinical
Laboratory tests
picture. If chronic meningitis is suspected, a lumbar puncture should be performed for CSF analysis.

Using a brief test of cognitive screening or multifunctional battery of medium coverage is suggested, with at least one task
Cognitive assessment
to examine each cognitive domain; complement by applying a functional assessment tool, as described above.

Brain CT or MRI (preferably) is essential to rule out other causes of dementia and further investigate mesial structures,
Structural neuroimaging
with visual scales or manual or automated volumetry.

Using biomarkers is indicated in cases of diagnostic doubt between AD and other neurodegenerative dementias not in
the amyloid spectrum, such as FTD, to correctly follow the guidelines for the use of AD approved medications, such as
cholinesterase inhibitors and memantine. Other situations are referred to in biomarkers sections. Importantly, the future
Biomarker assessment
emergence and availability of potentially disease-modifying drugs will require evaluating all patients with mild AD as potential
candidates for these treatments. Biomarkers can be requested from the secondary level of health care if they are reserved
for selected cases and requested and interpreted by trained professionals.

Diagnosis in Tertiary Care

Anamnesis Conduct a detailed initial interview with the patient and their relative/caregiver.

Perform a general physical examination looking for signs of systemic diseases and a complete neurological examination
Clinical examination
attentive to focal signs.

Perform laboratory tests to detect causes of secondary dementias and comorbidities that may contribute to the clinical
Laboratory tests picture and other tests if suspecting a relevant systemic disease. If chronic meningitis is suspected, a lumbar puncture
should be performed for CSF analysis.
Continue...

30   Diagnostic Criteria for AD in Brazil.   Schilling LP, et al.

 Dement Neuropsychol 2022 September;16(3 Suppl. 1):21-35

Table 2. Continuation.
A comprehensive neuropsychological evaluation using a cognitive screening test is suggested for applying instruments
Cognitive assessment
to further examine all cognitive domains and to assess functionality and neuropsychiatric disorders.

Brain MRI is essential to rule out other causes of dementia and further investigate the mesial temporal and other brain
Structural neuroimaging
regions using visual scales or manual or automated volumetry.

FDG-PET or single-photon emission computerized tomography (SPECT) studies may show regional alterations in brain
Functional neuroimaging metabolism or changes in blood flow in cases of incipient and/or mild dementia, even in the absence of structural changes
in neuroimaging.

Using biomarkers is indicated in cases of diagnostic doubt between AD and other neurodegenerative dementias not in
the amyloid spectrum, such as FTD, to correctly follow the guidelines for the use of AD approved medications, such as
Biomarker assessment cholinesterase inhibitors and memantine. Other situations are referred to in biomarkers sections. Importantly, the future
emergence and availability of potentially disease-modifying drugs will require evaluating all patients with mild AD as potential
candidates for these treatments.

FUTURE PROSPECTS instrumentation in AD diagnosis. Moreover, de-

Diagnosis of preclinical AD
The pathogenic process of AD begins many years before
the first clinical manifestations of the disease, and the
analysis of biomarkers indicates the presence of asymp-
tomatic individuals127. Preclinical AD is therefore a long
and silent stage of the disease that precedes the first
cognitive alterations which will later lead to the diag-
nosis of mild cognitive impairment (MCI) due to AD. It
corresponds to a window of opportunity to implement
interventions for delaying (or, ideally, interrupting)
the pathogenic process of AD128. The existence of inter-
ventions modifying the pathogenesis of AD, associated
with the possibility of identifying the disease in the
asymptomatic phase will represent an effective way to
establish the prevention of dementia.
The diagnostic criteria for preclinical AD, restricted
to the research context, were proposed to identify
individuals at risk of AD in the asymptomatic phase129-131.
Three evolutionary stages inherent to preclinical
AD were proposed: the first shows isolated evidence
of cerebral amyloidogenesis according to the positivity
of Aβ biomarkers; the second shows evidence of ongoing
neurodegenerative process according to CSF and/or
brain imaging biomarkers; and the third, indicates very
subtle cognitive or behavioral alterations, insufficient
for the diagnosis of MCI129.
Peripheral biomarkers of AD
Limitations for using these methods to better diag-
nose AD include the low availability and high cost of
molecular image obtainment by PET and the need
to perform lumbar puncture to obtain CSF samples.
Developing new biomarkers in peripheral blood,
with good diagnostic accuracy and predictive sensi-
tivity, would thus significantly advance laboratory
termining plasma levels of Aβ, tau protein, and
neurofilament light chain (NFL) –another neuronal
cytoskeletal protein – with ultrasensitive methods
could provide reliable estimates of cerebral amyloi-
dogenesis and neurodegeneration in early stages of
AD121,132,133. Plasma amyloid levels present a reliable
correlation, measured by the relationship between
peptides Aβ1-42 and Aβ1-40, and future positivity in am-
yloid PET134. Phosphorylated tau levels are present in
other degenerative disorders but have been reported
as elevated in plasma in individuals with AD, with the
181
P-tau form showing greater specificity 133,135 .
The presence of NFL in CSF indicates nonspecific neu-
ronal damage. Recent studies have shown a positive
correlation between plasma and NFL cerebrospinal
fluid levels, but only regarding neurodegeneration136.
A recent meta-analysis showed that NFL levels in
both CSF and plasma have high diagnostic sensitivity
for AD and other neurodegenerative dementias137.
Other approaches using genomics, transcriptomics,
metabolomics, lipidomics, and proteomics have been
applied to generate different biomarkers for AD.
One study showed that altered microRNAs resulting
from the failure of the synaptic function are potential
plasma biomarkers for AD138. A Brazilian study showed
decreased levels of ADAM10 PPA-secretases in platelets,
decreased PSEN1 levels in platelets and leukocytes,
and lower bace1 (β-secretase) levels in leukocytes139.
Implications of early diagnosis for
disease-modifying therapies
The biomarker-based classification system proposed in
2018 indicates a broader concept of the pathological
process in AD. However, clinical trials still face many
challenges. Despite a growing understanding that
clinical evaluation alone is limited for evaluating an

Schilling LP, et al.   Diagnostic Criteria for AD in Brazil.   31

 Dement Neuropsychol 2022 September;16(3 Suppl. 1):21-35
intervention outcome, cognitive improvement mea-
sures are still the main outcomes in all clinical trials.
Identifying the best molecular targets or a combination
of them by developing better protocols to assess the
results of interventions using biochemical, physiolog-
ical, and neuropsychological measures as outcomes is
essential to identify individuals in preclinical stages of
AD and facilitate early therapeutic interventions. This
is the premise of most efforts to find new therapies.
REFERENCES
1. Gauthier S, Rosa-Neto P, Morais JA, Webster C. World Alzheimer Report
2021: Journey through the diagnosis of dementia. London: Alzheimer’s
Disease International (UK); 2021. 313 p.
2. Melo SC, Champs APS, Goulart RF, Malta DC, Passos VMA. Dementias
in Brazil: increasing burden in the 2000–2016 period. Estimates
from the Global Burden of Disease Study 2016. Arq Neuropsiquiatr.
2020 ;78(12):762-71. doi:10.1590/0004-282X20200059
3. Robinson M, Lee BY, Hane FT. Recent progress in Alzheimer’s disease
research, part 2: genetics and epidemiology. J Alzheimers Dis.
2017;57(2):317-30. doi:10.3233/JAD-161149
4. Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S,
et al. Dementia prevention, intervention, and care: 2020 report of the
Lancet Commission. Lancet. 2020;396(10248):413-46. doi:10.1016/
S0140-6736(20)30367-6
5. Kim JH. Genetics of Alzheimer’s disease. Dement Neurocogn Disord.
2018;17(4):131-36. doi:10.12779/dnd.2018.17.4.131
6. Berkowitz CL, Mosconi L, Rahman A, Scheyer O, Hristov H, Isaacson RS.
Clinical application of APOE in Alzheimer’s prevention: a precision medicine
approach. J Prev Alzheimers Dis. 2018;5(4):245-52. doi:10.14283/jpad.2018.35
7. Braak H, Zetterberg H, Del Tredici K, Blennow K. Intraneuronal tau
aggregation precedes diffuse plaque deposition, but Amyloid-β changes
occur before increases of tau in cerebrospinal fluid. Acta Neuropathol.
2013;126(5):631-41. doi:10.1007/s00401-013-1139-0
8. Brundel M, Bresser J, van Dillen JJ, Kappelle LJ, Biessels GJ. Cerebral
microinfarcts: a systematic review of neuropathological studies. J Cereb
Blood Flow Metab. 2012;32(3):425-36. doi:10.1038/jcbfm.2011.200
9. Sáiz-Vazquez O, Puente-Martínez A, Ubillos-Landa S, Pacheco-Bonrostro J,
Santabárbara J. Cholesterol and Alzheimer’s disease risk: a meta-meta-
analysis. Brain Sci. 2020;10(6):386. doi:10.3390/brainsci10060386
10. Schilling LP, Pascoal TA, Zimmer ER, Mathotaarachchi S, Shin M, Rieder
CRM, et al. Regional Amyloid-β load and white matter abnormalities
contribute to hypometabolism in Alzheimer’s dementia. Mol Neurobiol.
2019;56(7):4916-24. doi:10.1007/s12035-018-1405-1
11. Guerrero-Muñoz MJ, Gerson J, Castillo-Carranza DL. Tau oligomers:
the toxic player at synapses in Alzheimer’s disease. Front Cell Neurosci.
2015;9:464. doi:10.3389/fncel.2015.00464
12. Sengupta P, Satpute-Krishnan P, Seo AY, Burnette DT, Patterson GH,
Lippincott-Schwartz J. ER trapping reveals Golgi enzymes continually
revisit the ER through a recycling pathway that controls Golgi organization.
Proc Natl Acad Sci U S A. 2015;112(49):E6752-E61. doi:10.1073/
pnas.1520957112
13. Frota NAF, Nitrini R, Damasceno BP, Forlenza OV, Dias-Tosta E, Silva AB,
et al. Criteria for the diagnosis of Alzheimer’s disease. Recommendations
os the Scientific Department of Cognitive Neurology and Aging of the
Brazilian Academy of Neurology. Dement Neuropsychol. 2011;5(3):146-52.
doi:10.1590/S1980-57642011DN05030002
14. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr,
Kawas CH, et al. The diagnosis of dementia due to Alzheimer’s disease:
recommendations from the National Institute on Aging-Alzheimer’s
Association workgroups on diagnostic guidelines for Alzheimer’s disease.
Alzheimers Dement. 2011;7(3):263-9. doi:10.1016/j.jalz.2011.03.005
15. Gorno-Tempini ML, Hillis AE, Weintraub S, Kertesz A, Mendez M,
Cappa SF, et al. Classification of primary progressive aphasia and its
variants. Neurology. 2011;76(11):1006-14.
16. Montembeault M, Brambati SM, Gorno-Tempini ML, Migliaccio R. Clinical,
anatomical, and pathological features in the three variants of primary
progressive aphasia: a review. Front Neurol. 2018;9:692. doi:10.3389/
fneur.2018.00692
32   Diagnostic Criteria for AD in Brazil.   Schilling LP, et al.
ACKNOWLEDGEMENTS
PC, LCS and RN are funded by CNPq, Brazil (bolsa de
produtividade em pesquisa).
Authors’ contributions. LPS, MLFB, MR, OVF, MLS, BPD, RN,
JS, BJAPB: concept; LPS, MLFB, MR, OVF, MLS, BPD, RN:
drafting of the manuscript; BJAPB, FACV, JS, LCS, LPS,
MLFB, MLFC, NAFF, PC, PHFB, RN, SMDB: critical revision
of the manuscript for important intellectual content.
17. Crutch SJ, Schott JM, Rabinovici GD, Murray M, Snowden JS, van der
Flier WM, et al. Consensus classification of posterior cortical atrophy.
Alzheimers Dement. 2017;13(8):870-84. doi:10.1016/j.jalz.2017.01.014
18. Fumagalli GG, Basilico P, Arighi A, Mercurio M, Scarioni M, Carandini T,
et al. Parieto-occipital sulcus widening differentiates posterior cortical
atrophy from typical Alzheimer disease. Neuroimage Clin. 2020;28:102453.
doi:10.1016/j.nicl.2020.102453
19. Alladi S, Xuereb J, Bak T, Nestor P, Knibb J, Patterson K, et al. Focal
cortical presentations of Alzheimer’s disease. Brain. 2007;130(10):2636-45.
doi:10.1093/brain/awm213
20. Ossenkoppele R, Pijnenburg YA, Perry DC, Cohn-Sheehy BI,
Scheltens NM, Vogel JW, et al. The behavioural/dysexecutive variant of
Alzheimer’s disease: clinical, neuroimaging and pathological features.
Brain. 2015;138(9):2732-49. doi:10.1093/brain/awv191
21. Ossenkoppele R, Singleton EH, Groot C, Dijkstra AA, Eikelboom WS,
Seeley WW, et al. Research criteria for the behavioral variant of Alzheimer
disease: a systematic review and meta-analysis. JAMA Neurol.
2022;79(1):48-60.
22. Townley RA, Graff-Radford J, Mantyh WG, Botha H, Polsinelli AJ,
Przybelski SA, et al. Progressive dysexecutive syndrome due to Alzheimer’s
disease: a description of 55 cases and comparison to other phenotypes.
Brain Commun. 2020;2(1):1-19. doi:10.1093/braincomms/fcaa068
23. Graff-Radford J, Yong KXX, Apostolova LG, Bouwman FH, Carrillo M,
Dickerson BC, et al. New insights into atypical Alzheimer’s disease in
the era of biomarkers. Lancet Neurol. 2021;20(3):222-34. doi:10.1016/
S1474-4422(20)30440-3
24. Snowden JS, Stopford CL, Julien CL, Thompson JC, Davidson Y,
Gibbons L, et al. Cognitive phenotypes in Alzheimer’s disease and genetic
risk. Cortex. 2007;43(7):835-45. doi:10.1016/s0010-9452(08)70683-x
25. Mendez MF, Joshi A, Tassniyom K, Teng E, Shapira JS. Clinicopathologic
differences among patients with behavioral variant frontotemporal dementia.
Neurology. 2013;80(6):561-8. doi:10.1212/WNL.0b013e3182815547
26. Reisberg B, Ferris SH, Leon MJ, Crook T. The Global Deterioration Scale
for assessment of primary degenerative dementia. Am J Psychiatry.
1982;139(9):1136-9. doi:10.1176/ajp.139.9.1136
27. Tatsch MF, Bottino CMC, Azevedo D, Hototian SR, Moscoso MA,
Folquitto JC, et al. Neuropsychiatric symptoms in Alzheimer disease and
cognitively impaired, nondemented elderly from a community-based sample
in Brazil: prevalence and relationship with dementia severity. Am J Geriatr
Psychiatry. 2006;14(5):438-45. doi:10.1097/01.JGP.0000218218.47279.db
28. Gauthier S, Cummings J, Ballard C, Brodaty H, Grossberg G, Robert P, et al.
Management of behavioral problems in Alzheimer’s disease. Int Psychogeriatr.
2010;22(3):346-72. doi:10.1017/S1041610209991505
29. Lacerda IB, Santos RL, Belfort T, Neto JPS, Dourado MCN. Patterns
of discrepancies in different objects of awareness in mild and
moderate Alzheimer’s disease. Aging Ment Health. 2020;24(5):789-96.
doi:10.1080/13607863.2018.1544219
30. Palop JJ, Mucke L. Epilepsy and cognitive impairments in Alzheimer’s
disease. Arch Neurol. 2009;66(4):435-40. doi:10.1001/archneurol.2009.15
31. Xu Y, Lavrencic L, Radford K, Booth A, Yoshimura S, Anstey KJ, et al.
Systematic review of coexistent epileptic seizures and Alzheimer’s disease:
incidence and prevalence. J Am Geriatr Soc. 2021;69(7):2011-20.
doi:10.1111/jgs.17101
32. Vermunt L, Sikkes SAM, van den Hout A, Handels R, Bos I,
van der Flier WM, et al. Duration of preclinical, prodromal, and dementia
stages of Alzheimer’s disease in relation to age, sex, and APOE genotype.
Alzheimers Dement. 2019;15(7):888-98. doi:10.1016/j.jalz.2019.04.001
33. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM,
et al. Toward defining the preclinical stages of Alzheimer’s disease:
recommendations from the National Institute on Aging-Alzheimer’s Association

workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers
Dement. 2011;7(3):280-92. doi:10.1016/j.jalz.2011.03.003
34. Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, et al.
The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease.
Nature. 2016;537(7618):50-6. doi:10.1038/nature19323
35. S m i d J , C é s a r- F r e i t a s K G , D o u r a d o M C N , K o c h h a n n R ,
Studart-Neto A, Barbosa BJAPB, et al. Subjective cognitive decline,
mild cognitive impairment, and dementia – syndromic approach. Dement
Neuropsychol. 2022;16(S1).
36. Jak AJ, Bondi MW, Delano-Wood L, Wierenga C, Corey-Bloom J,
Salmon DP, et al. Quantification of five neuropsychological approaches
to defining mild cognitive impairment. Am J Geriatr Psychiatry.
2009;17(5):368-75. doi:10.1097/JGP.0b013e31819431d5
37. Bondi MW, Edmonds EC, Jak AJ, Clark LR, Delano-Wood L, McDonald CR,
et al. Neuropsychological criteria for mild cognitive impairment improves
diagnostic precision, biomarker associations, and progression rates.
J Alzheimers Dis. 2014;42(1):275-89. doi:10.3233/JAD-140276
38. Ortega LFV, Aprahamian I, Borges MK, Cação JC, Yassuda MS. Screening
for Alzheimer’s disease in low-educated or illiterate older adults in Brazil:
a systematic review. Arq Neuropsiquiatr. 2019;77(4):279-88. doi:10.1590/
0004-282X20190024
39. Folstein MF, Folstein SE, Folstein, McHugh PR. “Mini-mental state”.
A practical method for grading the cognitive state of patients for the clinician.
J Psychiatr Res. 1975;12(3):189-98. doi:10.1016/0022-3956(75)90026-6
40. Brucki SM, Nitrini R, Caramelli P, Bertolucci PH, Okamoto IH. Suggestions for
utilization of the mini-mental state examination in Brazil. Arq Neuropsiquiatr.
2003;61(3B):777-81. doi:10.1590/s0004-282x2003000500014
41. Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V,
Collin I, et al. The Montreal Cognitive Assessment, MoCA: a brief screening
tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695-9.
Errata em: J Am Geriatr Soc. 2019;67(9):1991. doi:10.1111/
j.1532-5415.2005.53221.x
42. Memória CM, Yassuda MS, Nakano EY, Forlenza OV. Brief screening
for mild cognitive impairment: validation of the Brazilian version of the
Montreal cognitive assessment. Int J Geriatr Psychiatry. 2013;28(1):34-40.
doi:10.1002/gps.3787
43. Teng EL, Larson EB, Lin KN, Graves AB, Liu HC. Screening for dementia:
the Cognitive Abilities Screening Instrument – short version (CASI Short).
Proceedings of the 106th Annual Convention of the American Psychological
Association; 1998 Aug 14-18; San Francisco, US. Washington, DC:
American Psychological Association; 1998.
44. Damasceno A, Delicio AM, Mazo DFC, Zullo JFD, Scherer P, Ng RTY, et al.
Validation of the Brazilian version of mini-test CASI-S. Arq Neuropsiquiatr.
2005;63(2b): 416-21. doi:10.1590/S0004-282X2005000300010
45. Nitrini R, Lefèvre BH, Mathias SC, Caramelli P, Carrilho PE,
Sauaia N, et al. Neuropsychological tests of simple application for
diagnosing dementia. Arq Neuropsiquiatr. 1994;52(4):457-65. doi:10.1590/
s0004-282x1994000400001
46. Nitrini R, Brucki SMD, Yassuda MS, Fichman HC, Caramelli P.
The Figure Memory Test: diagnosis of memory impairment in populations
with heterogeneous educational background. Dement. Neuropsychol.
2021;15(2):173-85. doi:10.1590/1980-57642021dn15-020004
47. Mioshi E, Dawson K, Mitchell J, Arnold R, Hodges JR. The Addenbrooke’s
Cognitive Examination Revised (ACE-R): a brief cognitive test battery
for dementia screening. Int J Geriatr Psychiatry. 2006;21(11):1078-85.
doi:10.1002/gps.1610
48. Carvalho VA, Caramelli P. Brazilian adaptation of the Addenbrooke’s
Cognitive Examination-Revised (ACE-R). Dement Neuropsychol.
2007;1(2):212-216. doi:10.1590/S1980-57642008DN10200015
49. Roth M, Tym E, Mountjoy CQ, Huppert FA, Hendrie H, Verma S, et al.
CAMDEX. A standardised instrument for the diagnosis of mental disorder
in the elderly with special reference to the early detection of dementia.
Br J Psychiatry. 1986;149:698-709. doi:10.1192/bjp.149.6.698
50. Nunes PV, Diniz BS, Radanovic M, Abreu ID, Borelli DT, Yassuda MS, et al.
CAMcog as a screening tool for diagnosis of mild cognitive impairment
and dementia in a Brazilian clinical sample of moderate to high education.
Int J Geriatr Psychiatry. 2008;23(11):1127-33. doi:10.1002/gps.2038
51. Aprahamian I, Martinelli JE, Cecato J, Izbicki R, Yassuda MS. Can the
CAMCOG be a good cognitive test for patients with Alzheimer’s disease
with low levels of education? Int Psychogeriatr. 2011;23(1):96-101.
doi:10.1017/S104161021000116X
52. Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease.
Am J Psychiatry. 1984;141(11):1356-64. doi:10.1176/ajp.141.11.1356
53. Schultz RR, Siviero MO, Bertolucci PH. The cognitive subscale of
the “Alzheimer’s Disease Assessment Scale” in a Brazilian sample.
Braz J Med Biol Res. 2001;34(10):1295-1302. doi:10.1590/
S0100-879X2001001000009
54. Morris JC, Heyman A, Mohs RC, Hughes JP, van Belle G, Fillenbaum G, et al.
The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD).
Dement Neuropsychol 2022 September;16(3 Suppl. 1):21-35
Part I. Clinical and neuropsychological assessment of Alzheimer’s disease.
Neurology. 1989;39(9):1159-65. doi:10.1212/wnl.39.9.1159
55. Bertolucci PHF, Okamoto IH, Brucki SMD, Siviero MO, Toniolo J Neto,
Ramos LR. Applicability of the CERAD neuropsychological battery to
Brazilian elderly. Arq Neuropsiquiatr. 2001;59(3A):532-36. doi:10.1590/
S0004-282X2001000400009
56. Vitaliano PP, Breen AR, Russo J, Albert M, Vitiello MV, Prinz PN. The
clinical utility of the dementia rating scale for assessing Alzheimer patients.
J Chronic Dis. 1984;37(9-10):743-53. doi:10.1016/0021-9681(84)90043-2
57. Porto CS, Fichman HC, Caramelli P, Bahia VS, Nitrini R. Brazilian
version of the Mattis dementia rating scale: diagnosis of mild dementia
in Alzheimer’s disease. Arq Neuropsiquiatr. 2003;61(2B):339-45.
doi:10.1590/s0004-282x2003000300004
58. Rey A. L’examen clinique en psychologie [The clinical examination in
psychology]. Paris (France): Presses Universitaires de France; 1964. French.
59. Malloy-Diniz LF, Lasmar VA, Gazinelli LS, Fuentes D, Salgado JV.
The Rey Auditory-Verbal Learning Test: applicability for the Brazilian
elderly population. Braz J Psiquiatry. 2007;29(4):324-29. doi:10.1590/
S1516-44462006005000053
60. Osterrieth PA. Le test de copie d’une figure complexe; contribution à
l’étude de la perception et de la mémoire [Test of copying a complex
figure; contribution to the study of perception and memory]. Arch Psychol.
1944;30:206-356.
61. Foss MP, Bastos-Formigheri MS, Speciali JG. Rey’s complex figures for
the elderly. Aval Psicol. 2010;9(1):53-61.
62. Hazin I, Leite G, Oliveira RM, Alencar JC, Fichman HC, Marques PN,
et al. Brazilian Normative Data on Letter and Category Fluency Tasks:
effects of gender, age, and geopolitical region. Front Psychol. 2016;7:684.
doi:10.3389/fpsyg.2016.00684
63. Caramelli P, Carthery-Goulart MT, Porto CS, Fichman HC, Nitrini R.
Category fluency as a screening test for Alzheimer disease in illiterate
and literate patients. Alzheimer Dis Assoc Disord. 2007;21(1):65-7.
doi:10.1097/WAD.0b013e31802f244f
64. Kaplan EF, Goodglass H, Weintraub S. The Boston Naming Test. 2a ed.
Philadelphia: Lippincott Williams & Wilkins; 2001.
65. Mansur LL, Radanovic M, Araújo GC, Taquemori LY, Greco LL. Boston
Naming Test: performance of Brazilian population from São Paulo.
Pro Fono. 2006;18(1):13-20. doi:10.1590/S0104-56872006000100003
66. Wechsler D. Wechsler Adult Intelligence Scale-III. San Antonio:
The Psychological Corporation; 1997.
67. Zimmermann N, Cardoso CO, Trentini CM, Grassi-Oliveira R, Fonseca RP.
Brazilian preliminary norms and investigation of age and education effects
on the Modified Wisconsin Card Sorting Test, Stroop Color and Word test
and Digit Span test in adults. Dement Neuropsychol. 2015;9(2):120-7.
doi:10.1590/1980-57642015DN92000006
68. Shulman KI, Shedletsky R, Silver IL. The challenge of time: clock-drawing and
cognitive function in the elderly. Int J Geriatr Psychiatry. 1986;1(2):135-40.
doi:10.1002/gps.930010209
69. Fuzikawa C, Lima-Costa MF, Uchoa E, Barreto SM, Shulman K; Bambuí
Health and Ageing Study. A population based study on the intra and inter-rater
reliability of the clock drawing test in Brazil: the Bambuí Health and Ageing
Study. Int J Geriatr Psychiatry. 2003;18(5):450-6. doi:10.1002/gps.863
70. Pfeffer RI, Kurosaki TT, Harrah CH Jr, Chance JM, Filos S. Measurement
of functional activities in older adults in the community. J Gerontol.
1982;37(3):323-9. doi:10.1093/geronj/37.3.323
71. Herrera E Jr, Caramelli P, Silveira AS, Nitrini R. Epidemiologic survey of
dementia in a community-dwelling Brazilian population. Alzheimer Dis Assoc
Disord. 2002;16(2):103-8. doi:10.1097/00002093-200204000-00007
72. Jorm AF, Jacomb PA. The Informant Questionnaire on Cognitive Decline
in the Elderly (IQCODE): socio-demographic correlates, reliability, validity
and some norms. Psychol Med. 1989;19(4):1015-22. doi:10.1017/
s0033291700005742
73. Sanchez MA, Lawrence RA. Informant Questionnaire on Cognitive
Decline in the Elderly (IQCODE): adaptação transcultural para uso
no Brasil. Cad Saude Publica. 2009; 25(7):1455-65. doi:10.1590/
S0102-311X2009000700003
74. Loewnstein DA, Bates CB. The Direct Assessment of Functional
Status-Revised (DAFS-R). Manual for administration and scoring. Miami:
Mount Sinai Medical Center; 2006.
75. Pereira FS, Oliveira AM, Diniz BS, Forlenza OV, Yassuda MS. Cross-cultural
adaptation, reliability and validity of the DAFS-R in a sample of Brazilian
older adults. Arch Clin Neuropsychol. 2010;25(4):335-43. doi:10.1093/
arclin/acq029
76. Gauthier L, Gélinas I, McIntyre M, Gauthier S, Laberge H, Dauphinee SW.
Disability Assessment for Dementia (DAD) user’s guide; 1994.
77. Bahia VS, Carthery-Goulart MT, Novelli MM, Kato-Narita EM,
Areza-Fegyveres R, Caramelli P, et al. Functional disability in Alzheimer
disease: a validation study of the Brazilian version of Disability Assessment
Schilling LP, et al.   Diagnostic Criteria for AD in Brazil.   33
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):21-35
for Dementia (DAD-Br). Alzheimer Dis Assoc Disord. 2010;24(3):291-5.
doi:10.1097/WAD.0b013e3181cfc878
78. Johnson N, Barion A, Rademaker A, Rehkemper G, Weintraub S.
The Activities of Daily Living Questionnaire: a validation study in patients
with dementia. Alzheimer Dis Assoc Disord. 2004;18(4):223-30.
79. Medeiros ME, RO Guerra. Translation, cultural adaptation and
psychometric analysis of the Activities of Daily Living Questionnaire (ADLQ)
for functional assessment of patients with Alzheimer’s disease. Braz J
Phys Ther. 2009;13(3):257-66. doi:10.1590/S1413-35552009005000027
80. Hindmarch I, Lehfeld H, Jongh P, Erzigkeit H. The Bayer Activities of Daily
Living Scale (B-ADL). Dement Geriatr Cogn Disord. 1998;9(Suppl 2):20-6.
doi:10.1159/000051195
81. Folquitto JC, Bustamante SEZ, Barros SB, Azevedo D, Lopes MA,
Hototian SR, et al. The Bayer: Activities of Daily Living Scale (B-ADL) in the
differentiation between mild to moderate dementia and normal aging. Braz J
Psychiatry . 2007;29(4):350-3. doi:10.1590/S1516-44462006005000037
82. Galvin JE, Roe CM, Powlishta KK, Coats MA, Muich SJ, Grant E, et al.
The AD8: a brief informant interview to detect dementia. Neurology.
2005;65(4):559-64. doi:10.1212/01.wnl.0000172958.95282.2a
83. Katz S, Ford AB, Moskowitz RW, Jackson BA, Jaffe MW. Studies of
illness in the aged. The index of ADL: a standardized measure of biological
and psychosocial function. JAMA. 1963;185:914-9. doi:10.1001/
jama.1963.03060120024016
84. Lino VTS, Pereira SRM, Camacho LAB, Ribeiro ST Filho, Buksman S.
Cross-cultural adaptation of the Independence in Activities of Daily Living
Index (Katz Index). Cad Saude Publica. 2008;24(1):103-12. doi:10.1590/
s0102-311x2008000100010
85. Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL. A new clinical
scale for the staging of dementia. Br J Psychiatry. 1982;140:566-72.
doi:10.1192/bjp.140.6.566
86. Chaves ML, Camozzato AL, Godinho C, Kochhann R, Schuh A,
Almeida VL, et al. Validity of the clinical dementia rating scale for the
detection and staging of dementia in Brazilian patients. Alzheimer Dis
Assoc Disord. 2007;21(3):210-7. doi:10.1097/WAD.0b013e31811ff2b4
87. O’Bryant SE, Waring SC, Cullum CM, Hall J, Lacritz L, Massman PJ, et al.
Staging dementia using Clinical Dementia Rating Scale Sum of Boxes
scores: a Texas Alzheimer’s research consortium study. Arch Neurol.
2008;65(8):1091-5. doi:10.1001/archneur.65.8.1091
88. Knopman DS, DeKosky ST, Cummings JL, Chui H, Corey-Bloom J,
Relkin N, et al. Practice parameter: diagnosis of dementia (an evidence-
based review). Report of the Quality Standards Subcommittee of the
American Academy of Neurology. Neurology. 2001;56(9):1143-53.
doi:10.1212/wnl.56.9.1143
89. Nitrini R, Caramelli P, Bottino CM, Damasceno BP, Brucki SM, Anghinah R, et al.
Diagnosis of Alzheimer’s disease in Brazil: cognitive and functional evaluation.
Recommendations of the Scientific Department of Cognitive Neurology
and Aging of the Brazilian Academy of Neurology. Arq Neuropsiquiatr.
2005;63(3A):720-7. doi:10.1590/s0004-282x2005000400034
90. van der Flier WM, Scheltens P. Epidemiology and risk factors of dementia.
J Neurol Neurosurg Psychiatry. 2005;76(Suppl 5):v2-7. doi:10.1136/
jnnp.2005.082867
91. Hort J, O’Brien JT, Gainotti G, Pirttila T, Popescu BO, Rektorova I,
et al. EFNS guidelines for the diagnosis and management of Alzheimer’s
disease. Eur J Neurol. 2010;17(10):1236-48. doi:10.1111/
j.1468-1331.2010.03040.x
92. Caramelli P, Teixeira AL, Buchpiguel CA, Lee HW, Livramento JA,
Fernandez LL, et al. Diagnosis of Alzheimer’s disease in Brazil:
supplementary exams. Dement Neuropsychol. 2011;5(3):167-77.
doi:10.1590/S1980-57642011DN05030004
93. Sintini I, Graff-Radford J, Senjem ML, Schwarz CG, Machulda MM, Martin PR,
et al. Longitudinal neuroimaging biomarkers differ across Alzheimer’s disease
phenotypes. Brain. 2020;143(7):2281-94. doi:10.1093/brain/awaa155
94. Barkhof F, Fox NC, Bastos-Leite AJ, Scheltens P. Neuroimaging in
dementia. Berlin: Springer; 2011.
95. Amato ACS Filho, Balthazar MLF. Neuroimagem nas demências: como
ela pode nos ajudar? In: Neurologia cognitiva e do envelhecimento:
do conhecimento básico à abordagem clínica. São Paulo: Omnifarma; 2016.
96. Wattjes MP, Henneman WJ, van der Flier WM, de Vries O,
Träber F, Geurts JJ, et al. Diagnostic imaging of patients in a memory
clinic: comparison of MR imaging and 64-detector row CT. Radiology.
2009;253(1):174-83. doi:10.1148/radiol.2531082262
97. Frisoni GB, Fox NC, Jack CR Jr, Scheltens P, Thompson PM.
The clinical use of structural MRI in Alzheimer’s disease. Nat Rev Neurol.
2010;6(2):67-77. doi:10.1038/nrneurol.2009.215
98. Leocadi M, Canu E, Calderaro D, Corbetta D, Filippi M, Agosta F.
An update on magnetic resonance imaging markers in AD. Ther Adv
Neurol Disord. 2020;13:1-17. doi:10.1177/1756286420947986
34   Diagnostic Criteria for AD in Brazil.   Schilling LP, et al.
99. Lombardi G, Crescioli G, Cavedo E, Lucenteforte E, Casazza G,
Bellatorre AG, et al. Structural magnetic resonance imaging for the early
diagnosis of dementia due to Alzheimer’s disease in people with mild
cognitive impairment. Cochrane Database Syst Rev. 2020;3(3):CD009628.
doi:10.1002/14651858.CD009628.pub2
100. Maul S, Giegling I, Rujescu D. Proton magnetic resonance spectroscopy
in common dementias – current status and perspectives. Front Psychiatry.
2020;11:769. doi:10.3389/fpsyt.2020.00769
101. Koedam EL, Lehmann M, van der Flier WM, Scheltens P, Pijnenburg YA,
Fox N, et al. Visual assessment of posterior atrophy development of
an MRI rating scale. Eur Radiol. 2011;21(12):2618-25. doi:10.1007/
s00330-011-2205-4
102. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L.
Association between CSF biomarkers and incipient Alzheimer’s disease in
patients with mild cognitive impairment: a follow-up study. Lancet Neurol.
2006;5(3):228-34. doi:10.1016/S1474-4422(06)70355-6
103. Diniz BS, Pinto JA Jr, Forlenza OV. Do CSF total tau, phosphorylated
tau, and beta-amyloid 42 help to predict progression of mild cognitive
impairment to Alzheimer’s disease? A systematic review and meta-
analysis of the literature. World J Biol Psychiatry. 2008;9(3):172-82.
doi:10.1080/15622970701535502
104. Forlenza OV, Radanovic M, Talib LL, Aprahamian I, Diniz BS, Zetterberg H,
et al. Cerebrospinal fluid biomarkers in Alzheimer’s disease: diagnostic
accuracy and prediction of dementia. Alzheimers Dement (Amst).
2015;1(4):455-63. doi:10.1016/j.dadm.2015.09.003
105. Dorey A, Perret-Liaudet A, Tholance Y, Fourier A, Quadrio I. Cerebrospinal
fluid Aβ40 improves the interpretation of Aβ42 concentration for diagnosing
Alzheimer’s disease. Front Neurol. 2015;6:247. doi:10.3389/fneur.2015.00247
106. Racine AM, Koscik RL, Nicholas CR, Clark LR, Okonkwo OC, Oh JM,
et al. Cerebrospinal fluid ratios with Aβ42 predict preclinical brain β-amyloid
accumulation. Alzheimers Dement (Amst). 2016;2:27-38. doi:10.1016/
j.dadm.2015.11.006
107. Hansson O, Lehmann S, Otto M, Zetterberg H, Lewczuk P. Advantages
and disadvantages of the use of the CSF Amyloid β (Aβ) 42/40 ratio in
the diagnosis of Alzheimer’s disease. Alzheimers Res Ther. 2019;11(1):34.
doi:10.1186/s13195-019-0485-0
108. Silverman DH, Small GW, Phelps ME. Clinical value of neuroimaging in the
diagnosis of dementia. Sensitivity and specificity of regional cerebral metabolic
and other parameters for early identification of Alzheimer’s disease. Clin Positron
Imaging. 1999;2(3):119-30. doi:10.1016/s1095-0397(99)00020-5
109. Silverman DH, Small GW, Chang CY, Lu CS, De Aburto MAK, Chen W,
et al. Positron emission tomography in evaluation of dementia: regional
brain metabolism and long-term outcome. JAMA. 2001;286(17):2120-7.
doi:10.1001/jama.286.17.2120
110. Mosconi L. Brain glucose metabolism in the early and specific diagnosis
of Alzheimer’s disease. FDG-PET studies in MCI and AD. Eur J Nucl Med
Mol Imaging. 2005;32(4):486-510. doi:10.1007/s00259-005-1762-7
111. Schöll M, Damián A, Engler H. Fluorodeoxyglucose PET in neurology and
psychiatry. PET Clin. 2014;9(4):371-90. doi:10.1016/j.cpet.2014.07.005
112. Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP,
et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh
Compound-B. Ann Neurol. 2004;55(3):306-19. doi:10.1002/ana.20009
113. Schilling LP, Zimmer ER, Shin M, Leuzy A, Pascoal TA, Benedet AL, et al.
Imaging Alzheimer’s disease pathophysiology with PET. Dement Neuropsychol.
2016;10(2):79-90. doi:10.1590/S1980-5764-2016DN1002003
114. Fleisher AS, Pontecorvo MJ, Devous MD, Lu M, Arora AK, Truocchio SP,
et al. Positron emission tomography imaging with [18F]flortaucipir and
postmortem assessment of Alzheimer disease neuropathologic changes.
JAMA Neurol. 2020;77(7):829-39. doi:10.1001/jamaneurol.2020.0528
115. Cho H, Choi JY, Hwang MS, Lee JH, Kim YJ, Lee HM, et al. Tau PET
in Alzheimer’s disease and mild cognitive impairment. Neurology.
2016;87(4):375-83. doi:10.1212/WNL.0000000000002892
116. Counts SE, Ikonomovic MD, Mercado N, Vega IE, Mufson EJ. Biomarkers
for the early detection and progression of Alzheimer’s disease.
Neurotherapeutics. 2017;14(1):35-53. doi:10.1007/s13311-016-0481-z
117. Matsuda H, Shigemoto Y, Sato N. Neuroimaging of Alzheimer’s disease:
focus on amyloid and tau PET. Jpn J Radiol. 2019;37(11):735-49.
doi:10.1007/s11604-019-00867-7
118. Ossenkoppele R, Schonhaut DR, Schöll M, Lockhart SN, Ayakta N,
Baker SL, et al. Tau PET patterns mirror clinical and neuroanatomical
variability in Alzheimer’s disease. Brain. 2016;139(5):1551-67. doi:10.1093/
brain/aww027
119. Cummings J, Lee G, Ritter A, Sabbagh M, Zhong K. Alzheimer’s
disease drug development pipeline: 2019. Alzheimers Dement (N Y).
2019;5(1):272-93. doi:10.1016/j.trci.2019.05.008
120. Jack CR, Jr, Bennett DA, Blennow K, Carrillo MC, Feldman HH, Frisoni GB,
et al. A/T/N: An unbiased descriptive classification scheme for Alzheimer
disease biomarkers. Neurology. 2016;87(5):539-47. doi:10.1212/
WNL.0000000000002923

121. Blennow K. A review of fluid biomarkers for Alzheimer’s disease: moving
from CSF to blood. Neurol Ther. 2017;6(Suppl 1):15-24. doi:10.1007/
s40120-017-0073-9
122. Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB,
et al. NIA-AA research framework: toward a biological definition of
Alzheimer’s disease. Alzheimers Dement. 2018;14(4):535-62. doi:10.1016/
j.jalz.2018.02.018
123. Hampel H, Frank R, Broich K, Teipel SJ, Katz RG, Hardy J, et al. Biomarkers
for Alzheimer’s disease: academic, industry and regulatory perspectives.
Nat Rev Drug Discov. 2010;9(7):560-74. doi:10.1038/nrd3115
124. Wang L, Benzinger TL, Su Y, Christensen J, Friedrichsen K, Aldea P,
et al. Evaluation of tau imaging in staging Alzheimer disease and revealing
interactions between β-Amyloid and tauopathy. JAMA Neurol.
2016;73(9):1070-7. doi:10.1001/jamaneurol.2016.2078
125. Price JL, McKeel DW Jr, Buckles VD, Roe CM, Xiong C, Grundman M,
et al. Neuropathology of nondemented aging: presumptive evidence for
preclinical Alzheimer’s disease. Neurobiol Aging. 2009;30(7):1026-36.
doi:10.1016/j.neurobiolaging.2009.04.002
126. Josefsson M, Luna X, Pudas S, Nilsson LG, Nyberg L. Genetic and lifestyle
predictors of 15-year longitudinal change in episodic memory. J Am Geriatr
Soc. 2012;60(12):2308-12. doi:10.1111/jgs.12000
127. Bateman RJ, Xiong C, Benzinger TLS, Fagan AM, Goate A, Fox NC, et al.
Clinical and biomarker changes in dominantly inherited Alzheimer’s disease.
N Engl J Med. 2012;367(9):795-804. doi:10.1056/NEJMoa1202753
128. Mormino EC, Sperling RA, Holmes AJ, Buckner RL, De Jager PL,
Smoller JW, et al. Polygenic risk of Alzheimer’s disease is associated with
early- and late-life processes. Neurology. 2016;87(5):481-8. doi:10.1212/
WNL.0000000000002922
129. Jack CR Jr, Albert MS, Knopman DS, McKhann GM, Sperling RA,
Carrillo MC, et al. Introduction to the recommendations from the National
Institute on Aging-Alzheimer’s Association workgroups on diagnostic
guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):257-62.
doi:10.1016/j.jalz.2011.03.004
130. Jessen F, Amariglio RE, van Boxtel M, Breteler M, Ceccaldi M, Chételat G,
et al. A conceptual framework for research on subjective cognitive decline
Dement Neuropsychol 2022 September;16(3 Suppl. 1):21-35
in preclinical Alzheimer’s disease. Alzheimers Dement. 2014;10(6):844-52.
doi:10.1016/j.jalz.2014.01.001
131. Bondi MW, Edmonds EC, Salmon DP. Alzheimer’s disease: past, present,
and future. J Int Neuropsychol Soc. 2017;23(9-10):818-31. doi:10.1017/
S135561771700100X
132. Henriksen K, O’Bryant SE, Hampel H, Trojanowski JQ, Montine TJ,
Jeromin A, et al. The future of blood-based biomarkers for Alzheimer’s disease.
Alzheimers Dement. 2014;10(1):115-31. doi:10.1016/j.jalz.2013.01.013
133. Bateman RJ, Blennow K, Doody R, Hendrix S, Lovestone S, Salloway S,
et al. Plasma biomarkers of AD emerging as essential tools for drug
development: an EU/US CTAD task force report. J Prev Alzheimers Dis.
2019;6(3):169-73. doi:10.14283/jpad.2019.21
134. Ovod V, Ramsey KN, Mawuenyega KG, Bollinger JG, Hicks T, Schneider T,
et al. Amyloid β concentrations and stable isotope labeling kinetics of
human plasma specific to central nervous system amyloidosis. Alzheimers
Dement. 2017;13(8):841-9. doi:10.1016/j.jalz.2017.06.2266
135. Zetterberg H, Wilson D, Andreasson U, Minthon L, Blennow K, Randall J,
et al. Plasma tau levels in Alzheimer’s disease. Alzheimers Res Ther.
2013;5(2):9. doi:10.1186/alzrt163
136. Mattsson N, Andreasson U, Zetterberg H, Blennow K, Alzheimer’s Disease
Neuroimaging Initiative. Association of plasma neurofilament light with
neurodegeneration in patients with Alzheimer disease. JAMA Neurol.
2017;74(5):557-66. doi:10.1001/jamaneurol.2016.6117
137. Zhao Y, Xin Y, Meng S, He Z, Hu W. Neurofilament light chain protein
in neurodegenerative dementia: a systematic review and network
meta-analysis. Neurosci Biobehav Rev. 2019;102:123-38. doi:10.1016/
j.neubiorev.2019.04.014
138. Siedlecki-Wullich D, Català-Solsona J, Fábregas C, Hernández I,
Clarimon J, Lleó A, et al. Altered microRNAs related to synaptic function
as potential plasma biomarkers for Alzheimer’s disease. Alzheimers Res
Ther. 2019;11(1):46. doi:10.1186/s13195-019-0501-4
139. Bram JMF, Talib LL, Joaquim HPG, Sarno TA, Gattaz WF, Forlenza OV.
Protein levels of ADAM10, BACE1, and PSEN1 in platelets and leukocytes
of Alzheimer’s disease patients. Eur Arch Psychiatry Clin Neurosci.
2019;269(8):963-72. doi:10.1007/s00406-018-0905-3
Schilling LP, et al.   Diagnostic Criteria for AD in Brazil.   35
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):36-48 Consensus
https://doi.org/10.1590/1980-5764-DN-2022-S103EN

Diagnosis of frontotemporal dementia:

recommendations of the Scientific Department
of Cognitive Neurology and Aging of the
Brazilian Academy of Neurology
Leonardo Cruz de Souza1,2 , Mirna Lie Hosogi3 , Thais Helena Machado2,4 ,
Maria Teresa Carthery-Goulart3,5 , Mônica Sanches Yassuda3,6 , Jerusa Smid3 ,
Breno José Alencar Pires Barbosa3,7,8 , Lucas Porcello Schilling9,10,11 ,
Marcio Luiz Figueredo Balthazar12 , Norberto Anízio Ferreira Frota13,14 ,
Francisco Assis Carvalho Vale15 , Paulo Caramelli1,2 , Paulo Henrique Ferreira Bertolucci16 ,
Márcia Lorena Fagundes Chaves17,18 , Sonia Maria Dozzi Brucki3 , Ricardo Nitrini3 ,
Valéria Santoro Bahia19 , Leonel Tadao Takada3

Universidade Federal de Minas Gerais, Departamento de Clínica Médica, Belo Horizonte MG, Brazil.
1

2
Universidade Federal de Minas Gerais, Faculdade de Medicina, Departamento de Clínica Médica, Grupo de Pesquisa em Neurologia Cognitiva e do Comportamento,
Belo Horizonte MG, Brazil.
Universidade de São Paulo, Faculdade de Medicina, Departamento de Neurologia, Grupo de Neurologia Cognitiva e do Comportamento, São Paulo SP, Brazil.
3

Universidade Federal de Minas Gerais, Faculdade de Medicina, Departamento de Fonoaudiologia, Belo Horizonte MG, Brazil.
4

5
Universidade Federal do ABC, Grupo de Estudos em Neurociência da Linguagem e Cognição, Programa de Pós-Graduação em Neurociência e Cognição,
Centro de Matemática, Computação e Cognição, Santo André SP, Brazil.
Universidade de São Paulo, Gerontologia, Ciências e Humanidades, Escola de Artes, São Paulo SP, Brazil.
6

Universidade Federal de Pernambuco, Centro de Ciências Médicas, Área Acadêmica de Neuropsiquiatria, Recife PE, Brazil.
7

Instituto de Medicina Integral Prof. Fernando Figueira, Recife PE, Brazil.

8

Pontifícia Universidade do Rio Grande do Sul, Escola de Medicina, Serviço de Neurologia, Porto Alegre RS, Brazil.
9

10
Pontifícia Universidade do Rio Grande do Sul, Instituto do Cérebro do Rio Grande do Sul, Porto Alegre RS, Brazil.
11
Pontifícia Universidade do Rio Grande do Sul, Programa de Pós-Graduação em Gerontologia Biomédica, Porto Alegre RS, Brazil.
12
Universidade Estadual de Campinas, Faculdade de Ciências Médicas, Departamento de Neurologia, Campinas SP, Brazil.
13
Hospital Geral de Fortaleza, Serviço de Neurologia, Fortaleza CE, Brazil.
14
Universidade de Fortaleza, Fortaleza CE, Brazil.
15
Universidade Federal de São Carlos, Centro de Ciências Biológicas e da Saúde, Departamento de Medicina, São Carlos SP, Brazil.
16
Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Neurologia e Neurocirurgia, São Paulo SP, Brazil.
17
Hospital de Clínicas de Porto Alegre, Serviço de Neurologia, Porto Alegre RS, Brazil.
18
Universidade Federal do Rio Grande do Sul, Faculdade de Medicina, Departamento de Medicina Interna, Porto Alegre RS, Brazil.
19
Universidade Cidade de São Paulo, São Paulo SP, Brazil.
Correspondence: Leonardo Cruz de Souza; Email: leocruzsouza@ufmg.br.
Conflict of interest: LCS: Participation in advisory board for Biogen. Participation as speaker in symposia sponsored by Biogen; JS: Participation as speaker in symposia
sponsored by Roche laboratory; LPS: Participation in advisory boards for Biogen. Participation as speaker in symposia sponsored by Aché, Apsen and Biogen laboratories;
MLFB: Participation in advisory boards for Biogen. Development of material for continuous medical education and participation as speaker in symposia sponsored by EMS
and Torrent laboratories; PC: Participation as principal investigator in clinical trials for Novo Nordisk and Roche laboratories. Participation in advisory boards for Aché, Biogen,
EMS, Nutricia and Roche laboratories. Development of material for continuous medical education and participation as speaker in symposia sponsored by Aché, Nutricia,
Libbs, Roche, Sandoz, Torrent and Zodiac laboratories; PHFB: Participation in advisory boards for Biogen and Novo Nordisk laboratories. Supervision of training activities for
Biogen, Janssen-Cilag and Novo Nordisk laboratories and for Quintiles. Participation as speaker in symposia sponsored by Apsen, Nutricia, Roche and Sandoz laboratories;
RN: Participation in advisory board for Biogen; MLH, THM, MTCG, MSY, BJAPB, NAFF, FACV, MLFC, SMDB, VSB, LTT: There is no conflict of interest to declare.
Received on August 10, 2021; Received in its final form on December 08, 2021; Accepted on April 27, 2022.

36   Diagnosis of frontotemporal dementia.   de Souza LC, et al.

 Dement Neuropsychol 2022 September;16(3 Suppl. 1):36-48

ABSTRACT. “Frontotemporal dementia” (FTD) is a clinical syndrome characterized by the focal involvement of the frontal and/or temporal lobes. FTD has
three clinical phenotypes: the behavioral variant and two linguistic subtypes, namely, non-fluent/agrammatic primary progressive aphasia (PPA-NF/A) and
semantic PPA (PPA-S). FTD is the second most common cause of dementia in individuals under the age of 65 years. This article presents recommendations
for the diagnosis of FTD in the Brazilian scenario, considering the three levels of complexity of the health system: primary health care, secondary and
tertiary levels. Diagnostic guidelines are proposed, including cognitive testing, behavioral and language assessments, laboratory tests, and neuroimaging.
Keywords: Frontotemporal Dementia; Aphasia, Primary Progressive.

DIAGNÓSTICO DA DEMÊNCIA FRONTOTEMPORAL: RECOMENDAÇÕES DO DEPARTAMENTO CIENTÍFICO DE NEUROLOGIA COGNITIVA E DO ENVELHECIMENTO

DA ACADEMIA BRASILEIRA DE NEUROLOGIA
RESUMO. A “demência frontotemporal” (DFT) é uma síndrome clínica, cujo denominador comum é o acometimento focal dos lobos frontais e/ou temporais.
A DFT tem três fenótipos clínicos distintos: a variante comportamental e dois subtipos linguísticos, a saber, a afasia progressiva primária não-fluente/
agramática (APP-NF/A) e a afasia progressiva primária semântica (APP-S). A DFT é a segunda causa mais comum de demência em indivíduos com idade
inferior a 65 anos, após a doença de Alzheimer. O presente artigo apresenta recomendações para diagnóstico da DFT no cenário brasileiro, considerando
os três níveis de complexidade do sistema de saúde: atenção primária à saúde e níveis secundários. São propostos protocolos de investigação diagnóstica
abrangendo testagem cognitiva, avaliação comportamental, avaliação fonoaudiológica, exames laboratoriais e de neuroimagem.
Palavras-chave: Demência Frontotemporal; Afasia Progressiva Primária.

INTRODUCTION Such indices make FTD the second most common

“F rontotemporal dementia” (FTD) is defined as

a clinical syndrome whose common denominator
is the focal involvement of the frontal and/or temporal
lobes. FTD has three distinct clinical phenotypes:
the behavioral variant, and two linguistic subtypes,
namely, non-fluent/agrammatic primary progressive
aphasia (PPA-NF/A) and semantic PPA (PPA-S). Recently,
the existence of a fourth subtype, the so-called right
temporal variant, has been considered. The behavioral
variant (bvFTD) is the most common phenotypic
presentation of FTD.
In turn, “frontotemporal lobar degeneration (FTLD)”
refers to the histopathological substrate of FTD.
The types FTLD-Tau and FTLD-“transactive response
DNA-binding protein with Mr 43 kDa” (TDP-43) are
the most common ones 1. Other subtypes, such as
FET family proteins, FUS (fused in sarcoma) and EWS
(Ewing’s sarcoma protein), are less frequent.
Thus, “FTD” should be used for clinical descriptions
and phenotypes, whereas “FTLD” should be used
to describe the histopathological classification and
not to refer to the clinical syndrome2.
International studies indicate that the prevalence
and incidence of FTD compose 15-22 cases/100,000
and 1.2-4.1 cases/100,000 population, respectively,
being higher in the 45-64 age group 3,4. There are
no epidemiological studies that have specifically
investigated the prevalence of F TD in Brazil,
but epidemiological sur veys on dementias
indicate a prevalence of 0.18% among individuals
over 65 years old3.
cause of presenile dementia, after Alzheimer’s
disease (AD). Indeed, the majority of FTD cases are of
young onset, but it is now recognized that up to 30%
of cases start after 65 years old2.
This article presents recommendations for the
diagnosis of FTD in the Brazilian scenario, considering
the three complexity levels of the health system: primary
health care, secondary and tertiary levels. Diagnostic
guidelines are proposed, covering cognitive testing,
behavioral and language assessments, laboratory tests,
and neuroimaging. The right temporal variant, whose
clinical definition is still in debate5 and is not part of
the latest diagnostic consensus6,7, is not addressed
in this article.
DIAGNOSIS
The diagnostic criteria for FTD, both for the behavioral6
and the language variants 7 , were established
by international expert consensus.
The diagnosis of bvFTD is based on the identification
of progressive cognitive-behavioral decline6. The current
criteria determine three levels of diagnostic reliability
(Table 1): (I) possible diagnosis, for patients presenting
characteristic cognitive-behavioral alterations, but have
neither typical neuroimaging alterations nor manifest
functional decline; (II) probable diagnosis, for patients
who, in addition to characteristic cognitive-behavioral
manifestations, have impaired autonomy and evidence
of frontotemporal involvement on structural or
functional neuroimaging; and (III) definitive diagnosis,
when histopathological changes are observed on brain

de Souza LC, et al.   Diagnosis of frontotemporal dementia.   37

 Dement Neuropsychol 2022 September;16(3 Suppl. 1):36-48
biopsy or on post-mortem examination, or patients with
evidence of pathogenic mutation.
According to the same consensus6, for possible
or probable diagnosis, the patient must meet at least
three of the following criteria: (I) early disinhibition;
(II) apathy or early inertia; (III) early loss of empathy/
sympathy; (IV) perseverative, stereotyped, or early
compulsive/ritualistic behavior; (V) hyperorality and
dietary changes; and (VI) neuropsychological profile
with executive dysfunction and relative preservation
of episodic memor y and visuospatial abilities.
The symptom is early if it occurs within the first three
years after the onset of symptoms.
Table 1. Diagnostic Criteria for Frontotemporal Dementia
(behavioral variant) – adapted from Rascovsky et al. (2011).
Frontotemporal dementia: behavioral variant
Progressive deterioration in behavior and/or cognition, evidenced
by observation or clinical history (requires an informant).
Possible diagnosis
Must meet at least 3 of the 6 criteria listed below:
(I) behavioral disinhibition (socially inappropriate behavior;
impulsiveness; loss of social rules or decorum);
(II) apathy or inertia;
(III) loss of empathy/sympathy (decreased affective resonance
to the needs and feelings of others; diminished social interest,
reduced interpersonal “heat”);
(IV) perseverative, stereotyped, or compulsive/ritualistic behaviors;
(V) hyperorality and dietary changes (alteration of food
preference, increased consumption of alcohol or cigarettes,
oral exploration of objects);
(VI) neuropsychological profile with executive deficits and relative
preservation of episodic memory and visuospatial functions.
Probable diagnosis
Must meet criteria for possible FTD and have:
(I) Significant functional decline, demonstrated
in specific inventories; and
(II) Evidence of typical FTD alterations on neuroimaging
examination (atrophy or hypometabolism or hypoperfusion
in frontotemporal regions).
Definite diagnosis
Must meet criteria for possible or probable FTD and have:
(I) Pathological confirmation of frontotemporal lobe degeneration; or
(II) Evidence of causative genetic mutation.
PPA, in turn, is a clinical syndrome characterized
by a language disorder of insidious onset and
progressive course, which affects the functioning
38   Diagnosis of frontotemporal dementia.   de Souza LC, et al.
of the language network in the language-dominant
temporal and frontal lobes7,8. In most cases, there is
predominant involvement of the left hemisphere,
with rare exceptions (crossed aphasia and/or conditions
that start with neurodegeneration on the right
hemisphere and with initial symptoms of prosopagnosia
and/or visual agnosia)9. Language disorders involve one
or more levels of linguistic processing (phonological,
semantic, syntactic) and are associated with cognitive
(i.e., speech apraxia) and/or motor (dysarthria)
speech alterations. In addition, language impairment
impacts communication skills; thus, functional
deficits vary depending on the language demands
related to professional occupation and daily activities,
and to the cognitive resources and strategies that
patients use to compensate for the deficits, as well.
Environmental factors can also mitigate or enhance
the functional impairment10.
Gorno-Tempini et al. (2011) suggested unifying the
nomenclature and defined criteria for the syndromic
diagnosis of PPA and its three main variants,
in terms of clinical manifestations, neuroanatomical
and neuropatholo g ical cor relates. PPA -NF/A
(non-fluent/agrammatic) and PPA-S (semantic) are
part of the clinical syndrome of FTD. On the contrary,
the logopenic subtype of PPA (PPA-L) is considered
an atypical presentation of AD. It should be noted,
however, that about 1/3 of the patients have mixed
conditions or do not fit the criteria for these variants11,12.
Thus, although the diagnosis of PPA can be accurately
distinguished from bvFTD and/or other dementia
conditions, classification into variants requires speech
and language examination by experts. In the present
consensus, we have chosen the terms PPA-S, PPA-NF/A
and PPA-L. Other terminologies are also used, including:
“semantic variant of PPA,” “non-fluent variant of PPA,”
and “logopenic variant of PPA.”
According to Gorno-Tempini et al. (2011) 7 ,
the clinical diagnosis of PPA requires fulfilling three
criteria: (1) the most prominent clinical feature is
language difficulty; (2) language difficulties are the
main cause of functional impairment (difficulty
in communication); and (3) aphasia must be the
most prominent deficit at the beginning of the
condition. Furthermore, the pattern of deficits must
not be explained by another neurological or psychiatric
disorder, and patients must not initially present
significant behavioral disturbances or other cognitive
impairments. However, deficits in other cognitive
functions appear in the neuropsychological assessment,
especially in cognitive skills that share neuroanatomical
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):36-48

correlates with the language network (such as verbal
immediate memory; numerical and calculation skills;
ideomotor praxis). However, these deficits should be
milder compared to the language deficit. In addition
to the clinical level, the consensus predicts two other
diagnostic levels: one supported by neuroimaging exams
and another supported by histopathological findings.
Next, we propose ways to carry out the diagnostic
investigation of FTD (all subtypes) at different levels
of health care (Figures 1 and 2).

Behavioral or Language Disorder

General practioner
Primary care:

Clinical Interview
Mini-Mental State Exam
Laboratory screening

Brain CT

Detailed Clinical Interview

Brief Cognitive Battery or
Addenbrooke Cognitive Assessment
Specialist (neurologist)

Frontal Assessment Battery or INECO Frontal Screening

Secondary care:

Neuropsychiatric Inventory

Brain MRI If normal

Psychiatric consultation
Lumbar puncture if age < 65 years-old

Behavioral Disorder Language Disorder

Expand cognitive assessment Language Assessment
(RAVLT; Rey Complex Figure; Hayling Test; Mini-SEA; FRS) with Speech therapist
Multidisciplinary team
Tertiary care:

Consider:
FDG-PET
Genetic Investigation
Biomarkers for Alzheimer’s disease

Figure 1. Diagnostic procedures for frontotemporal dementia

de Souza LC, et al.   Diagnosis of frontotemporal dementia.   39

 Dement Neuropsychol 2022 September;16(3 Suppl. 1):36-48

PRIMARY HEALTH CARE: SUSPICION OF PPA

Patient with language or speech complaint Patient with memory complaint

(with no functional decline).
Examples: word-finding difficulties, effortful
speech, comprehension disorders
(oral or written language). Complaint of memory Other memory Complaint about
for words complaints memory, language or
other cognitive domain
with functional decline.
Sudden onset Insidious onset Slowly progressive disorder SUSPICION OF PPA

Laboratory screening CT scan

SECUNDARY LEVEL: SYNDROMIC CONFIRMATION

CONFIRMATION OF THE
Neurological evaluation HYPOTHESIS OF PPA
DIAGNOSIS OF PPA

TERTIARY LEVEL: CLASSIFICATION OF PPA

Investigation:
Avaliação Especializada: Neurological follow up
– Biomarkers
– Speech therapy Pharmacological treatment
– Genetics
– Neuropsychology Non-pharmacological treatment
– Functional neuroimaging

Figure 2. Procedures for the diagnosis of Primary Progressive Aphasia

Primary health care
Clinical assessment (bvFTD and PPA)
In primary health care, the patient will be initially
evaluated by a general practitioner, who must carry out
a careful anamnesis in order to identify a condition of
cognitive-behavioral decline or progressive language
disorder and then refer the patient to the appropriate
workup. Therefore, it is important to describe how
symptoms appear. Due to its degenerative nature,
the onset of FTD symptoms is usually insidious and
progressive, unlike vascular conditions, in which the
“stepwise deterioration” of symptoms is more common.
Considering the clinical suspicion of cognitive-
behavioral decline, the physician must actively inquire
about psychiatric (past admission to psychiatric
institutions) and infectious (syphilis, HIV) antecedents
and about the use of psychotropic drugs that may
interfere with cognitive-behavioral functioning.
Mood symptoms and maniform manifestations should
also be always investigated, as they may indicate
a psychiatric cause for the patient’s clinical condition.
On physical examination, the physician should perform
a brief neurological examination, looking for focal deficits
that suggest stroke or expansive intracranial lesions.
Regarding progressive language disorders, patients
and family members seek medical care due to complaints
of memory or specific language and/or speech problems
(Figure 2). When faced with the memory complaint,
it is important to differentiate which memory problem
the patient and family refer to. Often, patients having
difficulty finding words and forgetting the names of
people and objects (essentially linguistic alterations)
report that they have memory failures, but these are
not episodic memory alterations (common in AD),
but rather word memory (lexical access difficulties and
anomie), suggesting language impairment. In some
cases, it is possible that the memory complaint is related
to the gradual loss of knowledge of the meaning of
words and concepts (for example: having doubts about
what the words mean, which is a symptom of impaired
verbal semantic memory).
Initial language complaints may be diverse. The most
frequent are lexical access difficulties and anomia.
However, there are also reports of exchange of words,
exchange of phonemes, stuttering, slowing down

40   Diagnosis of frontotemporal dementia.   de Souza LC, et al.


of speech production, language comprehension
difficulties, failures in reading or writing and so forth.
It is important to investigate whether the patient and/or
informant (e.g., family member) notices an insidious
worsening of language in relation to premorbid
performance. There is great heterogeneity of language
in the population, depending on education, reading and
writing habits, and occupation. It may be tough to detect
difficulties in individuals who, throughout life, had poor
language skills (for example, writing errors, low reading
fluency, impoverished vocabulary). Therefore, in some
cases, it may be necessary to conduct a longitudinal
follow-up to identify the progression of the condition.
Clinical history is fundamental for the diagnosis of PPA.
Speech-language disorders, in the initial phase, do not
significantly impact functional activities, and some
patients even keep their work activities.
Cognitive and behavioral assessments
The assessment of cognitive performance represents an
important component of the diagnostic procedures of
FTD. Cognitive changes in bvFTD can be heterogeneous,
but the diagnostic criteria of Rascovsky et al. (2011)
suggest that the neuropsychological profile should
include executive dysfunction, relative preservation
of episodic memory and of visuospatial functions.
However, in the early stages of the disease, especially
among people with a high level of education, executive
dysfunction may not be evident 13 . Additionally,
other diseases (including AD) can lead to executive
dysfunction 14. Another challenging factor is that
patients with bvFTD can also present episodic memory
deficit, in a pattern similar to that observed in AD15,16.
Even so, documenting the cognitive profile suggested
in the international criteria 6 is important for the
diagnosis of bvFTD. According to this perspective,
identifying a reduction in global cognitive efficiency
and executive dysfunction of magnitude greater than
episodic memory deficits may suggest bvFTD.
In primary care, complaints from patients and their
families suggesting the presence of cognitive deficits
should be carefully analyzed, especially those indicating
difficulties in planning and organizing activities.
The Mini-Mental State Examination (MMSE)17,18 should
be applied for the global assessment of cognition,
and the score should be interpreted in relation to the
individual’s educational level. Patients with bvFTD
are likely to lose points in mental calculation and
the command sub-items (due to attention deficit);
orientation in time and space are usually preserved19,
as the drawing. Impairment in the MMSE may suggest
Dement Neuropsychol 2022 September;16(3 Suppl. 1):36-48
the presence of dementia, which should be confirmed
in further evaluations in secondary care.
Social cognition involves processing information
that is relevant to social interaction. In bvFTD, social
cognition may be altered, as the patient may fail
to understand what others are thinking or feeling.
The clinician should ask the caregiver whether the
patient understands the problems and concerns of
those around them (cognitive empathy) and whether
they care, suffer, or rejoice in what happens to
others (emotional empathy). Questions can be asked
about their ability to socialize and changes in their
moral rules. From this perspective, primary care
physicians should inquire caregivers and observe
patients regarding typical behavioral changes of FTD,
in addition to other neuropsychiatric manifestations,
such as delusions and hallucinations, which may
suggest primary psychiatric disorders.
The performance of patients with PPA on the MMSE
will depend on the intensity of the aphasia, as it is
a test that is highly dependent on language. MMSE
results may overestimate cognitive decline, as cognitive
functions such as temporal orientation and memory are
assessed by language. On the other hand, the language
deficit can be underestimated, since the MMSE linguistic
tasks have low complexity to assess the production and
comprehension of words and sentences. Thus, initial
cases of PPA can obtain scores within the expected
range for their schooling.
Laboratory investigation
Metabolic and/or infectious disorders (renal or liver
failure, hypothyroidism, neurosyphilis and HIV
infection, and so on) that cause neuropsychiatric
manifestations can be ruled out through blood tests.
Thus, all suspected cases of FTD (regardless of the
phenotypic presentation) should undergo laboratory
investigation to screen for reversible causes of cognitive-
behavioral decline 20 : blood count, vitamin B12,
folic acid, liver, kidney and thyroid functions, protein
electrophoresis, and anti-HIV serology.
Neuroimaging investigation
In primary health care, CT scan can be a useful procedure
as an initial propaedeutic. This exam evaluates the
presence of frontotemporal lesions (e.g., tumors,
hematomas), ventricular dilatation or cerebrovascular
lesions that are associated with behavioral symptoms.
Computed tomography in bvFTD usually shows
asymmetric increase in sulci and fissures in the frontal
and/or temporal lobes. These findings, however,
can only be observed when the disease is at a more
de Souza LC, et al.   Diagnosis of frontotemporal dementia.   41
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):36-48
advanced stage. In the linguistic variants, frontoinsular
atrophy in the dominant hemisphere can be observed,
in the case of the PPA-NF/A variant, and atrophy
of temporal poles, in the case of the PPA-S.
Secondary level
Clinical assessment
At the secondary level, the patient will be evaluated
by a neurologist, who must carry out a thorough
neurological examination, preceded by a detailed
anamnesis, which aims to recapitulate the main
elements of clinical and family history. The neurologist
should actively look for signs of parkinsonian
syndrome, in addition to changes in oculomotricity
(conjoined down-gaze palsy), which may evoke
progressive supranuclear palsy. Similarly, signs
of asymmetric muscle atrophy, fasciculations and
pyramidal signs (Babinski and Hofmann signs) should
be looked for to identify signs of motor neuron disease.
The neurologist should also look for the presence
of primitive signs (grasping, glabellar, snouting)
that suggest severe frontal involvement.
Cognitive and behavioral assessments
At this level of care, the assessment of cognition must
be comprehensive and evaluate the main cognitive
domains. The application of the Brief Cognitive
Screening Batter y (BBRC) is recommended 21,22 .
The BBRC includes the Figure Memory Test, which
requires naming and recalling ten figures to assess
episodic memory. In this battery, executive functions
are investigated with the Animal Verbal Fluency Test
and the Clock Drawing Test, which are followed by the
delayed recall of the ten figures previously presented
(after 5 minutes). Special attention should be paid to
the delayed recall (cut-off score ≤ 5 pictures), as it is
a marker of episodic memory impairment. The BBRC
can be used in populations with different educational
backgrounds23. Slowness in naming, lack of responses
and/or phonological/semantic errors may indicate
difficulties in understanding or expressing the language.
Episodic memory is preserved in the early stages of PPA.
Patients usually perform well in the recognition task,
as it does not require oral recall.
The Addenbrooke Cognitive Examination –
Revised (ACE-R)24,25 is also an excellent tool for the
global assessment of cognition. The ACE-R includes
the MMSE. Additionally, it provides individualized
scores for attention and orientation, episodic
memory, verbal fluency, language, and visual-spatial
skills. The scores for the verbal fluency and language
42   Diagnosis of frontotemporal dementia.   de Souza LC, et al.
domains can be especially relevant for the diagnosis
of bvFTD and PPA, respectively.
The Frontal Assessment Battery (FAB)26,27 and the
INECO Frontal Screening (IFS)28 can identify executive
dysfunction and help detect patients with bvFTD.
However, these instruments may fail in the differential
diagnosis of dementia subtypes29.
Regarding social cognition, the physician should ask
the caregiver if the patient understands the problems
and concerns of the people around them (cognitive
empathy) and if they care, suffer, or are happy with what
happens to others (emotional empathy). Questions
about their social skills and changes in their moral
rules can also be asked.
The short version of the Neuropsychiatric Inventory
(NPI)30,31, the NPI-Q32, can be used in the investigation
of neuropsychiatric symptoms. The NPI-Q can detect
the behavioral symptoms of bvFTD. The NPI-Q has been
validated for the Brazilian population33. The Frontal
Behavioral Inventory can also be used34.
Laboratory investigation
At the secondary level, the physician must review
all laboratory tests to screen for reversible causes
of dementia. For pre-senile patients, it may be necessary
to include tests of autoimmune diseases, such as
vasculitis and systemic lupus erythematosus, depending
on the patient’s clinical context.
For patients suffering from the condition
before turning 65 years old, or for those with a
rapidly progressive decline, lumbar puncture is
mandatory, to rule out inflammatory and/or infectious
causes of dementia.
Neuroimaging investigation
In secondary care, magnetic resonance imaging (MRI) of
the brain should be performed. On MR images, an increase
in sulci and fissures can be observed, with frontotemporal
predominance (Figure 3). bvFTD is characterized by early
atrophy of frontotemporal regions, affecting the anterior
cingulate and orbitofrontal cortex35,36. Hippocampus
may be atrophied in bvFTD to a similar degree to that
seen in AD37. Some atrophic patterns may suggest
FTD associated with genetic mutations: pronounced
bitemporal atrophy occurs in patients with a MAPT
mutation; markedly asymmetric frontotemporal atrophy is
common in patients with a progranulin (GRN) mutation38.
Extensive white matter lesions can also occur in patients
with progranulin mutation39. As disease progresses,
atrophy gets more pronounced in the frontotemporal
lobes, with relative preservation of the posterior regions.
In PPA-NF/A, atrophy of the inferior frontal gyrus

of the dominant hemisphere is detected, whereas in
PPA-S there is typically focal atrophy of the temporal pole,
uni- or bilaterally.
Figure 3. A. Focal atrophy of frontotemporal regions in the behavioral variant of Frontotemporal Dementia; B. Atrophy of the inferior frontal gyrus of the dominant
hemisphere in primary non-fluent/agrammatic progressive aphasia (PPA-NF/A); C. Focal temporal pole atrophy in semantic primary progressive aphasia (PPA-S).
Tertiary level
Clinical Evaluation
At the tertiary level of health care, the patient will be
assisted by a multidisciplinary team. The recommended
clinical assessment consists of anamnesis, clarifying
previously obscure points and confirming previous data.
The clinical-neurological examination must follow the
guidelines described for the secondary health level.
Cognitive and behavioral assessments
Behavioral variant (bvFTD)
At this level of care, it may be useful for diagnostic
purposes to characterize the patient’s neuropsychological
profile, with specific and detailed parameters for each
domain of cognition. Qualitative observation of the
patient’s behavior during the assessment may be especially
relevant. The presence of unusual behaviors and strategies
during testing, such as impulsiveness, behavioral rigidity,
ritualized or obsessive behaviors, and repetitive speech,
can support the diagnosis of bvFTD40.
Next, we suggest instruments composing a minimal
neuropsychological battery. This proposal can be expanded,
according to available time and expert facilities:
• Verbal episodic memory – Rey Auditory-Verbal
Learning Test41. Scores within the expected range
for age and education, or minor impairment,
may be compatible with a diagnosis of bvFTD;
• Visual episodic memory – Rey Complex Figure42,
which requires the individual to copy a complex
Dement Neuropsychol 2022 September;16(3 Suppl. 1):36-48
MRI also allows the identification of hypersignal on
T2-weighted and FLAIR sequences, which could suggest
vascular dementia or leukoencephalopathy.
geometric figure, which is later drawn using
visual memory. The copy is used to assess visual-
constructive skills and the subsequent recall of
the figure is a measure of visual episodic memory;
• Attention and Executive Functions – Trail
Making Test A and B assess visual attention and
shifting, respectively; Wechsler Adult Intelligence
Scale (WAIS-III) Forward and Backward Digit
Span Test assess auditory attention and working
memory, respectively; Wisconsin Card Sorting
Test assesses working memory and mental
flexibility. These cognitive parameters may be
especially important to characterize executive
dysfunction, which is part of the formal criteria
of bvFTD6. However, they may not discriminate
between types of dementia43;
• Inhibitory Control – The Hayling Test assesses
the individual’s ability to complete sentences
with words that make sense or with words
that prevent the logical sense of the sentence.
The test could help differentiate bvFTD from
other dementias such as AD, but results are
inconclusive44. Likewise, the Stroop test may
not be discriminative43;
• Processing Speed – WAIS-III Digit Symbol
Substitution test assesses visual attention and
processing speed, which, if altered, can affect
performance in other domains of cognition45;
• Visuospatial Functions – Rey Complex Figure.
The copy of the figure can be used as a parameter
to assess planning and visuoconstructive skills;
de Souza LC, et al.   Diagnosis of frontotemporal dementia.   43
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):36-48
WAIS-III Block Design also assesses visual-
constr uctive skills and is a timed task ;
the Visual Object and Space Perception (VOSP)
test can be used to assess visual-perceptual
abilities46. According to current criteria, patients
with bvFTD have unimpaired visuospatial
capabilities6. For example, in the Rey Complex
Figure test, patients with bvFTD tend to perform
well, and errors are usually related to failures in
organization and planning, while patients with
AD commit visuospatial errors43;
• Language – the Boston Naming Test assesses the
ability to perceive, interpret and name 60 common
figures. The importance of using the version
adapted for Brazil is highlighted47. The WAIS-III
Vocabulary test may also be helpful45;
• Social cognition – Although not included
in current criteria for diagnosing bvFTD,
a growing body of evidence suggests that
tests of social cognition may be useful for the
differential diagnosis between bvFTD and
other dementias, such as AD48,49. Studies have
shown that the Facial Emotion Recognition
Test (FERT) and the Faux-Pas Test (which
assesses theory of mind) are useful in the
differential diagnosis between bvFTD and AD48,49.
The short version of the Social and Emotional
Assessment (Mini-SEA) 50 – consisting of the
FERT and the Faux-Pas test – is an efficient
instrument to differentiate bvFTD from AD,
regardless of executive dysfunction51, apathy52
and episodic amnesia53. It also differentiates
bvFTD from depressive disorder50, and it is also
recommended to distinguish bvFTD from other
primary psychiatric disorders54. Despite the lack
of formal validation of the Mini-SEA in Brazil,
its clinical validity among Brazilian patients has
already been demonstrated in research51,52. There
is a cross-cultural study of FERT with normative
data for the Brazilian population55 and a cross-
cultural adaptation of the Faux-Pas test, with the
assessment of its psychometric properties56;
• The Frontotemporal Dementia Rating Scale
(FRS)57 is a useful scale for staging the disease.
It has been validated for use in Brazil58.
Concerning the investigation of behavioral
changes, the Frontal Behavioral Inventory (FBI)59,60
is useful in the differential diagnosis between bvFTD
and other dementias and has good psychometric
properties60-62. Recently, the FBI has been recommended
for the differential diagnosis between FTD and Primary
44   Diagnosis of frontotemporal dementia.   de Souza LC, et al.
Psychiatric Diseases54. There is no validation of this
scale in Brazil, but there is a translation34.
The DAPHNE scale63 is based on the bvFTD diagnostic
criteria 6 and on the FBI items. There is only one study
to evaluate its application in the differential diagnosis
between bvFTD and AD (frontal variant), with good
clinical accuracy64. There is no Brazilian validation or
translation of this scale, but it appears to be promising.
For an accurate differential diagnosis between FTD
and PPD, a formal evaluation by a psychiatrist with
experience in degenerative dementias is recommended.
Linguistic variants (PPA-NF/A and PPA-S)
The investigation and characterization of language
and speech impairments should encompass both
spontaneous conversation and the testing of specific
language skills, including phonological, lexical/semantic
and syntactic levels.
Spontaneous conversation, in addition to the
elaboration of speech from a picture, provides
information on oral fluency and speech motor capacity.
Patients with PPA-NF/A often have reduced oral
production; they may manifest articulatory and/or
syntactic errors, slow speech rhythm, and difficulty
in lexical access. Patients with PPA-S are fluent,
with preservation of the syntactic structure, but with
difficulties in lexical access; they also manifest semantic
and verbal paraphasias, and frequently use generic
words (“things,” for example), circumlocutions
and compensatory gestures7,65.
Variable degree of anomia is a symptom common to
all PPA subtypes; for this reason, visual confrontation
naming tests should always be used. Not only the final
score, but the types of paraphasias, are important for
the diagnosis of the PPA variant. In PPA-S, the difficulty
in naming is accompanied by semantic impairment,
with frequent semantic paraphasias, use of circumlocution
and supracategorization (name a dog as an animal,
for example), while in PPA-NF/A the deficit comes from
failure to access the lexicon. In PPA-S, it is possible
that the patient does not identify the visual stimulus.
So, in addition to paraphasias, there are answers
such as “what is this?”, “I don’t understand this one.”
In PPA-S, per for mance on specif ic tests of
word comprehension is necessar i ly impa ired,
and performance on object knowledge tests may be
altered, especially on less familiar items; patients
with PPA-NF/A have satisfactory results in both
tasks. Conversely, the comprehension of complex
sentences is frequently altered in PPA-NF/A, but it
is generally preserved in PPA-S.

Repetition of sentences with different lengths and
complexities is used to investigate the phonological
loop of working memory. Patients with PPA-NF/A may
have repetition difficulties due to praxis problems.
Individuals with PPA-S, however, show no difficulty
in this activity.
The analysis of the type of errors in reading
and writing tasks of regular, irregular words and
pseudowords makes it possible to differentiate
patients with semantic impairment from those with
phonological difficulties. Patients with semantic
deficits manifest dyslexia and/or surface dysgraphia,
in which irregular words are read and/or written with
oral support. The production of sentences and written
texts also contributes to the recognition of syntactic
difficulties. Patients with PPA-NF/A may present
dyslexia and/or phonological dysgraphia.
Motor and praxis assessment of speech, including
diadochokinesia tests, helps the identification of
dysarthria and/or speech apraxia. Speech apraxia
is a disturbance in the planning and programming
of sensorimotor commands necessary to perform
ar ticulator y movements. It is different from
dysarthria, which compromises the motor system.
Speech apraxia is a primarily articulatory disorder,
and prosody impairment may occur secondarily.
As it is also responsible for changes in speech sounds,
it can be misdiagnosed as phonological impairments
in oral emission.
Performance on language tasks is significantly
impacted by education, occupation, and language
experiences (reading and writing habits, bilingualism,
participation in social activities and hobbies involving
language). Research in Brazil has advanced to validate
and obtain standards for language tests. For a review
of available instruments to assess adult language,
see Parente et al.66.
Due to neuropathology, motor deficits are often
associated with cognitive and behavioral conditions.
Thus, the speech therapy assessment should investigate
difficulties related to swallowing.
Laboratory investigation
For patients who undergo lumbar puncture, the
investigation of CSF biomarkers (beta-amyloid peptide,
Tau and P-Tau) is useful to rule out AD, in cases of
difficult differential diagnosis67,68. However, it should
be noted that there are methodological issues that
must be considered when indicating and interpreting
the dosage of biomarkers: the absence of established
universal reference values, analytical variability,
the significant occurrence of false-positive results in
Dement Neuropsychol 2022 September;16(3 Suppl. 1):36-48
patients over 70 years old, the difficulty of performing
the exam, and the onerous cost69.
Unlike the existing biomarkers for AD, there are
currently no specific biomarkers of pathophysiological
changes associated with FTLD. The light chain
neurofilament (NFL) has been intensively researched
i n d e g e n e ra t i v e d e m e n t i a s , i n c l u d i n g F T D.
NFL reflects axonal damage and is increased in FTD,
as in other neurodegenerative diseases, such as AD.
NFL measurement is useful in differentiating FTD from
other non-degenerative conditions such as primary
psychiatric disorders 68. NFL dosage also appears
to correlate with disease severity68. Despite its potential
interest, the measurement of NFL is not currently
available for use in Brazil.
Most cases of FTD are sporadic70. However, in about
40% of cases, a family history of dementia is identified.
In approximately 10 to 15% of patients, an autosomal
dominant transmission pattern can be found, such as
mutations in the MAPT gene (“microtubule-associated
protein tau”), in the progranulin (GRN) gene or the
expansion. In Brazil, we found mutations in the
progranulin gene in about a third of familial cases,
while c9orf72 expansions and pathogenic variants in
MAPT were found in about 10% of familial cases each70.
Knowledge about monogenic forms of FTD has grown
significantly over the last ten years and, currently,
more than twenty genes with pathogenic variants
are known as genetic causes of FTD (many of them also
cause amyotrophic lateral sclerosis [ALS]).
The most frequent clinical presentations in
pathogenic variants of the progranulin gene are bvFTD
(about 40% of cases in a multicenter study), PPA-NF/A
in 9%, and corticobasal syndrome in 4%. About 8%
of patients with this mutation have been diagnosed
with dementia of the Alzheimer type. The syndromes
most frequently associated with c9orf72 expansions
are bvFTD (31%), FTD with ALS (11%) and ALS (20%).
In cases of pathogenic variants in the MAPT gene,
the most frequently described clinical syndromes are
bvFTD (44%), progressive supranuclear palsy (4%),
and Parkinson’s disease (5%)71.
Currently, the genetic investigation of familial FTD
cases is done by requesting the search for pathogenic
variants in gene panels associated with FTD or, preferably,
given the wide range of possible genes related to the disease
in a given family through exome sequencing. Importantly,
the search for c9orf72 expansion cannot be evaluated
by exome analysis and a separate analysis is needed to
identify the presence of this mutation. In cases of FTD
with ALS, the search for c9orf72 expansion may even
precede exome sequencing. Of note, even in familial cases,
de Souza LC, et al.   Diagnosis of frontotemporal dementia.   45
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):36-48
the exome sequencing and expansion search in c9orf72
may be negative, and a mutation may not be identified.
In a recent multicenter study, pathogenic variants in
the three major genes (GRN, MAPT, c9orf72) were only
identified in 61% of familial cases72.
Neuroimaging investigation
At the tertiary level, MRI is also used as the main
diagnostic imaging method. However, in the early
stages of the bvFTD, structural changes may be subtle
or even absent. In this context, the use of functional
neuroimaging (cerebral perfusion scintigraphy
and, mainly, positron emission tomography with
fluorodeoxyglucose) may allow the identification
of alterations that suggest a neurodegenerative
process (hyperfusion or hypometabolism), before
the atrophy is undoubted. Functional neuroimaging
exams may show metabolic or perfusion dysfunction in
the prefrontal cortex and temporal poles, depending on
the clinical type of FTD. Positron emission tomography
has better diagnostic accuracy than scintigraphy.
Currently, there are molecular neuroimaging
methods of positron emission tomography, which
allow the detection of cerebral beta-amyloid
(such as PET with Pittsburgh Compound B, or PiB).
Although it does not help in the diagnosis of
bvFTD, it is a method that allows the diagnosis
REFERENCES
1. Perry DC, Brown JA, Possin KL, Datta S, Trujillo A, Radke A, et al.
Clinicopathological correlations in behavioural variant frontotemporal
dementia. Brain. 2017;140(12):3329-45. doi:10.1093/brain/awx254.
2. Bang J, Spina S, Miller BL. Frontotemporal dementia. Lancet.
2015;386(10004):1672-82. doi:10.1016/S0140-6736(15)00461-4.
3. Custodio N, Herrera-Perez E, Lira D, Montesinos R, Bendezu L. Prevalence
of frontotemporal dementia in community-based studies in Latin America:
a systematic review. Dement Neuropsychol. 2013;7(1):27-32. doi:10.1590/
S1980-57642013DN70100005.
4. O’Connor CM, Landin-Romero R, Clemson L, Kaizik C, Daveson N,
Hodges JR,et al. Behavioral-variant frontotemporal dementia: Distinct
phenotypes with unique functional profiles. Neurology. 2017;89(6):570-77.
doi: 10.1212/WNL.0000000000004215.
5. Ulugut Erkoyun H, Groot C, Heilbron R, Nelissen A, Rossum J, Jutten R, et al.
A clinical-radiological framework of the right temporal variant of frontotemporal
dementia. Brain. 2020;143(9):2831-43. doi:10.1093/brain/awaa225.
6. Rascovsky K, Hodges JR, Knopman D, Mendez MF, Kramer JH,
Neuhaus J, et al. Sensitivity of revised diagnostic criteria for the behavioural
variant of frontotemporal dementia. Brain. 2011;134(Pt 9):2456-77.
doi:10.1093/brain/awr179.
7. Gorno-Tempini ML, Hillis AE, Weintraub S, Kertesz A, Mendez M, Cappa SF,
et al. Classification of primary progressive aphasia and its variants. Neurology.
2011;76(11):1006-14. doi:10.1212/WNL.0b013e31821103e6.
8. Carthery-Goulart MT. Primary Progressive Aphasia. In: Pachana NA,
editora. Encyclopedia of Geropsychology. Singapore: Springer; 2017.
p. 1-11. doi:10.1007/978-981-287-082-7_315
9. Snowden JS, Thompson JC, Neary D. Knowledge of famous faces and
names in semantic dementia. Brain. 2004;127(Pt 4):860-72. doi:10.1093/
brain/awh099.
10. Springer L. Therapeutic Approaches in Aphasia Rehabilitation. In: Stemmer B,
Whitaker H, editores. Handbook of the Neuroscience of Language;
2008. p. 397-406.
11. Senaha MLH, Caramelli P, Brucki SMD, Smid J, Takada LT, Porto CS, et al.
Primary progressive aphasia: classification of variants in 100 consecutive
46   Diagnosis of frontotemporal dementia.   de Souza LC, et al.
of the frontal (or dysexecutive) variant of AD 73,
which is an atypical presentation of the disease
and manifests with apathy, emotional blunting,
depressive symptoms, and episodic memory deficit.
There are also radiotracers that bind to the tau
protein; however, so far, these tracers seem to be
better at detecting tau deposits related to AD.
In conclusion, the diagnosis of different variants
of FTD is mainly based on clinical interviews and the
assessment of cognitive, linguistic and behavioral
aspects. Complementary tests provide valuable
information to support the diagnosis and to rule
out causes that may be similar to FTD conditions.
The advent of new biological markers may provide
greater diagnostic accuracy in the years to come.
ACKNOWLEDGEMENTS
PC, LCS and RN are funded by CNPq, Brazil (bolsa de
produtividade em pesquisa).
Authors’ contributions. LCS, MLH, THM, MTCG, MSY,
VSB, LTT, JS, BJAPB, LPS: concept; LCS, MLH, THM,
MTCG, MSY, VSB, LTT: drafting of the manuscript;
BJAPB, FACV, JS, LCS, LPS, MLFB, MLFC, NAFF, PC,
PHFB, RN, SMDB: critical revision of the manuscript
for important intellectual content.
Brazilian cases. Dement Neuropsychol. 2013;7(1):110-21. doi:10.1590/
S1980-57642013DN70100017.
12. Wicklund MR, Duffy JR, Strand EA, Machulda MM, Whitwell JL,
Josephs KA. Quantitative application of the primary progressive aphasia
consensus criteria. Neurology. 2014;82(13):1119-26. doi:10.1212/
WNL.0000000000000261.
13. Reul S, Lohmann H, Wiendl H, Duning T, Johnen A. Can cognitive
assessment really discriminate early stages of Alzheimer’s and behavioural
variant frontotemporal dementia at initial clinical presentation? Alzheimers
Res Ther. 2017;9(1):61. doi:10.1186/s13195-017-0287-1.
14. Wong S, Bertoux M, Savage G, Hodges JR, Piguet O, Hornberger M.
Comparison of Prefrontal Atrophy and Episodic Memory Performance in
Dysexecutive Alzheimer’s Disease and Behavioral-Variant Frontotemporal
Dementia. J Alzheimers Dis. 2016;51(3):889-903. doi:10.3233/JAD-151016.
15. Bertoux M, Cassagnaud P, Lebouvier T, Lebert F, Sarazin M,
Le Ber I, et al. Does amnesia specifically predict Alzheimer’s pathology?
A neuropathological study. Neurobiol Aging. 2020;95:123-30.
doi:10.1016/j.neurobiolaging.2020.07.011.
16. Hornberger M, Piguet O. Episodic memory in frontotemporal dementia:
a critical review. Brain. 2012;135(Pt 3):678-92. doi:10.1093/brain/aws011.
17. Brucki SMD, Nitrini R, Caramelli P, Bertolucci PHF, Okamoto IH.
Suggestions for utilization of the mini-mental state examination
in Brazil. Arq Neuropsiquiatr. 2003;61(3B):777-81. doi:10.1590/
S0004-282X2003000500014.
18. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical
method for grading the cognitive state of patients for the clinician.
J Psychiatr Res. 1975;12(3):189-98. doi:10.1016/0022-3956(75)90026-6.
19. Yew B, Alladi S, Shailaja M, Hodges JR, Hornberger M. Lost and forgotten?
Orientation versus memory in Alzheimer’s disease and frontotemporal
dementia. J Alzheimers Dis. 2013;33(2):473-81. doi:10.3233/
JAD-2012-120769.
20. Caramelli P, Teixeira AL, Buchpiguel CA, Lee HW, Livramento JA,
Fernandez LL, et al. Diagnosis of Alzheimer’s disease in Brazil:
Supplementary exams. Dement Neuropsychol. 2011;5(3):167-77.
doi:10.1590/S1980-57642011DN05030004.

21. Nitrini R, Bucki SMD, Yassuda MS, Fichman HC, Caramelli P.
The Figure Memory Test: diagnosis of memory impairment in populations
with heterogeneous educational background. Dement Neuropsychol.
2021;15(2):173-85. doi:10.1590/1980-57642021dn15-020004.
22. Nitrini R, Lefèvre BH, Mathias SC, Caramelli P, Carrilho PE, Sauaia N,
et al. Neuropsychological tests of simple application for diagnosing
dementia. Arq Neuropsiquiatr. 1994;52(4):457-65. doi:10.1590/
s0004-282x1994000400001.
23. Yassuda MS, Silva HS, Lima-Silva TB, Cachioni M, Falcão DVS, Lopes A,
et al. Normative data for the Brief Cognitive Screening Battery stratified
by age and education. Dement Neuropsychol. 2017;11(1):48-53.
doi:10.1590/1980-57642016dn11-010008.
24. Carvalho VA, Caramelli P. Brazilian adaptation of the Addenbrooke’s
Cognitive Examination-Revised (ACE-R). Dement Neuropsychol.
2007;1(2):212-16. doi:10.1590/s1980-57642008dn10200015.
25. César KG, Yassuda MS, Porto FHG, Brucki SMD, Nitrini R. Addenbrooke’s
cognitive examination-revised: normative and accuracy data for seniors
with heterogeneous educational level in Brazil. Int Psychogeriatr.
2017;29(8):1345-53. doi:10.1017/S1041610217000734.
26. Beato R, Amaral-Carvalho V, Guimarães HC, Tumas V, Souza CP,
Oliveira GN, et al. Frontal assessment battery in a Brazilian sample of
healthy controls: normative data. Arq Neuropsiquiatr. 2012;70(4):278-80.
doi:10.1590/s0004-282x2012005000009.
27. Dubois B, Slachevsky A, Litvan I, Pillon B. The FAB: a Frontal Assessment
Battery at bedside. Neurology. 2000;55(11):1621-6. doi:10.1212/
wnl.55.11.1621.
28. Torralva T, Roca M, Gleichgerrcht E, López P, Manes F. INECO Frontal
Screening (IFS): a brief, sensitive, and specific tool to assess executive
functions in dementia. J Int Neuropsychol Soc. 2009;15(5):777-86.
doi:10.1017/S1355617709990415.
29. Bahia VS, Cecchini MA, Cassimiro L, Viana R, Lima-Silva TB, de Souza LC,
et al. The Accuracy of INECO Frontal Screening in the Diagnosis of
Executive Dysfunction in Frontotemporal Dementia and Alzheimer
Disease. Alzheimer Dis Assoc Disord. 2018;32(4):314-9. doi:10.1097/
WAD.0000000000000255.
30. Cummings JL. The Neuropsychiatric Inventory: assessing psychopathology
in dementia patients. Neurology 1997;48(5 Suppl 6):S10-6. doi:10.1212/
wnl.48.5_suppl_6.10s.
31. Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA,
Gornbein J. The Neuropsychiatric Inventory: comprehensive assessment
of psychopathology in dementia. Neurology. 1994;44(12):2308-14.
doi:10.1212/wnl.44.12.2308.
32. Kaufer DI, Cummings JL, Ketchel P, Smith V, MacMillan A, Shelley T,
et al. Validation of the NPI-Q, a brief clinical form of the Neuropsychiatric
Inventory. J Neuropsychiatry Clin Neurosci. 2000;12(2):233-9.
doi:10.1176/jnp.12.2.233.
33. Camozzato AL, Godinho C, Kochhann R, Massochini G,
Chaves ML. Validity of the Brazilian version of the Neuropsychiatric
Inventory Questionnaire (NPI-Q). Arq Neuropsiquiatr. 2015;73(1):41-5.
doi:10.1590/0004-282X20140177.
34. Bahia VS, Silva MNM, Viana R, Smid J, Damin AE, Radanovic M, et al. Behavioral
and activities of daily living inventories in the diagnosis of frontotemporal
lobar degeneration and Alzheimer’s disease. Dement Neuropsychol.
2008;2(2):108-13. doi:10.1590/S1980-57642009DN20200006.
35. de Souza LC, Lehéricy S, Dubois B, Stella F, Sarazin M. Neuroimaging in
dementias. Current Opinion in Psychiatry. 2012;25(6):473-9. doi:10.1097/
YCO.0b013e328357b9ab.
36. Whitwell JL. FTD spectrum: Neuroimaging across the FTD spectrum.
Prog Mol Biol Transl Sci. 2019;165:187-223. doi:10.1016/
bs.pmbts.2019.05.009.
37. de Souza LC, Chupin M, Bertoux M, Lehéricy S, Dubois B, Lamari F,
et al. Is Hippocampal Volume a Good Marker to Differentiate Alzheimer’s
Disease from Frontotemporal Dementia? Journal of Alzheimers Disease
2013;36(1):57-66. doi:10.3233/JAD-122293.
38. Cash DM, Bocchetta M, Thomas DL, Dick KM, Swieten JC, Borroni B,
et al. Patterns of gray matter atrophy in genetic frontotemporal dementia:
results from the GENFI study. Neurobiol Aging. 2018;62:191-6.
doi:10.1016/j.neurobiolaging.2017.10.008.
39. Ameur F, Colliot O, Caroppo P, Ströer S, Dormont D, Brice A, et al.
White matter lesions in FTLD: distinct phenotypes characterize GRN
and C9ORF72 mutations. Neurol Genet. 2016;2(1):e47. doi:10.1212/
NXG.0000000000000047.
40. Harciarek M, Cosentino S. Language, executive function and social
cognition in the diagnosis of frontotemporal dementia syndromes. Int Rev
Psychiatry. 2013;25(2):178-96. doi:10.3109/09540261.2013.763340.
41. Malloy-Diniz LF, Lasmar VA, Gazinelli LS, Fuentes D, Salgado JV.
The Rey Auditory-Verbal Learning Test: applicability for the Brazilian
elderly population. Braz J Psychiatry. 2007;29(4):324-9.
Dement Neuropsychol 2022 September;16(3 Suppl. 1):36-48
42. Foss MP, Formigheri P, Speciali JG. Heterogeneity of cognitive aging
in Brazilian normal elderls. Dement Neuropsychol. 2009;3(4):344-51.
doi:10.1590/S1980-57642009DN30400014.
43. Johnen A, Bertoux M. Psychological and Cognitive Markers of Behavioral
Variant Frontotemporal Dementia-A Clinical Neuropsychologist’s View on
Diagnostic Criteria and Beyond. Front Neurol. 2019;10:594. doi:10.3389/
fneur.2019.00594.
44. Mariano LI, O’Callaghan C, Guimaraes HC, Gambogi LB,
Silva TBL, Yassuda MS, et al. Disinhibition in Frontotemporal Dementia
and Alzheimer’s Disease: A Neuropsychological and Behavioural
Investigation. J Int Neuropsychol Soc. 2020;26(2):163-71. doi:10.1017/
S1355617719000973.
45. Nascimento E, Figueiredo VLM. WISC-III and WAIS-III: alterations
in the current american original versions of the adaptations for
use in Brazil. Psicol Reflex Crit. 2002;15(3):603-12. doi:10.1590/
S0102-79722002000300014.
46. Quental NB, Brucki SM, Bueno OF. Visuospatial function in early
Alzheimer’s disease--the use of the Visual Object and Space Perception
(VOSP) battery. PLoS One. 2013;8(7):e68398. doi:10.1371/journal.
pone.0068398.
47. Miotto EC, Sato J, Lucia MC, Camargo CH, Scaff M. Development
of an adapted version of the Boston Naming Test for Portuguese
speakers. Braz J Psychiatry. 2010;32(3):279-82. doi:10.1590/
s1516-44462010005000006.
48. Bora E, Velakoulis D, Walterfang M. Meta-Analysis of Facial Emotion
Recognition in Behavioral Variant Frontotemporal Dementia: Comparison
With Alzheimer Disease and Healthy Controls. J Geriatr Psychiatry Neurol.
2016;29(4):205-11. doi:10.1177/0891988716640375.
49. Bora E, Walterfang M, Velakoulis D. Theory of mind in behavioural-variant
frontotemporal dementia and Alzheimer’s disease: a meta-analysis.
J Neurol Neurosurg Psychiatry. 2015;86(7):714-9. doi:10.1136/
jnnp-2014-309445.
50. Bertoux M, Delavest M, de Souza LC, Funkiewiez A, Lépine JP,
Fossati P, et al. Social Cognition and Emotional Assessment differentiates
frontotemporal dementia from depression. Neurol Neurosurg Psychiatry.
2012;83(4):411-6. doi:10.1136/jnnp-2011-301849.
51. Moura MVB, Mariano LI, Teixeira AL, Caramelli P, de Souza LC. Social
Cognition Tests Can Discriminate Behavioral Variant Frontotemporal
Dementia From Alzheimer’s Disease Independently of Executive Functioning.
Arch Clin Neuropsychol. 2020;26(5):831-7. doi:10.1093/arclin/acaa084.
52. Mariano LI, Caramelli P, Guimaraes HC, Gambogi LB, Moura MVB,
Yassuda MS, et al. Can Social Cognition Measurements Differentiate
Behavioral Variant Frontotemporal Dementia from Alzheimer’s Disease
Regardless of Apathy? J Alzheimers Dis. 2020;74(3):817-27. doi:10.3233/
JAD-190861.
53. Bertoux M, de Souza LC, O’Callaghan C, Greve A, Sarazin M, Dubois B,
et al. Social Cognition Deficits: The Key to Discriminate Behavioral Variant
Frontotemporal Dementia from Alzheimer’s Disease Regardless
of Amnesia? Journal of Alzheimers Disease. 2015;49(4):1065-74.
doi:10.3233/JAD-150686.
54. Ducharme S, Dols A, Laforce R, Devenney E, Kumfor F, Stock J, et al.
Recommendations to distinguish behavioural variant frontotemporal
dementia from psychiatric disorders. Brain. 2020;143(6):1632-50.
doi:10.1093/brain/awaa018.
55. de Souza LC, Bertoux M, Faria ÂRV, Corgosinho LTS, Prado ACA,
Barbosa IG, et al. The effects of gender, age, schooling, and cultural
background on the identification of facial emotions: a transcultural study. Int
Psychogeriatr. 2018;30(12):1861-70. doi:10.1017/S1041610218000443.
56. Watanabe RGS, Knochenhauer AE, Fabrin MA, Siqueira HH, Martins HF,
Oliveira Mello CD, et al. Faux Pas Recognition Test: transcultural adaptation
and evaluation of its psychometric properties in Brazil. Cogn Neuropsychiatry.
2021;26(5):3321-34. doi:10.1080/13546805.2021.
57. Mioshi E, Hsieh S, Savage S, Hornberger M, Hodges JR. Clinical
staging and disease progression in frontotemporal dementia. Neurology.
2010;74(20):1591-7. doi:10.1212/WNL.0b013e3181e04070.
58. Lima-Silva TB, Bahia VS, Cecchini MA, Cassimiro L, Guimarães HC,
Gambogi LB, et al. Validity and Reliability of the Frontotemporal Dementia
Rating Scale (FTD-FRS) for the Progression and Staging of Dementia
in Brazilian Patients. Alzheimer Dis Assoc Disord. 2018;32(3):220-5.
doi:10.1097/WAD.0000000000000246.
59. Kertesz A, Nadkarni N, Davidson W, Thomas AW. The Frontal Behavioral
Inventory in the differential diagnosis of frontotemporal dementia. J Int
Neuropsychol Soc. 2000;6(4):460-8. doi:10.1017/s1355617700644041.
60. Suhonen NM, Hallikainen I, Hanninen T, Jokelainen J, Krüger J, Hall A,
et al. The Modified Frontal Behavioral Inventory (FBI-mod) for Patients with
Frontotemporal Lobar Degeneration, Alzheimer’s Disease, and Mild Cognitive
Impairment. J Alzheimers Dis. 2017;56(4):1241-51. doi:10.3233/JAD-160983.
61. Konstantinopoulou E, Aretouli E, Ioannidis P, Karacostas D,
Kosmidis MH. Behavioral disturbances differentiate frontotemporal lobar
de Souza LC, et al.   Diagnosis of frontotemporal dementia.   47
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):36-48
degeneration subtypes and Alzheimer’s disease: evidence from the
Frontal Behavioral Inventory. Int J Geriatr Psychiatry. 2013;28(9):939-46.
doi:10.1002/gps.3907.
62. Milan G, Lamenza F, Iavarone A, Galeone F, Lorè E, Falco C, et al. Frontal
Behavioural Inventory in the differential diagnosis of dementia. Acta Neurol
Scand. 2008;117(4):260-5. doi:10.1111/j.1600-0404.2007.00934.x.
63. Boutoleau-Bretonniere C, Evrard C, Hardouin JB, Rocher L, Charriau T,
Etcharry-Bouyx F, et al. DAPHNE: A New Tool for the Assessment of the
Behavioral Variant of Frontotemporal Dementia. Dement Geriatr Cogn Dis
Extra. 2015;5(3):503-16. doi:10.1159/000440859.
64. Lehingue E, Gueniat J, Jourdaa S, Hardouin JB, Pallardy A,
Courtemanche H, et al. Improving the Diagnosis of the Frontal Variant
of Alzheimer’s Disease with the DAPHNE Scale. J Alzheimers Dis.
2021;79(1):1735-45. doi:10.3233/JAD-201088.
65. Montembeault M, Brambati SM, Gorno-Tempini ML, Migliaccio R. Clinical,
Anatomical, and Pathological Features in the Three Variants of Primary
Progressive Aphasia: A Review. Front Neurol. 2018;9:692. doi:10.3389/
fneur.2018.00692.
66. Parente MAMP, Baradel RR, Fonseca RP, Pereira N, Carthery-Goulart MT.
Evolution of language assessment in patients with acquired neurological
disorders in Brazil. Dement Neuropsychol. 2014;8(3):196-206.
doi:10.1590/S1980-57642014DN83000002.
67. de Souza LC, Lamari F, Belliard S, Jardel C, Houillier C, De Paz R, et al.
Cerebrospinal fluid biomarkers in the differential diagnosis of Alzheimer’s
disease from other cortical dementias. J Neurol Neurosurg Psychiatry.
2011;82(3):240-6. doi:10.1136/jnnp.2010.207183.
48   Diagnosis of frontotemporal dementia.   de Souza LC, et al.
68. Swift IJ, Sogorb-Esteve A, Heller C, Synofzik M, Otto M, Graff C, et al.
Fluid biomarkers in frontotemporal dementia: past, present and future.
J Neurol Neurosurg Psychiatry. 2021;92(2):204-15. doi:10.1136/
jnnp-2020-323520.
69. Frisoni GB, Boccardi M, Barkhof F, Blennow K, Cappa S, Chiotis K,
et al. Strategic roadmap for an early diagnosis of Alzheimer’s disease
based on biomarkers. Lancet Neurol. 2017;16(8):661-76. doi:10.1016/
S1474-4422(17)30159-X.
70. Takada LT. The Genetics of Monogenic Frontotemporal Dementia. Dement
Neuropsychol 2015;9(3):219-29. doi:10.1590/1980-57642015DN93000003.
71. Moore KM, Nicholas J, Grossman M, McMillan CT, Irwin DJ, Massimo L,
et al. Age at symptom onset and death and disease duration in genetic
frontotemporal dementia: an international retrospective cohort study.
Lancet Neurol. 2020;19(2):145-56. doi:10.1016/S1474-4422(19)30394-1.
72. Ramos EM, Dokuru DR, Van Berlo V, Wojta K, Wang Q, Huang AY, et al.
Genetic screening of a large series of North American sporadic and familial
frontotemporal dementia cases. Alzheimers Dement. 2020;16(1):118-30.
doi:10.1002/alz.12011.
73. Ossenkoppele R, Pijnenburg YA, Perry DC, Cohn-Sheehy BI, Scheltens NM,
Vogel JW, et al. The behavioural/dysexecutive variant of Alzheimer’s
disease: clinical, neuroimaging and pathological features. Brain.
2015;138(Pt 9):2732-49. doi:10.1093/brain/awv191.
Dement Neuropsychol 2022 September;16(3 Suppl. 1):49-68 Consensus
https://doi.org/10.1590/1980-5764-DN-2022-S104EN

Diagnosis of vascular
cognitive impairment:
recommendations of the scientific department
of cognitive neurology and aging of the
Brazilian Academy of Neurology
Breno José Alencar Pires Barbosa1,2,3 , José Ibiapina Siqueira Neto4 , Gilberto Sousa Alves5 ,
Felipe Kenji Sudo6 , Claudia Kimie Suemoto7 , Fernanda Tovar-Moll6 , Jerusa Smid3 ,
Lucas Porcello Schilling8,9,10 , Marcio Luiz Figueredo Balthazar11 , Norberto Anízio Ferreira Frota12,13 ,
Leonardo Cruz de Souza14 , Francisco Assis Carvalho Vale15 , Paulo Caramelli14 ,
Paulo Henrique Ferreira Bertolucci16 , Sonia Maria Dozzi Brucki3 , Ricardo Nitrini3 ,
Eliasz Engelhardt17 , Márcia Lorena Fagundes Chaves18,19

1
Universidade Federal de Pernambuco, Centro de Ciências Médicas, Área Acadêmica de Neuropsiquiatria, Recife PE, Brazil.
2
Instituto de Medicina Integral Prof. Fernando Figueira, Recife PE, Brazil.
3
Universidade de São Paulo, Faculdade de Medicina, Departamento de Neurologia, Grupo de Neurologia Cognitiva e do Comportamento, São Paulo SP, Brazil.
4
Faculdade de Medicina da Universidade Federal do Ceará. Fortaleza, Brazil.
5
Universidade Federal do Maranhão, Centro de Ciências da Saúde, Departamento de Medicina I, São Luís MA, Brazil.
6
Instituto D’Or de Pesquisa e Ensino, Rio de Janeiro RJ, Brazil.
7
Universidade de São Paulo, Faculdade de Medicina, Divisão de Geriatria, São Paulo SP, Brazil.
8
Pontifícia Universidade do Rio Grande do Sul, Escola de Medicina, Serviço de Neurologia, Porto Alegre RS, Brazil.
9
Pontifícia Universidade do Rio Grande do Sul, Instituto do Cérebro do Rio Grande do Sul, Porto Alegre RS, Brazil.
10
Pontifícia Universidade do Rio Grande do Sul, Programa de Pós-Graduação em Gerontologia Biomédica, Porto Alegre RS, Brazil.
11
Universidade Estadual de Campinas, Faculdade de Ciências Médicas, Departamento de Neurologia, Campinas SP, Brazil.
12
Hospital Geral de Fortaleza, Serviço de Neurologia, Fortaleza CE, Brazil.
13
Universidade de Fortaleza, Fortaleza CE, Brazil.
14
Universidade Federal de Minas Gerais, Departamento de Clínica Médica, Belo Horizonte MG, Brazil.
15
Universidade Federal de São Carlos, Centro de Ciências Biológicas e da Saúde, Departamento de Medicina, São Carlos SP, Brazil.
16
Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Neurologia e Neurocirurgia, São Paulo SP, Brazil.
17
Universidade Federal do Rio de Janeiro, Instituto de Neurologia Deolindo Couto e Instituto de Psiquiatria, Rio de Janeiro RJ, Brazil.
18
Hospital de Clínicas de Porto Alegre, Serviço de Neurologia, Porto Alegre RS, Brazil.
19
Universidade Federal do Rio Grande do Sul, Faculdade de Medicina, Departamento de Medicina Interna, Porto Alegre RS, Brazil.
Correspondence: Breno José Alencar Pires Barbosa; Email: brenojb@gmail.com.
Conflict of interest: JS: Participation as speaker in symposia sponsored by Roche laboratory; LPS: Participation in advisory boards for Biogen. Participation as speaker in
symposia sponsored by Aché, Apsen and Biogen laboratories; MLFB: Participation in advisory boards for Biogen. Development of material for continuous medical education
and participation as speaker in symposia sponsored by EMS and Torrent laboratories; PC: Participation as principal investigator in clinical trials for Novo Nordisk and Roche
laboratories. Participation in advisory boards for Aché, Biogen, EMS, Nutricia and Roche laboratories. Development of material for continuous medical education and participation
as speaker in symposia sponsored by Aché, Nutricia, Libbs, Roche, Sandoz, Torrent and Zodiac laboratories; PHFB: Participation in advisory boards for Biogen and Novo
Nordisk laboratories. Supervision of training activities for Biogen; Janssen-Cilag and Novo Nordisk laboratories and for Quintiles. Participation as speaker in symposia sponsored
by Apsen, Nutricia, Roche and Sandoz laboratories; LCS: Participation in advisory board for Biogen. Participation as speaker in symposia sponsored by Biogen;
RN: Participation in advisory board for Biogen; BJAPB, JISN, GSA, FKS, CKS, FTM, NAFF, FACV, SMDB, EE, MLFC: There is no conflict of interest to declare.
Received on August 02, 2021; Received in its final form on November 10, 2021; Accepted on April 27, 2022.

Barbosa BJAP, et al.   Vascular cognitive impairment.   49

 Dement Neuropsychol 2022 September;16(3 Suppl. 1):49-68

ABSTRACT. Since the publication of the latest recommendations for the diagnosis and treatment of Vascular Dementia by the Brazilian Academy of Neurology
in 2011, significant advances on the terminology and diagnostic criteria have been made. This manuscript is the result of a consensus among experts
appointed by the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology (2020-2022). We aimed to update practical
recommendations for the identification, classification, and diagnosis of Vascular Cognitive Impairment (VCI). Searches were performed in the MEDLINE,
Scopus, Scielo, and LILACS databases. This guideline provides a comprehensive review and then synthesizes the main practical guidelines for the diagnosis
of VCI not only for neurologists but also for other professionals involved in the assessment and care of patients with VCI, considering the different levels
of health care (primary, secondary and tertiary) in Brazil.
Keywords: Dementia, Vascular; Cognitive Dysfunction; Cerebral Infarction; Stroke.

DIAGNÓSTICO DO COMPROMETIMENTO COGNITIVO VASCULAR: RECOMENDAÇÕES DO DEPARTAMENTO CIENTÍFICO DE NEUROLOGIA COGNITIVA

E DO ENVELHECIMENTO DA ACADEMIA BRASILEIRA DE NEUROLOGIA
RESUMO. Desde a publicação das últimas recomendações para o diagnóstico e tratamento da Demência Vascular pela Academia Brasileira de Neurologia
em 2011, avanços significativos ocorreram na terminologia e critérios diagnósticos. O presente manuscrito é resultado do consenso entre especialistas
indicados pelo Departamento Científico de Neurologia Cognitiva e do Envelhecimento da Academia Brasileira de Neurologia (2020-2022). O objetivo foi
atualizar as recomendações práticas para a identificação, classificação e diagnóstico do Comprometimento Cognitivo Vascular (CCV). As buscas foram
realizadas nas plataformas MEDLINE, Scopus, Scielo e LILACS. As recomendações buscam fornecer uma ampla revisão sobre o tema, então sintetizar
as evidências para o diagnóstico do CCV não apenas para neurologistas, mas também para outros profissionais de saúde envolvidos na avaliação
e nos cuidados ao paciente com CCV, considerando as diferentes realidades dos níveis de atenção à saúde (primário, secundário e terciário) no Brasil.
Palavras-chave: Demência Vascular; Disfunção Cognitiva; Infarto Cerebral; Acidente Vascular Cerebral.

INTRODUCTION This guideline seeks to provide a comprehensive

V ascular Cognitive Impairment ( VCI) is the

term used to include the entire spectrum of
changes in cognition directly or indirectly related to
cerebrovascular disease1. It is a construct proposed
by Vladimir Hachinski (1994) to describe cases
associated with “cerebrovascular disease” (CVD)2 and
partially replace the concept of “Vascular Dementia”
(VD) proposed by Carlo Loeb3. The term VCI identifies
and includes all forms and severity levels of cognitive
impairment, constituting a continuum of clinical and
pathological presentations, from an asymptomatic
stage (the “brain-at-risk) to dementia VD, including
an intermediate stage of clinical deficits that do
not reach the dementia criteria, initially called the
“pre-dementia” stage2,4, which was named “Vascular
Cognitive Impairment Non-Dementia” (VCIND) 5,6
or “Vascular Mild Cognitive Impairment” (VMCI)7-9.
Thus, the symptomatic spectrum of the condition
comprises VCIND/VMCI and VCI (or VD).
Since the publication of the latest recommendations
for the diagnosis and treatment of Vascular Dementia
by the Brazilian Academy of Neurology in 201110-12,
significant advances on the terminology and diagnostic
criteria has been made1,9-15. New markers of structural
and functional neuroimaging allowed the understanding
of the heterogeneity of clinical presentations of VCI,
including the compensation mechanisms of neural
networks 16. We also highlight contributions from
Brazilian and Latin American groups to the area,
which will be highlighted throughout the text.
review and then synthesize the main practical guidelines
for the diagnosis of VCI not only for neurologists but
also for other professionals involved in the assessment
and care of patients with VCI, considering the reality
different levels of health care (primary, secondary
and tertiary) in Brazil and Latin America.
METHODS
This manuscript is the result of a consensus among
experts appointed by the Scientific Department
of Cognitive Neurology and Aging of the Brazilian
Academy of Neurolog y (2020-2022). We aimed
to update practical recommendations for the
identification, classification, and diagnosis of VCI.
There are currently several updated guidelines and
consensuses on the topic, many of which are cited
and discussed throughout the text, so it was not
our objective to carry out a new systematic review
or exhaustive classification of the evidence.
Searches were performed in the MEDLINE, Scopus,
Scielo, and LILACS databases until June 2021, using
the descriptors “vascular cognitive impairment”
or “vascular dementia”. We selected mostly articles
published in the last 10 years, but older relevant
publications were also included. Articles in English,
Portuguese, and Spanish were reviewed. We also
revised the reference list of the articles for relevant
additional references. Review articles were also
included when applicable.

50   Vascular cognitive impairment.   Barbosa BJAP, et al.


EPIDEMIOLOGY AND RISK FACTORS
The prevalence of VCI is too complex to estimate,
because of geographic factors that imply in very
heterogeneous societies, the huge variation in the
criteria used for diagnosis, different complementary
methods used in the investigation, or the scarcity
of studies, especially in Brazil and in low- and
middle-income countries 17,18. Despite the lack of
standardized diagnostic criteria, making it difficult
to determine its prevalence and risk factors (RF),
VD is accepted as the second leading cause of dementia
in the elderly, ranging from 8-45% of cases19,20.
Studies with post-stroke patients have detected
VCIND in 24 to 70% of cases21,22. Considering that
VD usually affects up to a third of individuals who
have suffered a stroke, it is observed that the VCIND
segment has a higher prevalence than dementia
conditions23. A Brazilian study evaluated 172 patients
one year after an ischemic stroke and found that
12.2% of cases met the criteria for probable VD24.
Another study estimated that approximately 5% of
individuals over 65 years of age had VCI, with 2.4%
in the VCI-ND stage and 1.5% in the DV stage 6.
Similarly, review studies showed that the prevalence
of VMCI ranged between 21 and 30%, affecting
24-75% in cases with diagnosed stroke and 4-19%
in those in which stroke had not been reported 25.
The high prevalence of VCI-ND/VMCI highlights the
importance of this etiology of dementia, especially
considering that early diagnosis and treatment
of RF for VCI can prevent, stabilize, or prevent the
development of VD19,26-28. A clinicopathological study
by the Biobank for Aging Studies of the University
of São Paulo described a prevalence of DV of 35%,
considering only the presence of chronic infarcts for
the neuropathological diagnosis, increasing to 49%
when the presence of moderate to severe small vessel
disease was included in the neuropathological criteria
for VD29. It should be remembered that mixed forms
of vascular pathology with neurodegenerative disease
[e.g., VCI + Alzheimer’s disease (AD)] are also included
in the VCI construct, with important participation in
the total prevalence of VCI19,30,31. The possibility that
mixed forms have their evolution attenuated and/or
delayed through preventive measures is another
aspect of great importance2,19,3.
The RFs for VCI are diverse. They are classically
divided into sociodemographic, clinical characteristics,
neuroimaging aspects, and VCI characteristics.
Non-modifiable RFs include advanced age, gender,
ethnicity, and genetic aspects (CADASIL, CARASIL,
VLDL-R, APOE ε-4, HERNS, FABRY, among others).
Dement Neuropsychol 2022 September;16(3 Suppl. 1):49-68
Classic metabolic and cardiovascular RFs are hypertension,
diabetes, dyslipidemia, atrial fibrillation, previous stroke,
metabolic syndrome, obesity, glucose intolerance, elevated
homocysteine, carotid stenosis, and hyperuricemia.
Toxic RFs include alcoholism, smoking, and other causes
such as low education, sedentary lifestyle, inadequate diet,
sleep apnea, and depression33.
MECHANISMS AND PATHOPHYSIOLOGY
Cerebral vascular injuries comprise the ischemic
(infarcts, microinfarcts, lacunae, white matter
hyperintensities, enlarged perivascular spaces) and
hemorrhagic lesions (hemorrhagic infarcts, cerebral
hemorrhages, and microhemorrhages), which present
in a variable way, with no single neuropathological
lesion characterizing VCI. In addition, there are no
widely accepted criteria in relation to the location and
number of lesions necessary for the neuropathological
diagnosis of VCI34-37. Several neuropathologic events
seem to contribute to the occurrence of VCI, including
loss of white matter integrity with consequent
disconnection between strategic areas for cognitive
networks 16, changes in the coagulation cascade 38
and oligodendrocytes39, and changes in endothelial cells
with alterations in cerebral blood perfusion40.
The presence of lesions on neuroimaging must be
interpreted considering the clinical context. To cause
clinical symptoms, several basic characteristics must be
met, such as extension, location and number of lesions.
In addition, other factors can influence the clinical
outcome of injuries, such as diaschisis, compensation
mechanisms, and cognitive reserve41-43.
The parameters for VCI-ND and DV regarding
location, extension, and the number of lesions were
previously examined by several authors. Lesions
located in limbic-paralimbic regions, heteromodal
associative areas, certain subcortical structures,
or in their connections tend to produce especially
relevant pictures of VCI 44,45 . T hus, lesions in
the following areas are related to clinical symptoms:
the anterior cerebral artery (affecting the prefrontal
region), the middle cerebral artery (associative areas of
the parietal lobe, parietotemporal, temporo-occipital),
the posterior cerebral artery (inferotemporal region),
hippocampus, and thalamus nuclei [anterior, medial
dorsal]) 45-47 . As for the white matter, which is
partly made up of long intra-hemispheric bundles,
the frontosubcortical pathways (fronto-striatum-pale-
thalamus-frontal circuits) underlying the executive
function should be highlighted. Damage to these
tracts is frequent in cases of VCI, even in the
Barbosa BJAP, et al.   Vascular cognitive impairment.   51
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):49-68

early stages 48. It should also be remembered that,
regardless of their location, white matter lesions
in any location compromise the frontal function49.
However, the extent and number of detectable
lesions have been less studied. The most recent criteria
for VCI pointed to the need for a lower vascular
load (fewer number of lesions) for the diagnosis of
non-dementia presentations 1,9,14,50. It is important
to remember that white matter hyperintensities
(WMH) are not homogeneously constituted and may
present with different degrees of tissue alteration,
with varied rarefaction. This aspect has been described
in histopathology and diffusion tensor studies51,52.
In patholog ic studies, the definition of a
neuropathologic threshold to consider the lesion as
a cause of cognitive alteration in VCI is a difficult
task53,54. The same can be said about VCI as a whole.
Furthermore, evidence from the recent decades
indicates that isolated DV is much less prevalent
than mixed VCI, a product of degenerative AD type
and cerebrovascular lesions55. VCI Changes at any
stage can be associated with neurodegenerative
disorders, such as AD, constituting mixed pictures
(such as VD+AD) 23,56, as well as other conditions
(Frontotemporal lobar degeneration, Dementias
with Lewy’s Body) (Figure 1 A and B)1.

VaD
Vascular
pathology VCI

Neurodegenerative
pathology

Vascular
VCI/ pathology
Mixed
pathologies
AD pathology

VCI: vascular cognitive impairment; VaD: vascular dementia.

Figure 1 A and B. Relationship between vascular cognitive impairment and dementia, adapted99. VCI refers to any degree of cognitive decline related
to cerebrovascular pathology, from the pre-clinical stages (brain at risk), through VMCI and dementia. VCI can be an isolated cause of cognitive decline or,
to some degree, coexist with neurodegenerative pathology such as AD. The term Vascular Dementia refers to the subgroup of patients whose cognitive
decline is mostly cerebrovascular in nature.

THE VASCULAR COGNITIVE IMPAIRMENT SPECTRUM
Brain-at-risk
White-matter changes – especially symmetrical bilateral
punctiform lesions, located in periventricular and deep
subcortical regions – are commonly found in healthy
elderly subjects57. Although often detected in late-life,
WMH on T2 and FLAIR (fluid attenuated inversion
recovery) magnetic resonance imaging (MRI) are not
inherent features of normal brain aging58. In fact,
their occurrence is strongly associated with the presence
of vascular-related RF, such as metabolic diseases,
smoking, among others 59.
In addition, according to meta-analyses, extensive
WMH burden conferred a 73-84% increased risk
of incident dementia 59,60. Hence, the observation
that these neuroimaging findings precede the onset
of cognitive and behavioral abnormalities suggest
that, similarly to AD61, a preclinical stage may exist
in VCI (Figure 2).

52   Vascular cognitive impairment.   Barbosa BJAP, et al.


With the high prevalence of cerebrovascular disease
in older population, determining the odds of cognitive
decline attributed to individual or combined biomarkers,
including the lesion type at neuroimaging (WMH,
lacunes, microbleeds, perivascular space dilations, amyloid
angiopathy etc.), the lesion load, the speed of infarct
Brain at risk Vascular and
(preclinical phase) mild cognitive impairment
Figure 2. The spectrum of vascular cognitive impairment.
Vascular Cognitive Impairment No-Dementia / Vascular
Mild Cognitive Impairment (VCIND / VMCI)
Within the VCI spectrum, the earliest symptomatic
phase, in which cognitive impairment does not fulfill
dementia criteria, has been referred to as VCIND5,6
or VMCI7-9. Moreover, the 5th edition of the Diagnostic
and Statistical Manual of Mental Disorders (DSM-5)
suggested a novel nomenclature, which was endorsed
by the 11th edition of the International Classification
of Diseases (ICD-11)15,64. In these publications, Vascular
Dementia (VD) was identified as “Major Neurocognitive
Disorder”, whereas VCIND / VMCI was renamed
as “Mild Neurocognitive Disorder”15,64.
These conditions are associated with substantial risk
of cognitive worsening and progression to dementia65.
Longitudinal studies reported that 22 to 58% of subjects
diagnosed as VCIND progressed to VD after 2-7 years
of follow-up66-69. In contrast, cognitive recovery was
detected in 8-45% of the cases, while 38-74% remained
cognitively stable. Among those in the latest group,
30-34% presented subtle cognitive decline, which was
not sufficient for a transition from VCIND to VD66-69.
Dement Neuropsychol 2022 September;16(3 Suppl. 1):49-68
recurrence and the “allostatic load” (which refers to the
cumulative effects of multiple vascular RF) is needed.
The idea that broadly available therapeutic interventions
may effectively participate in the primary prevention of
symptomatic VCI emphasizes the importance of more
studies aiming at the characterization of this stage62,63.
Vascular dementia
Furthermore, risk of progression towards dementia
may vary across individuals classified as VCIND.
According to the DSM-5, magnitude of impairment
in neuropsychological testing in this diagnostic
group corresponds to performances between 1 to
2 standard deviations (SD) from mean normative
values 15. A longitudinal study reported that three
levels of severity could be distinguished within this
category: mild VCIND (cognitive deficits up to 1 SD
from normative data), moderate VCIND (cognitive
impairments of 1.5 SD from normative scores)
and severe VCIND (performances up to 2 SD from
expected scores, considering age and education).
It has been indicated that higher severity of cognitive
abnormalities in VCIND correlated with increased odds
of transition to dementia70.
Additionally, the number of vascular-related RF may
impact on cognitive performances, with those with
more elevated vascular burden presenting poorer scores
in neuropsychological tasks71,72. Table 1 depicts the most
relevant diagnostic criteria for VCIND.
Barbosa BJAP, et al.   Vascular cognitive impairment.   53
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):49-68

Table 1. Diagnostic Criteria for Vascular Cognitive Impairment, No Dementia (VCIND).

Criteria Description

VCIND
Cognitive impairment in ≥ 1 domain.
Zhao et al., 2010 49
ADLs maintained.
Does not meet accepted criteria for the diagnosis of dementia.

VMCI
Includes the 4 proposed subtypes for MCI: amnesic, amnesic + other domains, non-amnestic single
domain, and non-amnestic multiple domains.
VCCID The VMCI classification must be based on cognitive tests and at least 4 cognitive domains must be
Gorelick et al., 20119 assessed: executive/attention, memory, language, and visuospatial functions.
Classification should be based on presumed decline in cognitive function compared to a previous
baseline and impairment in ≥ 1 cognitive domain.
IADLs can be normal or mildly compromised (regardless of motor/sensory symptoms).

Mild VCD
Evidence of significant cognitive decline in > 1 domain compared to previous level of performance.
Cognitive impairment between 1 and 2 SD below the mean (or between the 3rd and 16th percentile)
VASCOG
(compared to individuals of similar age, sex, education and social-cultural profile).
Sachdev et al., 201414
Fronto-executive deficiencies are more likely to be present.
Preserved IADLs (the individual, although still independent, performs tasks with greater effort and uses
compensation strategies).

Mild VCI
VICCCS
Impairment in ≥ 1 cognitive domain.
Skrobot et al., 20181
BADLs or IADLs maintained or with mild impairment (regardless of motor/sensory symptoms).

CCVND
Cognitive impairment in ≥ 1 cognitive domain.
ABN 2021 Consensus Proposal Cognitive impairment between 1 and 2 SD below the mean (or between the 3rd and 16th percentile).
BADLs maintained (regardless of motor/sensory symptoms).
Preserved IADLs (although with greater effort + compensation strategies).
VCCID: Vascular Contributions to Cognitive Impairment and Dementia; VASCOG: International Society for Vascular Behavioral and Cognitive Disorders; VICCCS: Vascular Impairment of
Cognition Classification Consensus Study; VCIND: vascular cognitive impairment, no dementia; VMCI: vascular mild cognitive impairment; ADL: activities of daily living; BADLs: basic
activities of daily living; IADLs: instrumental activities of daily living; MCI: mild cognitive impairment; mild VCD: mild vascular cognitive disorder; SD: standard deviations.

Vascular Dementia (VD) and its classification the onset of cognitive abnormalities is only mandatory
Current diagnostic criteria for VD require the for the characterization of post-stroke dementia.
occurrence of significant impairment in at least one Other syndromes related to VD have been
cognitive domain (although more domains may be previously described in the literature 73,74. Among
affected), and severe functional disability, including those, small vessel disease associated with Cerebral
difficulties to perform instrumental or basic Amyloid Angiopathy (CAA) deserve to be commented.
activities of daily living1,9,14. Noteworthy, defining In addition to its relationship with cerebral hemorrhage,
thresholds to characterize “severe functional CAA has been linked to AD pathology in post-mortem
disability” might be challenging, since an array analyses75. Cognitive dysfunction may occur in these
of skills are implicated in one’s capacity to exert cases, even without evident brain hemorrhage.
everyday life activities, such as cognitive, behavioral, Some neuroimaging features associated with CAA
sensorial, and motor factors. Table 2 summarizes the include lobar microbleeds, lobar intraparenchymal
main diagnostic criteria for VD. hemorrhage, cortical superficial siderosis, WMH,
Once diagnosed as VD, patients should be convexity subarachnoid hemorrhage, and dilated
investigated for the underlying pathology (Table 3, perivascular spaces74.
Figure 3), and for the level of certainty of the vascular Among genetic syndromes, Cerebral Autosomal
etiology – check the next section for detailed information Dominant Arteriopathy with Subcortical Infarcts
about this theme. Objective 6-month temporal and Leukoencephalopathy (CADASIL), caused by
relationship between a cerebrovascular ictus and mutations in the NOTCH3 gene, ought to be outlined.

54   Vascular cognitive impairment.   Barbosa BJAP, et al.

 Dement Neuropsychol 2022 September;16(3 Suppl. 1):49-68

This condition induces deposition of granular may be observed in autosomal recessive mutations
osmiophilic material in the walls of vascular smooth in the HTRA1 gene, which causes Cerebral Autosomal
muscle cells. Clinical manifestations encompass Recessive Arteriopathy with Subcortical Infarcts
early-onset VD, with remarkable decrease in cognitive and Leukoencephalopathy (Cerebral autosomal
speed, executive dysfunction, and attentional deficits, recessive arteriopathy with subcortical infarcts
as well as depression, headache and positive family and leukoencephalopathy – CARASIL). Awareness
history. Brain MRI often evidences substantial white- should be raised to this diagnosis when alopecia and
matter damage, as a result of subcortical infarcts, spondylosis are detected along with the typical signs
and affected temporal poles. A similar phenomenon and symptoms of CADASIL74.

Table 2. Diagnostic Criteria for Vascular Cognitive Impairment – Dementia (VD)

Criteria Description

VD
The diagnosis of VD should be based on a presumption of decline in cognitive function compared to a
VCCID previous baseline and impairment in ≥ 2 cognitive domains sufficient to affect activities of daily living.
Gorelick et al., 20119 The diagnosis of VD must be based on cognitive tests, and at least 4 cognitive domains must be assessed:
executive/attention, memory, language, and visuospatial functions.
Deficits in ADLs must be independent of the motor/sensory sequelae of the vascular event.

Dementia, major VCD

Evidence of significant cognitive decline in > 1 domain compared to previous level of performance.
Cognitive impairment ≥ 2 SD below the average (or below the 3rd percentile) (compared to individuals of
VASCOG
similar age, sex, education and socio-cultural profile)
Sachdev et al., 201414
Fronto-executive deficiencies are more likely to be present.
Enough to interfere with independence (at least requires help with IADLs, e.g., complex tasks such as
managing finances or medications).

Major VCI, VD
VICCCS
Impairment in ≥ 1 cognitive domain.
Skrobot et al., 20181
Significant impairment of IADLs or ABVDs (regardless of motor/sensory symptoms).

Major VCI, VD
Cognitive impairment in ≥ 1 cognitive domain.
ABN 2021 Consensus Proposal
Cognitive impairment ≥ 2 SD below the mean (or below the 3rd percentile).
Significant impairment of IADLs or ADLs (regardless of motor/sensory symptoms).
VCCID: Vascular Contributions to Cognitive Impairment and Dementia; VASCOG: International Society for Vascular Behavioral and Cognitive Disorders; VICCCS: Vascular Impairment of
Cognition Classification Consensus Study; VD: Vascular Dementia; major VCD: major vascular cognitive disorder; VCI: vascular cognitive impairment; ADL: activities of daily living; BADLs:
basic activities of daily living; IADLs: instrumental activities of daily living; SD: standard deviations.

Table 3. Main forms of major VCI / Vascular Dementia, adapted from1.

Classification Description

Presence of new, sudden or subacute cognitive deficit up to 6 months after ischemic or hemorrhagic
stroke. It may be due to different cerebrovascular patterns (e.g., multiple cortico-subcortical infarctions,
Post-stroke dementia
strategic lesions, subcortical vascular dementia, etc.). The temporal relationship between the vascular
event and cognitive decline differentiates this form from VD.

Broad term that encompasses cognitive decline phenotypes combined between VCI and
Mixed dementias neurodegenerative diseases (e.g. VCI-AD, VCI-LBD etc). It is recommended to specify which underlying
pathology is suspected, avoiding the less specific term “mixed dementia.”

Small vessel cerebrovascular disease is the main cause in this group, mainly due to lacunar infarcts and white
Subcortical ischemic vascular dementia
matter lesions. It encompasses the phenotypes described as Binswanger’s Disease and the lacunar state.

Cortical multiple infarct dementia A group characterized by the presence of multiple cortical infarcts and their likely contribution to dementia.

Possible - more appropriate term if neuroimaging is unavailable.

Level of certainty
Probable - in the presence of compatible CT or MR. MR is the method of choice.
VCI: vascular cognitive impairment; VD: vascular dementia; AD: Alzheimer’s disease; LBD: Lewy Body dementia; CT: computer tomography; MR: magnetic resonance.

Barbosa BJAP, et al.   Vascular cognitive impairment.   55

 Dement Neuropsychol 2022 September;16(3 Suppl. 1):49-68

Post-stroke Subcortical Multi-infarct

Mixed pathologies
dementia ischemic VaD dementia

VaD-AD VaD-DLB VaD-X

VaD: vascular dementia; AD: Alzheimer’s disease; LBD: Lewy Body Dementia.
Figure 3. Classification of forms of vascular dementia according to the VICCCS (Vascular Impairment of Cognition Classification Consensus Study) (1).
Each form will be further stratified into possible and probable (Table 3). Mixed forms can occur in all of the above syndromes, and the suspected
neurodegenerative syndrome should be detailed (VD-AD and VD-LBD were used as examples, with X denoting other possible associations).

CLINICAL MANIFESTATIONS AND DIAGNOSTIC A detailed protocol must be followed to establish

WORKUP OF VCI/DEMENTIA
T he clinical manifestations of VCI/dementia
include cognitive impairment, functional decline,
neuropsychiatric symptoms, neurological manifestations
and autonomic dysfunction, in variable proportions and
associations, according to the type, location, number and
extent of the lesions10,11.
diagnosis, including several steps, i.e., clinical history
(clinical, cognitive, neurologic, psychiatric), physical
examination (clinical-cardiological, neurologic),
neuropsychological assessment (screening, comprehensive
assessment), functional assessment, neuropsychiatric
evaluation, and diagnostic exams (neuroimaging,
laboratory testing, among others)9,23,32 (Figure 4).

Anamnesis (global, cognitive, neurological, psychiatric)

Physical Examination (clinical, cardiological, neurovascular)

Secondary level Tertiary level

Primary care
(general neurologist, (research centers,
psychiatrists, geriatricians) specialist in cognitive
and behavioral neurology)

Cognitive and Cognitive screening Comprehensive testing

Expanded evaluation
function evaluation (MoCa or MMSE + BB + SVF + CDT) (MoCa, MMSE + CAMCOG subscale, ACE-R)
(NPS, cognitive protocol)
Depression screening Depression screening
NPI-Q, CDR CES-D ou GDS)

Complementary CSF studies Functional neuroimaging

BAsic laboratory tests
tests Structural neuroimaging Genetic studies
Basic neuroimaging*
Vascular neuroimaging Biomarkers
Biomarkers

MoCa: Montreal cognitive assessment; MMSE: Mini-Mental State Examination; BB: Brief Battery of Cognitive Screening; SVF: semantic verbal fluency; TDR: clock design test; CAMCOG:
Cambridge Cognitive Examination; ACE-R: Addenbrooke’s Cognitive Examination-Revised; NPS: neuropsychological assessment; NPI-Q: Neuropsychiatric Inventory Questionnaire; CDR:
clinical dementia rating; CES-D: Center for Epidemiologic Studies - Depression; GDS: Geriatric Depression Scale.
Figure 4. Flowchart proposed for the assessment and investigation of patients with suspected VCI / VD.
*Basic neuroimaging refers at least to Computed Tomography of the Skull.

56   Vascular cognitive impairment.   Barbosa BJAP, et al.


Which components of the history are essential in
evaluating patients with suspected VCI and dementia?76
The patient’s history is essential for characterizing
cognitive deficits, generating a differential diagnosis,
and determining the cause of dementia. The best way to
do this is to identify medical, neurologic and psychiatric
symptoms as clues to the probable cause of the
cognitive changes, establishing the order of appearance,
the severity and the associated features. Ideally in VD
the loss of function should be temporally correlated with
cerebrovascular events. A reliable relative/informant
plays an important role in providing information since
cognitive dysfunction may impair the patient’s ability
to report accurately.
VD should be suspected in any patient presenting
cerebrovascular RF, even if the neurologic examination
does not suggest stroke. A stepwise deterioration may
be observed. It may be present in patients with silent
stroke, in those with several small strokes, or in those
with severe diffuse subcortical cerebrovascular disease.
Which methods clinicians should use to detect VCI/VD?
At first, the indiscriminate assessment of elderly
individuals for dementia is not recommended 77,78.
In the evaluation of older patients for dementia,
clinicians should use a standardized screening tool,
along with a brief patient history obtained from
a reliable informant (a person who is directly in contact
with the patient).
Screening tools
The screening instrument must be easy to use,
highly sensitive, widely available and supported by
populational data76. The Mini-Mental State Examination
(MMSE) is widely used and contributes to the diagnosis
of dementia in low prevalence settings. However,
it should not be used in isolation to confirm or exclude
the disease79. To improve diagnostic accuracy in low
educated populations, we suggest the association
of Brief Cognitive Battery 80-82, which includes an
interference with a semantic verbal fluency (animals)
and the clock drawing test (CDT). Other options
are the Mini-Cog 83 and the Montreal Cognitive
Assessment (MoCA)84.
The Mini-Cog has the benefit of brevity and the
MoCA has the best sensitivity but lower specificity85.
The MoCA was originally developed for the detection
of MCI and may be difficult for people with moderate
or advanced dementia, as well as for populations
with low educational backgrounds. For those whose
previous cognitive function was measured with
the MMSE, there is a tool that links the MoCA scores
Dement Neuropsychol 2022 September;16(3 Suppl. 1):49-68
to the corresponding MMSE ones86. A meta-analysis
carried out by the Cochrane showed sensitivity
of 0.76 and specificity of 0.73 of the Mini-Cog for
the diagnosis of dementia in general 87 . For the
diagnosis of dementia in the primary care settings,
the number of studies evaluating the accuracy of the
Mini-Cog was limited.
Despite the large amount of short cognitive
screening tools, few are valid for patients with suspected
VCI. A systematic review on screening tests for
the identification of VCI88, the MoCA, the MMSE,
the Brief Memory and Executive Test – BMET –
and different versions of the Clock Design Test were
the most widely validated instruments. Based on
available evidence, the authors concluded that the
MoCA was the most accurate and reliable instrument,
however this finding still needs further validation
in our population. The BMET has already been adapted
for Brazilian individuals89.
Cognitive assessment tests in the context of VCI
Cognitive screening tests used in the assessment
of AD, particularly the MMSE, are not ideal for
vascular cognitive impairment. Those including the
assessment of frontal, executive, and subcortical
functions are preferred. Modifications of tests originally
developed for AD, such as the Vascular Version of
the Alzheimer’s Disease Assessment Scale-Cognitive
Subscale (VADAS-Cog), may be useful90. Some of them
may be able to differentiate AD from VCI, but even with
the use of biomarkers to eliminate the presence of AD
pathology (e.g., a negative amyloid PET), some overlap
may persist between the cognitive changes of vascular
cognitive impairment and AD91. Validation data exist
for the MoCA92,93 and for the Addenbrooke Cognitive
Exam Revised Version94, both already validated for the
Brazilian population95-97. There are some suggestions
for protocols of cognitive assessment for the detection
of VCI/VD that have been published in the last two
decades and are summarized in Suplementary Material.
In Brazil, a previous review on VD was published
by the Scientific Department of Cognitive Neurology
from the Brazilian Academy of Neurology (ABN)10.
In this document, the expert panel emphasized
that the pattern of cognitive changes was highly
variable, requiring sufficient sensitivity from the
neuropsychological protocols to detect a wide range of
domains, mainly executive function. The selected tests
must meet criteria of frequency and validity, be freely
available, and be well known and sensitive to detect
cognitive decline. The protocols must be broad, easy to
administer and relatively brief32. The recommendations
Barbosa BJAP, et al.   Vascular cognitive impairment.   57
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):49-68

included a brief screening protocol for VCI/VD,
consisting of the MMSE, the semantic verbal fluency
test (animals) and the CDT10. The authors also included
a broader and time-consuming protocol composed of
a wider range of tests (Appendix). This version included
the Cambridge Cognitive Examination (CAMCOG) scale
with the global and subscale scores, which has been
adapted and validated for the Brazilian population98,99.
The National Institute for Neurological Disorders
and Stroke (NINDS) and the Canadian Stroke Network
established a working group to define criteria for VCI23.
In this document, the Neuropsychological Working
Group proposed three separate protocols which were
recommended for multicenter investigations with
VCI patients, one requiring at least 60 minutes,
a second of 30 minutes and a third of five minutes
(Suplementary Material). The longer one, 60 minutes,
was developed for use in studies requiring an analysis
of cognitive skills by domain, thus the protocol
contained recommended tests in four domains:
executive/activation, language, visuospatial and
memory. In addition, tests were selected to examine
changes in behavior and mood. The other two protocols
were selected from within the 60-minute protocol to
be used as a clinical screening tool for suspected VCI
patients. The 5-minute protocol was projected for
potential use by primary care physicians, nurses,
and other health care professionals. The 5-minute
protocol was also designed for large epidemiological
studies or clinical trials where sensitivity and
ease of administration are especially important.
In addition, once validated the 5-minute protocol
was also designed to be administered over the phone.
Most of the tests included in these protocols are
available in Brazil, especially the 5-minute version
that is sourced from MoCA.
Based on all the above data, this panel recommends
the use of screening/cognitive assessment tests for the
detection of VCI according to the level of health care
in which the patient is inserted (Table 4).

Table 4. Cognitive screening recommendation on vascular cognitive impairment stratified by health care levels.

Health level Cognitive screening recommendation for CCV

General practitioners and professionals from the Family Health Strategy can use screening instruments such
Primary attention as MoCA, or alternatively the MMSE associated with the clock drawing test and semantic verbal fluency (animals)
and screening for depressive symptoms.

Specialist physicians (neurologists, geriatricians, and psychiatrists) who receive patients referred from primary
Secondary Care care can use a broader protocol that includes global function tests (MoCA or MMSE) associated with CAMCOG
subscales, or Addenbrooke battery (ACE-R) and screening for depressive symptoms.

Specialist physicians at referral centers can use expanded assessment including, in addition to a cognitive protocol,
Tertiary care the assessment of neuropsychiatric symptoms (NPI-Q), assessment of severity of dementia (CDR), and screening
for depressive symptoms (CES-D or GDS).

Assessment of functionality home/hobbies and personal care) (CDR FUNC) of

The use of the Clinical Dementia Rating scale (CDR)
presents some difficulties for cases of vascular nature,
although the scale has been validated for such cases
in the Brazilian settings 100. CDR is strongly based
on memory impairment. However, other domains,
such as executive function, are especially important
in vascular cases.
A study of subcortical VCI (70% of cases with
CDR 0.5) showed, in cases of moderate and severe
subcortical lesions, that the sum of the “functional”
boxes (judgment/problem solving, community affairs,
the CDR presented correlation with the Pfeffer’s
Functional Activities Questionnaire (FAQ), CLOX 2,
working memory and abstraction101.
A study with the CDR scale defined mild VCI as a MCI
status of VCI or a CDR 0.5 status with cardiovascular
disease. Thus, for the assessment of daily life the
information from caregivers is necessary, especially
in the domains (“boxes”) of “community affairs”,
“home and hobbies” and “personal care” 25. Thus,
the use of the CDR scale can be accepted, as long as the
sum of the functional boxes is considered valid.

58   Vascular cognitive impairment.   Barbosa BJAP, et al.


Laboratory diagnosis
No laboratory test or biomarker is specific for VCI.
Conversely, routine exams can assess comorbidities
or RF for cognitive decline. Evaluation of blood
count, serology, glucose levels, B12, thyroid, kidney,
and liver function, is often required – as detailed
in a specific article of the present consensus.
A metabolic profile with cholesterol and triglycerides
is also important. AD biomarkers (beta-amyloid,
tau, and phospho-tau) in the CSF may play a role in
selected cases when the presence of mixed pathology
is questionable 102 . O ther CSF measurements
(proteins, electrophoresis) may help to differentiate
inf lammator y causes or suggest a blood-brain
barrier dysfunction (e.g., vasculitis or demyelinating
diseases), albeit they are not part of the routine
assessment of suspected cases of VCI103.
Neuroimaging diagnosis
Neuroimaging is critical to detecting CVD causing
VCI. MRI is the best and most accurate technique to
visualize lesions produced by large vessels (infarctions),
lesions resulting from small vessel diseases (WMH,
small subcor tical infarcts, lacunae, enlarged
perivascular spaces, cerebral microhemorrhages).
Cerebral hemorrhages (lobar, deep) can be well
visualized through computed tomography (CT)25.
Currently, there are no criteria to define the
necessar y load of vascular lesions detected by
neuroimaging to confirm the presence of VMCI,
lacking a cutoff point for such definition 104 .
Macroscopic findings of conventional neuroimaging
(FLAIR sequences, CT) often partially explain the
clinical expression (phenotype) of VD and usually
represent heterogeneous pathological alterations52.
Thus, the presence of hidden aspects (“invisible
changes”) could contribute to clinical expression,
which can be verified by more advanced techniques,
such as diffusion tensor imaging (DTI) or other
techniques capable of identifying areas of “WM
of normal appearance” 51,105. In addition, advanced
MRI techniques with analysis of structural and
functional brain connectivity can contribute to
possible investigations of how changes in more
complex brain networks can explain the diversity of
clinical presentations in these conditions, even in
cases with anatomical changes in similar conventional
sequences 16, which can optimize the anatomical-
clinical correlation in the future.
Dement Neuropsychol 2022 September;16(3 Suppl. 1):49-68
A recent systematic review on VMCI (subcortical),
analyzing studies that assessed lesions qualitatively
(WM lesion extension) and semi quantitatively
(number of lacunes), showed the presence of moderate
to severe vascular lesion load106.
The application of visual scales can help the clinician
in the differential diagnosis, in the anatomical-clinical
correlation, especially with cognitive alterations,
as well as in therapeutic monitoring 107 (Table 5)
(Figure 5). Conversely, the characterization of CVD
through neuroimaging also usually contributes to
the systemic treatment of the patient. The occurrence
of WM lesions, either periventricular (PVWM) or diffuse
(DWM), may exhibit differences in etiopathogenesis;
for example, a combination of granular ependymitis
(ependymitis granularis) and axonal demyelination
may be related to PVWM 112 , whereas gliosis of
the subependymal areas (subependymal gliosis)
combined with chronic small vessel ischemia seems
to contribute in more significant proportion to the
occurrence of DWM113.
MRI can offer advantages in observing PVWH and
DWM through T2 and FLAIR sequences; conversely,
both CT and MRI seem to identify cortical and lacunar
infarcts in a similar way106. Evidence of hyperintensity,
once nonspecific, is associated with CVD and AD
pathology; the volume of WM alterations is regarded
as a possible independent marker of beta-amyloid
protein accumulation114.
The finding of lesions caused by multiple infarctions
can direct clinical investigation towards the occurrence
of coagulopathies, infectious and parasitic diseases,
alcoholism, and heart failure115,116. Perivascular disease,
seen as microintensities at the cortico-subcortical
junctions, has been independently associated with
an increased risk for cognitive decline117. In Brazil
and most countries of Latin America, the high
occurrence of subcortical ischemic vascular disease
is usually associated with late diagnosis of systemic
hypertension, diabetes and dyslipidemia, as reported
by the ELSA study118.
In conclusion, the evolution of the VCI concept
from preclinical stages to VMCI and VD turns
diagnostic assessment into a challenge for the
multidisciplinary team. The patient with suspected
VMCI should be evaluated from primary care by
general practitioners, with complementary work up
being carried out at the secondary and tertiary levels
in a horizontal manner, according to the need for
more advanced instruments, particularly advanced
neuroimaging techniques.
Barbosa BJAP, et al.   Vascular cognitive impairment.   59
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):49-68
Table 5. Main visual scales in CVD.
Scale [reference] Brain region [indication]
White matter hyperintensities
Fazekas et al.114
periventricular and deep
Deep white matter and subcortical
Modified Fazekas (LADIS)115
lesions (DSWM)
PVH, DWMH, basal and infratentorial
Scheltens et al.116
ganglia hyperintensities
Hyperintensities of hemispheres
ARWMC scale117
and basal ganglia
Figure 5. Evaluation of White Substance Hyperintensities according to the Fazekas visual scale107.
60   Vascular cognitive impairment.   Barbosa BJAP, et al.
Method [scores]
Periventricular hyperintensities:
0=absent
1= “hoods” or thin coat
2=smooth halo
3=periventricular hyperintensities extending into deep white matter
Deep white substance:
0=absent
1=point-like foci
2=initial confluence
3=large confluent areas
0=absent
1=[mild] punctiform lesions with maximum unit diameter below 10 mm
and areas of clustered lesions smaller than 20 mm
2=[moderate] single lesions between 10-20 mm in diameter, areas of
clustered lesions greater than 20 mm in diameter, no more than connecting
bridges between individual lesions 3=[severe] single lesions or confluent
areas of hyperintensities 20 mm or more in diameter
PVH (0-6), WMH (0-24), basal and infratentorial ganglia (both 0-24)
Total=0 to 84
White matter lesions:
0 = absence
1= focal lesions
2=initial confluent lesions
3= diffuse involvement of the entire region
Basal ganglia:
0=absence
1=focal lesions (≥5 mm)
2= >1 focal lesion
3=confluent lesions
Total = 0 to 30

ACKNOWLEDGEMENTS
PC, LCS and RN are funded by CNPq, Brazil (bolsa de
produtividade em pesquisa).
Authors’ contributions. BJAPB, JISN, GSA, FKS, CKS, FTM,
EE, MLFC, JS, LPS: concept; BJAPB, JISN, GSA, FKS,
REFERENCES
1. Skrobot OA, Black SE, Chen C, DeCarli C, Erkinjuntti T, Ford GA, et al.
Progress toward standardized diagnosis of vascular cognitive impairment:
Guidelines from the Vascular Impairment of Cognition Classification
Consensus Study. Alzheimers Dement. 2018;14(3):280-92. doi:10.1016/
j.jalz.2017.09.007.
2. Hachinski V. Vascular dementia: a radical redefinition. Dementia. 1994;5(3-4):
130-2. doi:10.1159/000106709.
3. Loeb C. Vascular dementia. In: Handbook of clinical neurology.
Amsterdam: Elsevier; 1985. p. 353-69. (Neurobehavioral Disorders; vol. 2).
4. Hachinski P. Preventable senility: a call for action against the vascular
dementias. Lancet. 1992;340(8820):645-8. doi:10.1016/0140-
6736(92)92177-h.
5. Ebly EM. Cognitive Impairment in the Nondemented Elderly: Results From
the Canadian Study of Health and Aging. Arch Neurol. 1995;52(6):612-9.
doi:10.1001/archneur.1995.00540300086018.
6. Rockwood K, Wentzel C, Hachinski V, Hogan DB, MacKnight C, McDowell I.
Prevalence and outcomes of vascular cognitive impairment. Neurology.
2000;54(2):447-51. doi:10.1212/wnl.54.2.447.
7. Petersen RC, Doody R, Kurz A, Mohs RC, Morris JC, Rabins PV,
et al. Current Concepts in Mild Cognitive Impairment. Arch Neurol.
2001;58(12):1985-92. doi:10.1001/archneur.58.
8. Meyer JS, Xu G, Thornby J, Chowdhury MH, Quach M. Is Mild Cognitive
Impairment Prodromal for Vascular Dementia Like Alzheimer’s Disease?
Stroke. 2002;33(8):1981-5. doi:10.1161/01.str.0000024432.34557.
9. Gorelick PB, Scuteri A, Black SE, DeCarli C, Greenberg SM, Iadecola C,
et al. Vascular Contributions to Cognitive Impairment and Dementia:
A Statement for Healthcare Professionals From the American Heart
Association/American Stroke Association. Stroke. 2011;42(9):2672-713.
doi:10.1161/STR.0b013e3182299496.
10. Engelhardt E, Tocquer C, André C, Moreira DM, Okamoto IH, Cavalcanti JLS.
Vascular dementia: Cognitive, functional and behavioral assessment.
Recommendations of the Scientific Department of Cognitive Neurology and
Aging of the Brazilian Academy of Neurology. Part II. Dement Neuropsychol.
2011;5(4):264-74. doi:10.1590/S1980-57642011DN05040004.
11. Engelhardt E, Tocquer C, André C, Moreira DM, Okamoto IH, Cavalcanti JLS.
Vascular dementia: Diagnostic criteria and supplementary exams.
Recommendations of the Scientific Department of Cognitive Neurology and
Aging of the Brazilian Academy of Neurology. Part I. Dement Neuropsychol.
2011;5(4):251-63. doi:10.1590/S1980-57642011DN05040003.
12. Brucki SMD, Ferraz AC, Freitas GR, Massaro AR, Radanovic M,
Schultz RR. Treatment of vascular dementia. Recommendations of the
Scientific Department of Cognitive Neurology and Aging of the Brazilian
Academy of Neurology. Dement Neuropsychol. 2011;5(4):275-87.
doi:10.1590/S1980-57642011DN05040005.
13. Skrobot OA, O’Brien J, Black S, Chen C, DeCarli C, Erkinjuntti T, et al.
The Vascular Impairment of Cognition Classification Consensus Study.
Alzheimers Dement. 2017;13(6):624-33. doi:10.1016/j.jalz.2016.10.007.
14. Sachdev P, Kalaria R, O’Brien J, Skoog I, Alladi S, Black SE, et al.
Diagnostic Criteria for Vascular Cognitive Disorders: A VASCOG
Statement. Alzheimer Dis Assoc Disord. 2014;28(3):206-18. doi:10.1097/
WAD.0000000000000034.
15. American Psychiatric Association. Diagnostic and statistical manual of
mental disorders. 5a ed. Washington (DC): APA; 2013. doi:10.1176/
appi.books.9780890425596.dsm05.
16. Ter Telgte A, Leijsen EMC, Wiegertjes K, Klijn CJM, Tuladhar AM, Leeuw
FE. Cerebral small vessel disease: from a focal to a global perspective.
Nat Rev Neurol. 2018;14(7):387-98. doi:10.1038/s41582-018-0014-y.
17. Calil V, Elliott E, Borelli WV, Barbosa BJAP, Bram J, Silva FO, et al. Chal-
lenges in the diagnosis of dementia: insights from the United Kingdom-
-Brazil Dementia Workshop. Dement Neuropsychol. 2020;14(3):201-8.
doi:10.1590/1980-57642020dn14-030001.
18. Rizzi L, Rosset I, Roriz-Cruz M. Global epidemiology of dementia:
Alzheimer’s and vascular types. Biomed Res Int. 2014;2014:908915.
doi:10.1155/2014/908915.
Dement Neuropsychol 2022 September;16(3 Suppl. 1):49-68
CKS, FTM, EE, MLFC: drafting of the manuscript; BJAPB,
FACV, JS, LCS, LPS, MLFB, MLFC, NAFF, PC, PHFB, RN,
SMDB: critical revision of the manuscript for important
intellectual content.
19. Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S,
et al. Dementia prevention, intervention, and care: 2020 report of the
Lancet Commission. Lancet. 2020;396(10248):413-46. doi:10.1016/
S0140-6736(20)30367-6.
20. Jørgensen IF, Aguayo-Orozco A, Lademann M, Brunak S. Age-stratified
longitudinal study of Alzheimer’s and vascular dementia patients.
Alzheimers Dement. 2020;16(6):908-17. doi:10.1002/alz.12091.
21. Stephens S, Kenny RA, Rowan E, Allan L, Kalaria RN, Bradbury M, et al.
Neuropsychological characteristics of mild vascular cognitive impairment
and dementia after stroke. Int J Geriat Psychiatry. 2004;19(11):1053-7.
doi:10.1002/gps.1209.
22. Rasquin SMC, Oostenbrugge RJ, Verhey FRJ, Lodder J. Vascular mild
cognitive impairment is highly prevalent after lacunar stroke but does not
increase over time: a 2-year follow-up Study. Dement Geriatr Cogn Disord.
2007;24(5):396-401. doi:10.1159/000109747.
23. Hachinski V, Iadecola C, Petersen RC, Breteler MM, Nyenhuis DL,
Black SE, et al. National Institute of Neurological Disorders and
Stroke-Canadian Stroke Network Vascular Cognitive Impairment
Harmonization Standards. Stroke. 2006;37(9):2220-41. doi:10.1161/
01.STR.0000237236.88823.47.
24. Brucki SMD, Machado MF, Rocha MSG. Vascular Cognitive Impairment
(VCI) after non-embolic ischemic stroke during a 12-month follow-up
in Brazil. Dement Neuropsychol. 2012;6:164-9. doi:10.1590/
S1980-57642012DN06030009.
25. Meguro K, Dodge HH. Vascular Mild Cognitive Impairment: Identifying
Disease in Community-Dwelling Older Adults, Reducing Risk Factors,
and Providing Support. The Osaki-Tajiri and Kurihara Projects.
Anstey K, Peters R, editors. J Alzheimers Dis. 201913;70(s1):S293-302.
doi:10.3233/JAD-180899.
26. Hughes TF, Liu A, Jacobsen E, Rosano C, Berman SB, Chang CCH, et al.
Exercise and the Risk of Mild Cognitive Impairment: Does the Effect
Depend on Vascular Factors? Alzheimer Dis Assoc Disord. 2021;35(1):30-5.
doi:10.1097/WAD.0000000000000410.
27. Alonso A, Knopman DS, Gottesman RF, Soliman EZ, Shah AJ, O’Neal WT,
et al. Correlates of Dementia and Mild Cognitive Impairment in Patients
With Atrial Fibrillation: The Atherosclerosis Risk in Communities
Neurocognitive Study (ARIC–NCS). J Am Heart Assoc. 2017;6(7).
doi:10.1161/JAHA.117.006014.
28. World Health Organization. Risk reduction of cognitive decline and
dementia: WHO guidelines [Internet]. 2019 [citado em 26 jul 2022].
Disponível em: https://www.who.int/publications/i/item/9789241550543
29. Suemoto CK, Ferretti-Rebustini REL, Rodriguez RD, Leite REP,
Soterio L, Brucki SMD, et al. Neuropathological diagnoses and clinical
correlates in older adults in Brazil: A cross-sectional study. PLoS Med.
2017;14(3):e1002267. doi:10.1371/journal.pmed.1002267.
30. Gorelick PB, Counts SE, Nyenhuis D. Vascular cognitive impairment and
dementia. Biochim Biophys Acta. 2016;1862(5):860-8. doi:10.1016/
j.bbadis.2015.12.015.
31. Livingston G, Sommerlad A, Orgeta V, Costafreda SG, Huntley J,
Ames D, et al. Dementia prevention, intervention, and care. Lancet.
2017;390(10113):2673-734. doi:10.1016/S0140-6736(17)31363-6.
32. Iadecola C, Duering M, Hachinski V, Joutel A, Pendlebury ST, Schneider JA,
et al. Vascular Cognitive Impairment and Dementia. J Am Coll Cardiol.
2019;73(25):3326-44. doi:10.1016/j.jacc.2019.04.034.
33. Grinberg LT. Vascular dementia: current concepts and nomenclature
harmonization. Dement Neuropsychol. 2012;6(3):122-6. doi:10.1590/
S1980-57642012DN06030002.
34. Skrobot OA, Attems J, Esiri M, Hortobágyi T, Ironside JW, Kalaria RN,
et al. Vascular cognitive impairment neuropathology guidelines (VCING):
the contribution of cerebrovascular pathology to cognitive impairment. Brain.
2016;139(11):2957-69. doi:10.1093/brain/aww214.
35. Jellinger KA. Current Pathogenetic Concepts of Vascular Cognitive
Impairment. J Neurol Neurol Sci Disord. 2016;2(1):10-6. doi:10.17352/
jnnsd.000009.
Barbosa BJAP, et al.   Vascular cognitive impairment.   61
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):49-68
36. Jokinen H, Koikkalainen J, Laakso HM, Melkas S, Nieminen T, Brander A,
et al. Global Burden of Small Vessel Disease-Related Brain Changes on
MRI Predicts Cognitive and Functional Decline. Stroke. 2020;51(1):170-8.
doi:10.1161/STROKEAHA.119.026170.
37. De Luca C, Virtuoso A, Maggio N, Papa M. Neuro-Coagulopathy: Blood
Coagulation Factors in Central Nervous System Diseases. Int J Mol Sci.
2017;18(10):2128. doi:10.3390/ijms18102128.
38. Rajani RM, Williams A. Endothelial cell-oligodendrocyte interactions
in small vessel disease and aging. Clin Sci. 2017;131(5):369-79.
doi:10.1042/CS20160618.
39. Ungvari Z, Tarantini S, Kiss T, Wren JD, Giles CB, Griffin CT, et al. Endothelial
dysfunction and angiogenesis impairment in the ageing vasculature.
Nat Rev Cardiol. 2018;15(9):555-65. doi:10.1038/s41569-018-0030-z.
40. Engelhardt E. Brown-Séquard: On neural networks and brain localization
of functions. Dement Neuropsychol. 2014;8(1):79-82. doi:10.1590/
S1980-57642014DN81000012.
41. Jellinger KA. Pathology and pathogenesis of vascular cognitive
impairment – a critical update. Front Aging Neurosci. 2013;5:1-19.
doi:10.3389/fnagi.2013.00017
42. Shin M, Sohn MK, Lee J, Kim DY, Lee SG, Shin YI, et al. Effect of
Cognitive Reserve on Risk of Cognitive Impairment and Recovery After
Stroke: The KOSCO Study. Stroke. 2020;51(1):99-107. doi:10.1161/
STROKEAHA.119.026829.
43. Mesulam MM, editor. Principles of behavioral and cognitive neurology.
2nd ed. Oxford: Oxford University Press; 2000.
44. Zekry D, Duyckaerts C, Belmin J, Geoffre C, Herrmann F, Moulias R,
et al. The vascular lesions in vascular and mixed dementia: the weight
of functional neuroanatomy. Neurobiology of Aging. 2003;24(2):213-9.
doi:10.1016/s0197-4580(02)00066-0.
45. Staekenborg SS, Straaten ECW, Flier WM, Lane R, Barkhof F,
Scheltens P. Small vessel versus large vessel vascular dementia: Risk
factors and MRI findings. J Neurol. 2008;255(11):1644-51. doi:10.1007/
s00415-008-0944-1.
46. Straaten ECW, Scheltens Ph, Barkhof F. MRI and CT in the diagnosis of
vascular dementia. Journal of the Neurological Sciences. 2004;226(1-2):
9-12. doi:10.1016/j.jns.2004.09.003.
47. Sudo FK, Amado P, Alves GS, Laks J, Engelhardt E. A continuum of
executive function deficits in early subcortical vascular cognitive impair-
ment: A systematic review and meta-analysis. Dement Neuropsychol.
2017;11(4):371-80. doi:10.1590/1980-57642016dn11-040006.
48. Tullberg M, Fletcher E, DeCarli C, Mungas D, Reed BR, Harvey DJ, et al.
White matter lesions impair frontal lobe function regardless of their location.
Neurology. 2004;63(2):246-53. doi:10.1212/01.wnl.0000130530.55104.b5.
49. Zhao QL, Zhou Y, Wang YL, Dong KH, Wang YJ. A new diagnostic algorithm
for vascular cognitive impairment: the proposed criteria and evaluation of its
reliability and validity. Chin Med J (Engl). 2010;123(3):311-9.
50. Gouw AA, Seewann A, Flier WM, Barkhof F, Rozemuller AM, Scheltens P,
et al. Heterogeneity of small vessel disease: a systematic review of
MRI and histopathology correlations. J Neurol Neurosurg Psychiatry.
2011;82(2):126-35. doi:10.1136/jnnp.2009.204685.
51. Min ZG, Shan HR, Xu L, Yuan DH, Sheng XX, Xie WC, et al. Diffusion
tensor imaging revealed different pathological processes of white matter
hyperintensities. BMC Neurol. 2021;21(1):128. doi:10.1186/s12883-
021-02140-9.
52. McAleese KE, Alafuzoff I, Charidimou A, De Reuck J, Grinberg LT,
Hainsworth AH, et al. Post-mortem assessment in vascular dementia:
advances and aspirations. BMC Med. 2016;14(1):129. doi:10.1186/
s12916-016-0676-5.
53. Grinberg LT, Heinsen H. Toward a pathological definition of vascular
dementia. J Neurol Sci. 2010;299(1-2):136-8. doi:10.1016/j.jns.2010.08.055.
54. Kalaria RN. Neuropathological diagnosis of vascular cognitive impairment
and vascular dementia with implications for Alzheimer’s disease.
Acta Neuropathol. 2016;131(5):659-85. doi:10.1007/s00401-016-1571-z.
55. Rockwood K, Davis H, MacKnight C, Vandorpe R, Gauthier S, Guzman A,
et al. The Consortium to Investigate Vascular Impairment of Cognition:
Methods and First Findings. Can J Neurol Sci. 2003;30(3):237-43.
doi:10.1017/s0317167100002663.
56. Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R,
et al. Neuroimaging standards for research into small vessel disease
and its contribution to ageing and neurodegeneration. Lancet Neurol.
2013;12(8):822-38. doi:10.1016/S1474-4422(13)70124-8.
57. Wardlaw JM, Valdés Hernández MC, Muñoz-Maniega S. What are
white matter hyperintensities made of? Relevance to vascular cognitive
impairment. J Am Heart Assoc. 2015;4(6):001140. doi:10.1161/
JAHA.114.001140.
58. Debette S, Schilling S, Duperron MG, Larsson SC, Markus HS. Clinical
Significance of Magnetic Resonance Imaging Markers of Vascular
Brain Injury: A Systematic Review and Meta-analysis. JAMA Neurol.
2019;76(1):81-94. doi:10.1001/jamaneurol.2018.3122.
62   Vascular cognitive impairment.   Barbosa BJAP, et al.
59. Hu HY, Ou YN, Shen XN, Qu Y, Ma YH, Wang ZT, et al. White matter
hyperintensities and risks of cognitive impairment and dementia:
A systematic review and meta-analysis of 36 prospective studies. Neurosci
Biobehav Rev. 2021;120:16-27. doi:10.1016/j.neubiorev.2020.11.007.
60. Jack CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB,
et al. NIA-AA Research Framework: Toward a biological definition of
Alzheimer’s disease. Alzheimers Dement. 2018;14(4):535-62. doi:10.1016/
j.jalz.2018.02.018.
61. Hachinski V, Einhäupl K, Ganten D, Alladi S, Brayne C, Stephan BCM,
et al. Preventing dementia by preventing stroke: The Berlin Manifesto.
Alzheimers Dement. 2019;15(7):961-84. doi:10.1016/j.jalz.2019.06.001.
62. Azarpazhooh MR, Hachinski V. Vascular cognitive impairment: A preventable
component of dementia. In: Dekosky ST, Asthana S. Handbook of Clinical
Neurology: Geriatric Neurology. Vol. 167. Amsterdam: Elsevier; 2019.
Chapter 20. doi:10.1016/B978-0-12-804766-8.00020-0
63. World Health Organization. ICD-11 for Mortality and Morbidity Statistics
[Internet]. 2016 [citado em 18 fev 2021]. Disponível em: https://icd.who.int/
browse11/l-m/en
64. Stephan BC, Matthews FE, Khaw KT, Dufouil C, Brayne C. Beyond mild
cognitive impairment: vascular cognitive impairment, no dementia (VCIND).
Alzheimers Res Ther. 2009;1(1):4. doi:10.1186/alzrt4.
65. Zanetti M, Ballabio C, Abbate C, Cutaia C, Vergani C, Bergamaschini L.
Mild Cognitive Impairment Subtypes and Vascular Dementia in Community-
Dwelling Elderly People: A 3-Year Follow-Up Study. J Am Geriatr Soc.
2006;54(4):580-6. doi:10.1111/j.1532-5415.2006.00658.x.
66. Wentzel C, Rockwood K, MacKnight C, Hachinski V, Hogan DB, Feldman H,
et al. Progression of impairment in patients with vascular cognitive
impairment without dementia. Neurology. 2001;57(4):714-6. doi:10.1212/
wnl.57.4.714.
67. Madureira S, Verdelho A, Moleiro C, Santos C, Scheltens P, Gouw A,
et al. White Matter Changes and Cognitive Decline in a Ten-Year Follow-Up
Period: A Pilot Study on a Single-Center Cohort from the Leukoaraiosis
and Disability Study. Dement Geriatr Cogn Disord. 2016;41(5-6):303-13.
doi:10.1159/000447121.
68. Madureira S. Neuropsychological contribution to the study of White
Matter Changes: a 10-year longitudinal study [tese na Internet]. Lisboa:
Universidade de Lisboa; 2017 [citado em 23 maio 2021]. Disponível
em: https://repositorio.ul.pt/bitstream/10451/28880/1/ulsd730661_td_
Sofia_Madureira.pdf
69. Palmer K, Wang HX, Bäckman L, Winblad B, Fratiglioni L. Differential
Evolution of Cognitive Impairment in Nondemented Older Persons: Results
From the Kungsholmen Project. Am J Psychiatry. 2002;159(3):436-42.
doi:10.1176/appi.ajp.159.3.436.
70. Kopchak OO, Bachinskaya NY, Pulyk OR. Vascular risk factors and
cognitive functions in the patients with cerebrovascular disease.
Wiad Lek. 2020;73(10):2250-4.
71. W iederkehr S, Laurin D, Simard M, Verreault R, Lindsay J.
Vascular Risk Factors and Cognitive Functions in Nondemented
Elderly Individuals. J Geriatr Psychiatry Neurol. 2009;22(3):196-206.
doi:10.1177/0891988709335797.
72. O’Brien JT, Erkinjuntti T, Reisberg B, Roman G, Sawada T, Pantoni L,
et al. Vascular cognitive impairment. Lancet Neurol. 2003;2(2):89-98.
doi:10.1016/s1474-4422(03)00305-3.
73. Graff-Radford J. Vascular Cognitive Impairment. Continuum (Minneap
Minn). 2019;25(1):147-64. doi:10.1212/CON.0000000000000684.
74. Arvanitakis Z, Leurgans SE, Wang Z, Wilson RS, Bennett DA, Schneider JA.
Cerebral amyloid angiopathy pathology and cognitive domains in older
persons. Ann Neurol. 2011;69(2):320-7. doi:10.1002/ana.22112.
75. Oh ES, Rabins PV. Dementia. Ann Intern Med. 2019;171(5):ITC33-48.
doi:10.7326/AITC201909030.
76. Ramos AM, Stein AT, Castro Filho ED, Chaves MLF, Okamato I, Nitrini R.
Demência do Idoso: diagnóstico na Atenção Primária. São Paulo:
Associação Médica Brasileira; 2009.
77. Patnode CD, Perdue LA, Rossom RC, Rushkin MC, Redmond N,
Thomas RG, et al. Screening for Cognitive Impairment in Older Adults:
An Evidence Update for the U.S. Preventive Services Task Force [Internet].
Rockville (MD): Agency for Healthcare Research and Quality (US); 2020
[citado em 3 jul 2021]. Evidence Synthesis, No. 189. Disponível em:
http://www.ncbi.nlm.nih.gov/books/NBK554654/
78. Creavin ST, Wisniewski S, Noel-Storr AH, Trevelyan CM, Hampton T,
Rayment D, et al. Mini-Mental State Examination (MMSE) for the
detection of dementia in clinically unevaluated people aged 65 and over in
community and primary care populations. Cochrane Database Syst Rev.
2016;2016(1):CD011145. doi:10.1002/14651858.CD011145.
79. Nitrini R, Lefèvre BH, Mathias SC, Caramelli P, Carrilho PEM, Sauaia N, et al.
Testes neuropsicológicos de aplicação simples para o diagnóstico de
demência. Arq Neuropsiquiatr. 1994;52(4):457-65. doi:10.1590/S0004-
282X1994000400001.
80. Nitrini R, Bucki SMD, Yassuda MS, Fichman HC, Caramelli P. The Figure
Memory Test: diagnosis of memory impairment in populations with

heterogeneous educational background. Dement Neuropsychol.
2021;15(2):173-85. doi:10.1590/1980-57642021dn15-020004.
81. Nitrini R, Caramelli P, Porto CS, Charchat-Fichman H, Formigoni AP,
Carthery-Goulart MT, et al. Brief cognitive battery in the diagnosis
of mild Alzheimer’s disease in subjects with medium and high levels
of education. Dement Neuropsychol. 2007;1(1):32-6. doi:10.1590/
S1980-57642008DN10100006.
82. Borson S, Scanlan J, Brush M, Vitaliano P, Dokmak A. The mini-cog:
a cognitive “vital signs” measure for dementia screening in multi-lingual
elderly. Int J Geriatr Psychiatry. 2000;15(11):1021-7. doi:10.1002/
1099-1166(200011)15:11<1021::aid-gps234>3.0.co;2-6.
83. Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V,
Collin I, et al. The Montreal Cognitive Assessment, MoCA: a brief screening
tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695-9.
doi:10.1111/j.1532-5415.2005.53221.x.
84. Roalf DR, Moberg PJ, Xie SX, Wolk DA, Moelter ST, Arnold SE.
Comparative accuracies of two common screening instruments for
classification of Alzheimer’s disease, mild cognitive impairment, and
healthy aging. Alzheimers Dement. 2013;9(5):529-37. doi:10.1016/
j.jalz.2012.10.001.
85. Saczynski JS, Inouye SK, Guess J, Jones RN, Fong TG, Nemeth E, et al.
The Montreal Cognitive Assessment: Creating a Crosswalk with the
Mini-Mental State Examination. J Am Geriatr Soc. 2015;63(11):2370-4.
doi:10.1111/jgs.13710.
86. Seitz DP, Chan CC, Newton HT, Gill SS, Herrmann N, Smailagic N, et al.
Mini-Cog for the diagnosis of Alzheimer’s disease dementia and other
dementias within a primary care setting. Cochrane Database Syst Rev.
2018;2(2):CD011415. doi:10.1002/14651858.CD011415.pub2.
87. Ghafar MZAA, Miptah HN, O’Caoimh R. Cognitive screening instruments
to identify vascular cognitive impairment: A systematic review. Int J Geriatr
Psychiatry. 2019;34(8):1114-27. doi:10.1002/gps.5136.
88. Gilly Nardy B. Instrumentos de rastreio para o Comprometimento Cognitivo
Vascular Subcortical: Revisão da literatura e adaptação do Brief Memory
and Executive Test (BMET) ao contexto brasileiro [dissertação na Internet].
Rio de Janeiro (RJ): Pontifícia Universidade Católica do Rio De Janeiro;
2019 [citado em 12 jul 2021]. Disponível em: http://www.maxwell.vrac.
puc-rio.br/Busca_etds.php?strSecao=resultado&nrSeq=46464@1
89. Ylikoski R, Jokinen H, Andersen P, Salonen O, Madureira S, Ferro J, et al.
Comparison of the Alzheimer’s Disease Assessment Scale Cognitive
Subscale and the Vascular Dementia Assessment Scale in differentiating
elderly individuals with different degrees of white matter changes.
The LADIS Study. Dement Geriatr Cogn Disord. 2007;24(2):73-81.
doi:10.1159/000103865.
90. Hong YJ, Yoon B, Shim YS, Han IW, Han SH, Park KH, et al.
Do Alzheimer’s disease (AD) and subcortical ischemic vascular dementia
(SIVD) progress differently? Arch Gerontol Geriatr. 2014;58(3):415-9.
doi:10.1016/j.archger.2013.11.005.
91. Pendlebury ST, Cuthbertson FC, Welch SJV, Mehta Z, Rothwell PM.
Underestimation of cognitive impairment by Mini-Mental State
Examination versus the Montreal Cognitive Assessment in patients with
transient ischemic attack and stroke: a population-based study. Stroke.
2010;41(6):1290-3. doi:10.1161/STROKEAHA.110.579888.
92. Webb AJS, Pendlebury ST, Li L, Simoni M, Lovett N, Mehta Z, et al.
Validation of the Montreal cognitive assessment versus mini-mental state
examination against hypertension and hypertensive arteriopathy after
transient ischemic attack or minor stroke. Stroke. 2014;45(11):3337-42.
doi:10.1161/STROKEAHA.114.006309.
93. Pendlebury ST, Mariz J, Bull L, Mehta Z, Rothwell PM. MoCA, ACE-R,
and MMSE versus the National Institute of Neurological Disorders
and Stroke-Canadian Stroke Network Vascular Cognitive Impairment
Harmonization Standards Neuropsychological Battery after TIA and stroke.
Stroke. 2012;43(2):464-9. doi:10.1161/STROKEAHA.111.633586.
94. Mioshi E, Dawson K, Mitchell J, Arnold R, Hodges JR. The Addenbrooke’s
Cognitive Examination Revised (ACE-R): a brief cognitive test battery
for dementia screening. Int J Geriatr Psychiatry. 2006;21(11):1078-85.
doi:10.1002/gps.1610.
95. César KG, Yassuda MS, Porto FHG, Brucki SMD, Nitrini R. Addenbrooke’s
cognitive examination-revised: normative and accuracy data for
seniors with heterogeneous educational level in Brazil. Int Psychogeriatr.
2017;29(8):1345-53. doi:10.1017/S1041610217000734.
96. César KG, Yassuda MS, Porto FHG, Brucki SMD, Nitrini R. MoCA Test:
normative and diagnostic accuracy data for seniors with heterogeneous
educational levels in Brazil. Arq Neuropsiquiatr. 2019;77(11):775-81.
doi:10.1590/0004-282X20190130.
97. Moreira IFH, Lourenço RA, Soares C, Engelhardt E, Laks J. Cambridge
Cognitive Examination: performance of healthy elderly Brazilians with low
education levels. Cad Saude Publica. 2009;25(8):1774-80. doi:10.1590/
S0102-311X2009000800013.
98. Moreira IFH, Bezerra AB, Sudo FK, Alves GS, Ericeira-Valente L, Tiel C,
et al. CAMCOG - valores das subescalas em idosos normais com níveis
Dement Neuropsychol 2022 September;16(3 Suppl. 1):49-68
diferentes de escolaridade. Aspectos preliminares. Rev Bras Neurol
[Internet]. 2013 [citado em 10 nov 2021];48(1):32-6. Disponível em:
http://files.bvs.br/upload/S/0101-8469/2013/v49n1/a3588.pdf
99. Chaves MLF, Camozzato AL, Godinho C, Kochhann R, Schuh A,
Almeida VL, et al. Validity of the clinical dementia rating scale for the
detection and staging of dementia in Brazilian patients. Alzheimer Dis
Assoc Disord. 2007;21(3):210-7. doi:10.1097/WAD.0b013e31811ff2b4.
100. Sudo FK, Alves GS, Moreira DM, Laks J, Engelhardt E. Subcortical
Vascular Cognitive Impairment staged through cdr’s functional subsum
(cdr-func): Preliminary results from an outpatient sample. eNeurologicalSci.
2016;5:7-10. doi:10.1016/j.ensci.2016.06.001.
101. Flier WM, Skoog I, Schneider JA, Pantoni L, Mok V, Chen CLH, et al.
Vascular cognitive impairment. Nat Rev Dis Primers. 2018;4:18003.
doi:10.1038/nrdp.2018.3.
102. Verdelho A, Wardlaw J, Pavlovic A, Pantoni L, Godefroy O, Duering M,
et al. Cognitive impairment in patients with cerebrovascular disease:
A white paper from the links between stroke ESO Dementia Committee.
Eur Stroke J. 2021;6(1):5-17. doi:10.1177/23969873211000258.
103. Consoli A, Pasi M, Pantoni L. Vascular mild cognitive impairment:
concept, definition, and directions for future studies. Aging Clin Exp Res.
2012;24(2):113-6. doi:10.1007/BF03325158.
104. Poggesi A, Salvadori E, Pantoni L, Pracucci G, Cesari F, Chiti A, et al.
Risk and Determinants of Dementia in Patients with Mild Cognitive
Impairment and Brain Subcortical Vascular Changes: A Study of
Clinical, Neuroimaging, and Biological Markers-The VMCI-Tuscany
Study: Rationale, Design, and Methodology. Int J Alzheimers Dis.
2012;2012:608013. doi:10.1155/2012/608013.
105. Sudo FK, Alves GS, Tiel C, Ericeira-Valente L, Moreira DM, Laks J, et al.
Neuroimaging criteria and cognitive performance in vascular mild cognitive
impairment: A systematic review. Dement Neuropsychol. 2015;9(4):394-404.
doi:10.1590/1980-57642015DN94000394.
106. Harper L, Barkhof F, Fox NC, Schott JM. Using visual rating to diagnose
dementia: a critical evaluation of MRI atrophy scales. J Neurol Neurosurg
Psychiatry. 2015;86(11):1225-33. doi:10.1136/jnnp-2014-310090.
107. Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA. MR signal
abnormalities at 1.5 T in Alzheimer’s dementia and normal aging.
AJR Am J Roentgenol. 1987;149(2):351-6. doi:10.2214/ajr.149.2.351.
108. Pantoni L, Basile AM, Pracucci G, Asplund K, Bogousslavsky J, Chabriat H,
et al. Impact of age-related cerebral white matter changes on the transition
to disability – the LADIS study: rationale, design and methodology.
Neuroepidemiology. 2005;24(1-2):51-62. doi:10.1159/000081050.
109. Scheltens P, Barkhof F, Leys D, Pruvo JP, Nauta JJ, Vermersch P, et al.
A semiquantative rating scale for the assessment of signal hyperintensities
on magnetic resonance imaging. J Neurol Sci. 1993;114(1):7-12.
doi:10.1016/0022-510x(93)90041-v.
110. Wahlund LO, Barkhof F, Fazekas F, Bronge L, Augustin M, Sjögren M, et al.
A new rating scale for age-related white matter changes applicable to MRI
and CT. Stroke. 2001;32(6):1318-22. doi:10.1161/01.str.32.6.1318.
111. Schmidt R, Schmidt H, Haybaeck J, Loitfelder M, Weis S, Cavalieri M, et al.
Heterogeneity in age-related white matter changes. Acta Neuropathol.
2011;122(2):171-85. doi:10.1007/s00401-011-0851-x.
112. Chowdhury MH, Nagai A, Bokura H, Nakamura E, Kobayashi S,
Yamaguchi S. Age-Related Changes in White Matter Lesions,
Hippocampal Atrophy, and Cerebral Microbleeds in Healthy Subjects
Without Major Cerebrovascular Risk Factors. J Stroke Cerebrovasc Dis.
2011;20(4):302-9. doi:10.1016/j.jstrokecerebrovasdis.2009.12.010.
113. Kandel BM, Avants BB, Gee JC, McMillan CT, Erus G, Doshi J, et al.
White matter hyperintensities are more highly associated with pre-
clinical Alzheimer’s disease than imaging and cognitive markers
of neurodegeneration. Alzheimers Dement (Amst). 2016;4:18-27.
doi:10.1016/j.dadm.2016.03.001.
114. Havakuk O, King KS, Grazette L, Yoon AJ, Fong M, Bregman N, et al.
Heart Failure-Induced Brain Injury. J Am Coll Cardiol. 2017;69(12):1609-16.
doi:10.1016/j.jacc.2017.01.022.
115. Doehner W, Ural D, Haeusler KG, Celutkiene J, Bestetti R, Cavusoglu Y,
et al. Heart and brain interaction in patients with heart failure: overview
and proposal for a taxonomy. A position paper from the Study Group on
Heart and Brain Interaction of the Heart Failure Association: Heart and
brain interaction in heart failure. Eur J Heart Fail. 2018;20(2):199-215.
doi:10.1002/ejhf.1100.
116. Passiak BS, Liu D, Kresge HA, Cambronero FE, Pechman KR, Osborn KE,
et al. Perivascular spaces contribute to cognition beyond other small
vessel disease markers. Neurology. 2019;92(12):e1309-21. doi:10.1212/
WNL.0000000000007124.
117. Teixeira MM, Passos VMA, Barreto SM, Schmidt MI, Duncan BB,
Beleigoli AMR, et al. Association between diabetes and cognitive function
at baseline in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil).
Sci Rep. 2020;10(1):1596. doi: 10.1038/s41598-020-58332-9.
Barbosa BJAP, et al.   Vascular cognitive impairment.   63
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):49-68

SUPPLEMENTARY MATERIAL
NINDS and the Canadian Stroke Network developed a 5-minute (12 points) subset of the MoCA to identify stroke
patients who developed VCI1. As the MoCA itself, the total scores on this screening test were inversely correlated
with age and positively correlated with education. The Oxford Cognitive Screen is a 15-minute test with fewer
language elements than the MoCA, making it particularly useful in acute stroke patients who may have language
deficits2. The LADIS neuropsychological battery was designed to assess the cognitive performance of a wide range
of functions in a cohort of independently living individuals with age-related white matter changes (ARWMC) during
a 3-year follow-up3. It is a short-comprehensive instrument that can be administered in a single visit. This battery
was chosen based on the test familiarity and the instrument validity to assess cognitive decline in vascular disease
patients. In addition to widely known and validated instruments (MMSE, Stroop Test, and Trail Tests), it included the
VADAS-Cog4; detailed information on global and selective cognitive functioning and time-dependent tasks (Delayed
Recall, Digit Symbol, Digit Extension, Maze, Digit Cancellation and Verbal Fluency) to complement the assessment
of attention, mental processing speed and motor control were provided. These cognitive domains and executive
function are possibly more affected by white matter alterations5. The authors concluded that the neuropsychological
performance of the patients was significantly influenced by age and education, with a higher educational level
being consistently associated with better performance on cognitive tasks. In contrast, older age was associated
with difficulties in memory and executive functions.
Tuscany - Vascular Cognitive Impairment (VCI) is a multicenter, prospective, observational study aiming
to evaluate predictors of transition from VCI (defined by the presence of moderate to severe WML) to dementia6.
The neuropsychological test battery was designed specifically for MCI due to small vessel disease (MCI-SVD),
enabling the automation and standardization of scores and a personalized cognitive profile. For the VCI-Tuscan
neuropsychological battery, tests were selected among those recommended for VCI and the protocols proposed by
the National Institute for Neurological Disorders and Stroke and the Canadian Stroke Network consensus conference
on harmonization standards for VCI7. The definition of cognitive domains followed a confirmatory analysis of
the dimensions assumed theoretically for the battery8, resulting in four cognitive clusters: memory (evaluated by
four cognitive scores), attention and executive functions (five cognitive scores), language (two cognitive scores),
and constructive praxis. Thus, the battery includes two tests of global cognitive functioning and another nine
tests covering these cognitive domains.

REFERENCES
1. Kennedy RE, Wadley VG, McClure LA, Letter AJ, Unverzagt FW, Crowe M,
et al. Performance of the NINDS-CSN 5-minute protocol in a national
population-based sample. J Int Neuropsychol Soc. 2014;20(8):856-67.
doi:10.1017/S1355617714000733.
2. Mancuso M, Demeyere N, Abbruzzese L, Damora A, Varalta V, Pirrotta F,
et al. Using the Oxford Cognitive Screen to Detect Cognitive Impairment
in Stroke Patients: A Comparison with the Mini-Mental State Examination.
Front Neurol. 2018;9:101. doi:10.3389/fneur.2018.00101.
3. Madureira S, Verdelho A, Ferro J, Basile AM, Chabriat H, Erkinjuntti T, et al.
Development of a neuropsychological battery for the Leukoaraiosis and
Disability in the Elderly Study (LADIS): experience and baseline data.
Neuroepidemiology. 2006;27(2):101-16. doi:10.1159/000095381.
4. Ferris SH. General measures of cognition. Int Psychogeriatr.
2003;15(Suppl 1):215-7. doi:10.1017/S1041610203009220.
5. Mohs RC, Knopman D, Petersen RC, Ferris SH, Ernesto C, Grundman M,
et al. Development of cognitive instruments for use in clinical trials of
antidementia drugs: additions to the Alzheimer’s Disease Assessment
Scale that broaden its scope. The Alzheimer’s Disease Cooperative Study.
Alzheimer Dis Assoc Disord. 1997;11(Suppl 2):S13-21.
6. Poggesi A, Salvadori E, Pantoni L, Pracucci G, Cesari F, Chiti A, et al.
Risk and Determinants of Dementia in Patients with Mild Cognitive
Impairment and Brain Subcortical Vascular Changes: A Study of Clinical,
Neuroimaging, and Biological Markers-The VMCI-Tuscany Study:
Rationale, Design, and Methodology. Int J Alzheimers Dis. 2012;2012:608013.
doi:10.1155/2012/608013.
7. Hachinski V, Iadecola C, Petersen RC, Breteler MM, Nyenhuis DL,
Black SE, et al. National Institute of Neurological Disorders and
Stroke-Canadian Stroke Network Vascular Cognitive Impairment
Harmonization Standards. Stroke. 2006;37(9):2220-41. doi:10.1161/
01.STR.0000237236.88823.47.
8. Salvadori E, Poggesi A, Pracucci G, Inzitari D, Pantoni L; VMCI-Tuscany
Study Group. Development and psychometric properties of a
neuropsychological battery for mild cognitive impairment with small vessel
disease: the VMCI-Tuscany Study. J Alzheimers Dis. 2015;43(4):1313-23.
doi:10.3233/JAD-141449.

64   Vascular cognitive impairment.   Barbosa BJAP, et al.

 Table. Characteristics of cognitive assessment protocols in different guidelines - cognitive tests included. References in the text.
LADIS Battery

COMMANDER
Trails
MEEM ADAS-Cog Digit- Digit span Cancellation Stroop
Maze Verbal Fluency AB
symbol WAIS-III Digits

Global Mental Functioning + +

Orientation +

Memory + +

Attention + + + +

Language +

Constructional abilities +

Executive function + + + +

Praxis +

Speed and motor control + + +

MCIV-Tuscany Battery

Rey Test Rey-Osterrieth

Digit- Short Trails
MEEM MoCA (RAVL) Copy Figure - Verbal Fluency Stroop Visual search
symbol story AB
immed - late Retrieval

Global Mental Functioning + +

Orientation

Memory ++ + +

Attention + Executive
+ ++ + +
function

Language +

Constructional abilities +

Continue...
Dement Neuropsychol 2022 September;16(3 Suppl. 1):49-68

Barbosa BJAP, et al.   Vascular cognitive impairment.   65

 Table. Continuation.

VCI-VICCCS criteria

Simple
Rey-Osterrieth
Boston Digit- Hopkins Verbal reaction
MEEM Copy Figure- Verbal Fluency NPI-Q CES-D
Naming symbol Learning Test time with
Retrieval
choice

Global Mental Functioning +

Orientation

Memory +

Attention + +

66   Vascular cognitive impairment.   Barbosa BJAP, et al.

Language + +
Dement Neuropsychol 2022 September;16(3 Suppl. 1):49-68

Constructional abilities +

Executive function + + +

Speed and motor control +

Depressive symptoms +

Neuropsychiatric
+
symptoms

Consensus Protocol A/ABN 2011

Clock
MEEM Verbal Fluency
Drawing Test

Global Mental Functioning +

Language +

Constructional abilities +

Executive function +

Continue...
 Table. Continuation.

Protocol B of consensus/ABN 2011

CAMCOG Cornell
Digit span Trails Boston Word List -
MEEM (global and Verbal Fluency CLOX NPI Depression CDR
WAIS-III AB Naming CERAD
subscales) Scale

Global Mental Functioning + +

Orientation + +

Memory +

Attention + + +

Language + + +

Constructional abilities +

Executive function + + + +

Praxis +

Gnosia +

Abstract reasoning +

Depressive symptoms +

Neuropsychiatric
+
symptoms

Severity +

Continue...
Dement Neuropsychol 2022 September;16(3 Suppl. 1):49-68

Barbosa BJAP, et al.   Vascular cognitive impairment.   67

 Table. Continuation.

NINDS - Canadian Stroke Network Vascular Cognitive Impairment (Hachinski et al., 2006)

30-minute Protocol

Hopkins
Digit- Trails Verbal
MEEM Verbal NPI-Q CES-D
symbol AB Fluency
Learning test

Global Mental Functioning +

Orientation

Memory +

Attention + +

68   Vascular cognitive impairment.   Barbosa BJAP, et al.

Language +
Dement Neuropsychol 2022 September;16(3 Suppl. 1):49-68

Constructional abilities

Executive function + + +

Speed and motor control

Depressive symptoms +

Neuropsychiatric
+
symptoms

5-minute Protocol - MoCA Subtests

Memory Phonemic
task with Orientation Verbal
words Fluency

Orientation +

Memory +

Attention + +

Executive function +
Dement Neuropsychol 2022 September;16(3 Suppl. 1):69-82 Consensus
https://doi.org/10.1590/1980-5764-DN-2022-S105EN

Diagnosis and management of

Parkinson’s disease dementia and
dementia with Lewy bodies:
recommendations of the Scientific Department
of Cognitive Neurology and Aging of the
Brazilian Academy of Neurology
Jacy Bezerra Parmera1 , Vitor Tumas2 , Henrique Ballalai Ferraz3 , Mariana Spitz4 ,
Maira Tonidandel Barbosa5,6 , Jerusa Smid1 , Breno José Alencar Pires Barbosa1,7,8 ,
Lucas Porcello Schilling9,10,11 , Márcio Luiz Figueiredo Balthazar12 , Leonardo Cruz de Souza13 ,
Francisco Assis Carvalho Vale14 , Paulo Caramelli13 , Paulo Henrique Ferreira Bertolucci3 ,
Márcia Lorena Fagundes Chaves15,16 , Sonia Maria Dozzi Brucki1 , Ricardo Nitrini1 ,
Raphael Machado Castilhos15 , Norberto Anízio Ferreira Frota17,18

1
Universidade de São Paulo, Faculdade de Medicina, Departamento de Neurologia, Grupo de Neurologia Cognitiva e do Comportamento, São Paulo SP, Brazil.
2
Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Neurociências e Ciências do Comportamento, São Paulo, SP, Brazil.
3
Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Neurologia e Neurocirurgia, São Paulo, SP, Brazil.
4
Universidade do Estado do Rio de Janeiro, Serviço de Neurologia, Rio de Janeiro, RJ, Brazil.
5
Universidade Federal de Minas Gerais, Faculdade de Medicina, Departamento de Medicina Interna, Belo Horizonte, MG, Brazil.
6
Faculdade Ciências Médicas de Minas Gerais, Medicina Geriátrica, Belo Horizonte, MG, Brazil.
7
Universidade Federal de Pernambuco, Centro de Ciências Médicas, Área Acadêmica de Neuropsiquiatria, Recife, PE, Brazil.
8
Instituto de Medicina Integral Prof. Fernando Figueira, Recife, PE, Brazil.
9
Pontifícia Universidade do Rio Grande do Sul, Escola de Medicina, Serviço de Neurologia, Porto Alegre, RS, Brazil.
10
Pontifícia Universidade do Rio Grande do Sul, Instituto do Cérebro do Rio Grande do Sul, Porto Alegre, RS, Brazil.
11
Pontifícia Universidade do Rio Grande do Sul, Programa de Pós-Graduação em Gerontologia Biomédica, Porto Alegre, RS, Brazil.
12
Universidade Estadual de Campinas, Faculdade de Ciências Médicas, Departamento de Neurologia, Campinas, SP, Brazil.
13
Universidade Federal de Minas Gerais, Departamento de Clínica Médica, Belo Horizonte, MG, Brazil.
14
Universidade Federal de São Carlos, Centro de Ciências Biológicas e da Saúde, Departamento de Medicina, São Carlos, SP, Brazil.
15
Hospital de Clínicas de Porto Alegre, Serviço de Neurologia, Porto Alegre, RS, Brazil.
16
Universidade Federal do Rio Grande do Sul, Faculdade de Medicina, Serviço de Neurologia, Porto Alegre, RS, Brazil.
17
Hospital Geral de Fortaleza, Serviço de Neurologia, Fortaleza CE, Brazil.
18
Universidade de Fortaleza, Fortaleza, CE, Brazil.
Correspondence: Jacy Bezerra Parmera; Email: jacy.parmera@hc.fm.usp.br.
Conflict of interest: JS: Participation as speaker in symposia sponsored by Roche laboratory; LPS: Participation in advisory boards for Biogen. Participation as
speaker in symposia sponsored by Aché, Apsen, and Biogen laboratories; MLFB: Participation in advisory boards for Biogen. Development of material for continuous
medical education and participation as speaker in symposia sponsored by EMS and Torrent laboratories; PC: Participation as principal investigator in clinical trials
for Novo Nordisk and Roche laboratories. Participation in advisory boards for Aché, Biogen, EMS, Nutricia, and Roche laboratories. Development of material for
continuous medical education and participation as speaker in symposia sponsored by Aché, Nutricia, Libbs, Roche, Sandoz, Torrent, and Zodiac laboratories; PHFB:
Participation in advisory boards for Biogen and Novo Nordisk laboratories. Supervision of training activities for Biogen, Janssen-Cilag, and Novo Nordisk laboratories
and for Quintiles. Participation as speaker in symposia sponsored by Apsen, Nutricia, Roche, and Sandoz laboratories; LCS: Participation in advisory board for
Biogen. Participation as speaker in symposia sponsored by Biogen; RN: Participation in advisory board for Biogen; JBP, VT, HBF, MS, MTB, BJAPB, FACV, MLFG,
SMDB, RMC, NAFF: There is no conflict of interest to declare.
Received on July 05, 2021; Received in its final form on October 13, 2022; Accepted on April 27, 2022.

Parmera JB, et al.   Brazilian consensus on Parkinson’s disease dementia.   69

 Dement Neuropsychol 2022 September;16(3 Suppl. 1):69-82

ABSTRACT. Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) represent the second most common type of degenerative dementia
in patients aged 65 years and older, leading to progressive cognitive dysfunction and impaired quality of life. This study aims to provide a consensus based
on a systematic Brazilian literature review and a comprehensive international review concerning PDD and DLB. Moreover, we sought to report on and give
recommendations about the best diagnostic approaches focusing on primary and secondary care. Based on the available data, we recommend clinicians
to apply at least one brief global cognitive instrument to assess PDD, such as the Mini-Mental State Examination and preferably the Montreal Cognitive
Assessment and the Addenbrooke’s Cognitive Examination-Revised. Validated instruments to accurately assess functional abilities in Brazilian PD patients
are still incipient. Further studies should focus on biomarkers with Brazilian cohorts.
Keywords: Consensus; Parkinson Disease; Lewy Bodies; Dementia.

DIAGNÓSTICO E MANEJO DA DEMÊNCIA DA DOENÇA DE PARKINSON E DEMÊNCIA COM CORPOS DE LEWY: RECOMENDAÇÕES DO DEPARTAMENTO CIENTÍFICO
DE NEUROLOGIA COGNITIVA E DO ENVELHECIMENTO DA ACADEMIA BRASILEIRA DE NEUROLOGIA
RESUMO. A demência da Doença de Parkinson (DDP) e a demência com corpos de Lewy (DCL) representam a segunda causa mais comum de demência
neurodegenerativa em pessoas com mais de 65 anos, ocasionando progressivo declínio cognitivo e comprometimento da qualidade de vida. O presente
estudo tem como objetivo prover um Consenso de especialistas sobre a DDP e DCL, baseado em revisão sistemática da literatura brasileira e revisão
não-sistemática de literatura internacional. Ademais, tal estudo visa a promover informação e conceder recomendações sobre abordagem diagnóstica,
com foco nos níveis de atenção primária e secundária em saúde. Com base nos dados disponíveis, recomendamos que os profissionais realizem pelo
menos um breve instrumento cognitivo global, como o Mini-Exame do Estado Mental, contudo de preferência optem pela Avaliação Cognitiva de Montreal e
o Exame Cognitivo de Addenbrooke-Revisado. Observa-se uma carência de instrumentos validados para a avaliação precisa das habilidades funcionais em
pacientes brasileiros com DDP e DCL. Além disso, mais estudos focando em biomarcadores com coortes brasileiras também demonstram ser necessários.
Palavras-chave: Consenso; Doença de Parkinson; Corpos de Lewy; Demência.

INTRODUCTION predictors of burden in Brazilian PD caregivers are

P arkinson’s disease dementia (PDD) and dementia

with Lewy bodies (DLB) are different clinical
syndromes that share the same pathological hallmark,
namely Lewy body disease, in which post-mortem
examination shows neuronal α-synuclein inclusions
(Lewy bodies) and neuronal loss. The umbrella term
Lewy Body Dementia (LBD) includes both of these
syndromes, representing the second most common type
of degenerative dementia in patients aged 65 years and
older and leading to progressive cognitive dysfunction,
motor deterioration, and impaired quality of life1,2.
Despite having the same pathological substrate,
Parkinson’s disease (PD) and DLB are classified
as different diseases based on the temporal
relationship of cognitive and motor symptoms.
Current criteria recommend diagnosing a patient
with PDD when dementia develops in the context
o f well-establishe d PD 1 and w ith DLB when
dementia precedes or coincides within one year of
the development of motor symptoms, namely the
“1-year rule”. This is considered an empirical approach
that avoids clinical practice mistakes and clarifies the
distinction in research and clinical studies2.
PDD and DLB significantly affect one’s psychological
and social life, decreasing the quality of life for both
patients and caregivers. In Brazil, most PD patients
are assisted in their homes by family members,
who act as informal caregivers. Caregivers of PD
patients face increasing burdens and may develop
burnout, depression, and anxiety. The most significant
cognitive and behavioral symptoms in PD patients,
the time of caregiving, and the occurrence of mood
disorders in caregivers3,4.
This work aimed to reach a specialist consensus
based on a systematic Brazilian literature review and
a comprehensive international review of other updated
and relevant literature on PDD and DLB. Moreover,
we sought to report on and provide a clinical guide with
recommendations focusing on primary and secondary
care in the workup of PDD and DLB.
METHODS
This study was conceptualized in meetings held from
April to June 2021 to design the review process and
draft the consensus. The consensus group comprised
seven members experts in the field.
Firstly, we performed a systematic review of the
Brazilian literature concerning epidemiological, clinical,
ancillary tests, and biomarkers and of management
studies regarding PDD and DLB. A systematic
computer-based literature search using the Start
program was performed on the PubMed, Scielo,
and PsycINFO electronic databases. For the search,
the medical subject headings [“Parkinson’s disease”]
OR [“Lewy Body dementia”] OR [“diffuse Lewy Body
disease”] AND [“dementia”] OR [“mild cognitive
impairment”] OR [“cognitive dysfunction”] and (Brazil)
using English and Portuguese and human studies filters.
Inclusion criteria were 1) Brazilian studies referring

70   Brazilian consensus on Parkinson’s disease dementia.   Parmera JB, et al.


to PD and DLB 2) investigating cognitive or associated
features 3) in older adults or those over 18 years old.
Exclusion criteria were 1) studies focusing on other
cognitive primary diagnoses.
The consensus group was later divided into three
subgroups concerning epidemiology and risk factors,
clinical features and neuropsychological assessment,
or biomarkers and management, each subgroup in
charge of critically reviewing the literature selected
based on predefined selection criteria. A comprehensive
literature search was also performed to add current
information and knowledge for insufficient data
acquired from the systematic review or if the specialists
wanted to enrich the consensus study.
Identification of studies via databases and registers
Records identified through database searching (n=732)
Identification
Records screened (n=106)
Screening
Full-text articles assessed for eligibility (n=60)
Included
Studies included in review (n=46)
Figure 1. Prisma flow diagram.
Epidemiology
The prevalence rate of parkinsonism in two community
studies with older adults aged 60 years and over
in Brazil ranged from 7.2%5 to 10.6%6, with idiopathic
Parkinson’s disease being the most frequent etiology.
Both studies obser ved a progressive increase
of parkinsonism with age, reaching 30.4% prevalence
in the population over 95 years old 6. Around 15%
of patients with parkinsonism had dementia in the
Parmera JB, et al.   Brazilian consensus on Parkinson’s disease dementia.   71
Dement Neuropsychol 2022 September;16(3 Suppl. 1):69-82
RESULTS
The search gathered 732 records identified by database
searching. After an initial exclusion, 106 articles
published in Brazilian cohorts were selected, of which
60 were later excluded due to the reasons explained
in Figure 1.
In total, 46 articles were included in this consensus.
For topics without specific articles in the Brazilian
literature, 17 studies, including research articles, review
articles, and international consensus, were added
to the 46 previously selected Brazilian articles, in a
sum of 63 studies.
The PRISMA flow diagram summarizes the search
(Figure 1).
Records removed before screening: 626
Duplicated
Case reports
Out of scope
Records excluded: 46
Duplicated
Case reports
Letters to the editor
Out of scope
Records excluded: 14
Duplicated
Case reports
Letter to the editor
Bambuí study5 and 56.7% had it in the Pietá study6.
In community-based studies, PDD represented 13.5%
of cases with parkinsonism and dementia6. DLB, in turn,
caused less than 5% of cases7,8.
In tertiary centers-based studies, the frequency
of these two etiologies ranged from 3.7% to 15% of
cases9-13 Similarly, a study based on neuropathological
diagnosis cases14 showed that LBD caused 15% of cases
of dementia, whether isolated or associated with other
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):69-82

pathologies. LBD was also the second most frequent Recommendations for the diagnosis of PDD and DLB
neurodegenerative etiology of dementia and related Dementia is usually defined by clinical diagnostic
to a higher risk of dementia with an odds ratio (OR) criteria. Historically, the most used criteria, even for
of 3.4 (CI: 1.94-5.97). The same study had high specificity patients with PD, were those of the various versions
for clinical diagnosis14. of the Diagnostic and Statistical Manual of Mental
Dementia frequently occurs in PD and its prevalence Disorders (DSM). This concept changed in 2007
increases with disease duration, ranging from 23% when a task force of the Movement Disorder Society
in the first years of the disease to 80% after over (MDS) developed specific diagnostic criteria for PDD1
15 years of symptoms 15-17. Understanding which and recommended procedures to operationalize the
risk factors are associated with the occurrence of diagnosis 18. Since then, clinical studies, including
dementia in PD patients and what differentiates LBD Brazilian studies, have used these criteria and
patients from other etiologies is essential for an earlier procedures the most. We recommend using these
diagnosis and more appropriate therapy for the disease. criteria with a few adaptations marked below with
These aspects will be discussed in the following topics. quotation marks (Table 1).

Table 1. Criteria for the diagnosis of probable and possible Parkinson’s disease dementia1.

The diagnosis is probable when:

A. Core features must be both present.
1. Diagnosis of Parkinson’s disease according to specific “diagnostic criteria” *
2. A syndrome of “cognitive decline” with insidious onset and slow progression, developing within the context of established PD and diagnosed by
history, clinical, and mental examination, defined as:
- Impairment in more than one cognitive domain (including: attention, executive functions, visuo-spatial functions, memory and language)
- Decline from a premorbid level of functioning
- Deficits severe enough to impair daily life (social, occupational, or personal care), regardless of the impairment from motor or autonomic symptoms

B. Associated clinical features.

Typical profile of cognitive deficits including impairment in at least two of the four core cognitive domains (impaired attention which may fluctuate,
impaired executive functions, impairment in visuo-spatial functions, and impaired free recall which usually improves with cueing)
Behavioral features such as apathy, changes in personality and mood, hallucinations, delusions, and excessive daytime sleepiness may be present
(but are not necessary for diagnosis)

C. Features which do not exclude PDD, but make the diagnosis uncertain.

Existence of any other abnormality which may cause cognitive impairment but is not as the cause of dementia, e.g., presence of relevant vascular
disease in imaging.
The time interval between the development of motor and cognitive symptoms is unknown**

D. There are none of the following features suggesting other conditions or diseases as the cause of mental impairment, which would hinder an
accurate diagnosis of PDD: delirium, diagnosis of major depression, evidence for diagnosis of probable vascular dementia.

The diagnosis is possible when:

A. Core features must be both present.

B. The cognitive decline presents with atypical profile of cognitive impairment in one or more domains, such as prominent or receptive (fluent) aphasia
or pure storage-failure type amnesia (memory does not improve with cueing or in recognition tasks) with preserved attention.
or

C. There are features that make the diagnosis uncertain (e.g., presence of relevant vascular disease in imaging).
or

D. Time interval between the development of motor and cognitive symptoms is unknown (“1-year rule”)
or

E. There are features suggesting other conditions or diseases as causes of mental impairment (delirium, diagnosis of major depression, evidence for
diagnosis of probable vascular dementia)
* United Kingdom Parkinson’s Disease Society Brain Bank diagnostic criteria (20) for PD or another validated criterion; ** Refers to the “1-year rule” to differentiate PDD from Lewy body
dementia. PDD develops within the context of established PD or arbitrarily at least a year after the onset of the classic motor symptoms.

72   Brazilian consensus on Parkinson’s disease dementia.   Parmera JB, et al.

 Dement Neuropsychol 2022 September;16(3 Suppl. 1):69-82

The fourth consensus report of the DLB Consortium,
in turn, has recently refined the recommendations for the
clinical and pathologic diagnosis of DLB19. It incorporated
recent developments to increase sensitivity and clearly
distinguished between clinical features and diagnostic
biomarkers. The report classified clinical symptoms and signs
as core or supportive and weighed biomarkers as indicative
or supportive based on their specificity and the volume
of high-quality evidence available. We also recommend
the use of these criteria in clinical practice (Table 2).

Table 2. Criteria for the diagnosis of probable and possible dementia with Lewy bodies2.
1. Essential: dementia is required for a diagnosis of DLB and defined as a progressive cognitive decline which affects social and occupational functions
or daily activities. It mainly affects attention, executive function, and visuoperceptual abilities, worsening memory impairment as it progresses.

Core clinical features:

Fluctuating cognition with pronounced variations in alertness.
Recurrent visual hallucinations.
REM sleep behavior disorder.
One or more spontaneous cardinal features of parkinsonism (bradykinesia, rest tremor, or rigidity).*

Supportive clinical features: severe sensitivity to antipsychotic agents, postural instability, repeated falls; syncope or other transient episodes of
unresponsiveness; severe autonomic dysfunction, e.g., constipation, orthostatic hypotension, urinary incontinence; hypersomnia; hyposmia; other
hallucination modalities; systematized delusions; apathy, anxiety, and depression.

Indicative biomarkers:
Reduced dopamine transporter uptake in basal ganglia demonstrated by SPECT or PET.
Abnormal (low uptake) 123iodine-MIBG myocardial scintigraphy.
Polysomnographic confirmation of REM sleep without atonia.

Supportive biomarkers:
Relative preservation of medial temporal lobe structures on CT/MRI scan.
Generalized low uptake on SPECT/PET perfusion/metabolism scan with reduced occipital activity. Cingulate island sign on FDG-PET imaging.
Prominent posterior slow-wave activity on EEG with periodic fluctuations in the pre-alpha/theta range.

Diagnosis is probable when:

Two or more core clinical features are present
OR
Only one core clinical feature is present but with one or more indicative biomarkers.

Diagnosis is possible when:

Only one core clinical feature (with no biomarkers)
One or more indicative biomarkers are present without core clinical features.
*We continue to recommend the existing 1-year rule between the onset of dementia and parkinsonism.

We suggest that the diagnosis of PD should use
validated diagnostic criteria, which can be either the
United Kingdom Parkinson’s Disease Society Brain Bank
diagnostic criteria20 or any other diagnostic criteria with
established accuracy for diagnosis, such as the recently
proposed MDS Parkinson’s Disease criteria21.
We also suggest maintaining the “1-year rule”
for clinical and research purposes, despite the
controversy over whether PDD and DLB are the
clinical spectra of the same disease. In turn, specialists
from the MDS have recently proposed not using
the “1-year rule” to distinguish PDD from DLB 21.
Nevertheless, this approach has been criticized and does
not present general agreement.
We recommend adopting the formal criteria for
PD-mild cognitive impairment (MCI) published
in 201222 to assess the progression of cognitive decline
in PD patients. Proposed research criteria for diagnosing
prodromal DLB have recently introduced three
possible presentations to the prodromal phase: MCI,
delirium-onset, and psychiatric-onset. We recommend
adopting the DLB-MCI criteria19.
Clinical features in PDD and DLB
The evaluations of PDD and DLB present two major
challenges. Regarding PDD, it is the prediction and early
identification of the progression of cognitive decline
to dementia. In DLB, it is probably the differentiation
from Alzheimer’s disease (AD)23.

Parmera JB, et al.   Brazilian consensus on Parkinson’s disease dementia.   73

 Dement Neuropsychol 2022 September;16(3 Suppl. 1):69-82
Parkinson’s Disease is mainly characterized by
classic motor symptoms, such as resting tremor,
rigidity, and bradykinesia. However, it is also associated
with many non-motor manifestations that are
well-recognized symptoms and predominant at the late
stages of the disease, such as hyposmia, constipation,
depression, and rapid eye movement (REM) sleep
behavior disorder (RBD). These may precede the motor
signs whereas dementia and psychosis are common
in the late stages of the illness1,20. DLB has the same
non-motor symptoms, but the cognitive decline
occurs earlier and the motor symptoms are milder,
sometimes absent. Dementia is essential to diagnose
an individual with DLB.
PDD and DLB cognitive profiles are characterized
by impairment mainly in attention, executive,
and visuospatial functions. Behavioral symptoms
such as affective changes, hallucinations, and apathy
are also frequent1. Most studies with Brazilian samples
showed the same pattern of cognitive impairment24,25.
On the other hand, episodic memory is less affected
and patients with MCI usually have more difficulty
in free recall than cued recall in memory tests (such as
a list of words or pictures). A previous study exploring
visuospatial dysfunctions in PD patients showed that
62.2% of 35 patients could not copy the pentagon
drawing26. Moreover, Machado et al. suggested that
language and visual organization tend to follow motor
skills and general cognitive performance in patients
with DLB27. Poor cognitive performance frequently
correlates with more advanced stages of the disease,
older age, low schooling level, depression, and poorer
quality of life15,17,28. Cardiovascular risk factors and PDD,
however, are not correlated with each other29.
The main cognitive feature in DLB is fluctuating
cognition, which represents a fluctuation in attention
or level of consciousness. This feature can range
from episodes of inattention and mental confusion,
with disorganized thinking and behavior, to lethargy
and excessive daytime sleepiness. DLB and PD have
differences of parkinsonism presentation. DLB presents
more symmetrical parkinsonism, less frequent rest
tremor, and greater postural instability and lower
responsiveness to levodopa2.
REM Behavior Disorder (RBD) has a high specificity
for suggesting an alpha-synucleinopathy. RBD is
a parasomnia characterized by loss of atony during REM
sleep. The current DLB2 criteria included this feature
among the core clinical manifestations of the disease.
Clinical suspicion is based on the patient history,
in which the caregiver usually describes that the patient
has abnormal vocalizations, aberrant motor behavior,
74   Brazilian consensus on Parkinson’s disease dementia.   Parmera JB, et al.
and vivid dreams. The suspicion is usually confirmed
by polysomnography (PSG), but questionnaires can
be used clinically if PSG is unavailable. The Brazilian
Portuguese version of the RBD screening questionnaire
(RBDSQ) for patients with PD may be helpful for
RBD diagnosis in the country28. This disorder should
be actively questioned since an individual could
develop it up to 15 years before developing dementia
or parkinsonism. Diagnosing this disorder is therefore
important to improve patient’s quality of life.
Hallucinations are one of the few features that
usefully distinguish between DLB/PDD and AD.
The phenomenology of hallucinations in PDD and
DLB is very similar. Visual hallucinations occur twice
as frequently as auditory ones, being mostly complex,
formed hallucinations of anonymous people, but they
may also be family members, body parts, animals,
or machines1,30. Overall, patients with PDD seem to
have less frequent or less severe psychiatric symptoms
than patients with DLB. Such differences, however,
may simply reflect the disparity in the overall dementia
severity between PDD and DLB1,31.
Depression, another non-motor symptom frequent
in PD patients, can worsen executive dysfunction,
especially in subjects with low schooling level32. Other
supportive clinical features in DLB are: severe sensitivity
to antipsychotic agents, postural instability, repeated falls,
syncope, or other transient episodes of unresponsiveness;
severe autonomic dysfunction, hypersomnia, hyposmia,
other hallucination modalities; systematized delusions;
and apathy, anxiety, and depression2.
Which diagnostic procedures and neuropsychological tests
should be used to diagnose and evaluate PDD and DLB?
Many different methods and instruments can be used
to assess cognition in patients with PD and DLB.
We recommend using an adapted version of the
procedures to operationalize the diagnostic criteria
proposed by the MDS for PDD diagnosis 18. These criteria
suggested two levels of diagnosis for PDD. In level I,
the diagnosis is based upon using straightforward
procedures and bedside cognitive tests, which a non-
specialist would easily apply in clinical consultations.
In level II, diagnosis would require a more extensive
and specialized neuropsychological evaluation.
Predictably, a previous Brazilian study showed that
the prevalence of PDD diagnosis was higher when the
more elaborate procedures of level II rather than of
level I were used (23.8% versus 14.9%, respectively).
This indicates that level I procedures had lower
sensitivity but greater specificity than level II for the
diagnosis of dementia15.
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):69-82

The MDS proposed practical procedures for level I
diagnosis of PDD based on an algorithm or checklist.
Both of these procedures are advantageous, either for
clinical routine or clinical research. However, they require
some adaptations that we suggest in Table 3.
Regarding the assessment of functionality, the best
functional assessment tool for impairment from cognitive
loss in PD patients is still undefined. Most studies
used functional assessment instruments applied in
other dementias, and no proper validation instrument
is available for patients with PD. The MDS primary
recommendation proposed the “pill questionnaire” as
a simple tool to define independence loss. According
to this instrument, patients without functional loss
are those who can describe in detail their drug schedule
treatment18. However, many studies suggested that the
questionnaire was insufficiently accurate. Accordingly,
two Brazilian studies suggested that the pill questionnaire
was less sensitive than other instruments to detect
functional impairment15,33.

Table 3. Modified algorithm for diagnosing Parkinson’s disease dementia at Level I.

Diagnosis of Parkinson’s disease*

Motor symptoms of PD developed at least “1-year” before the onset of dementia

Cognitive deficits severe enough to impact daily living**

Abnormal performance on a brief global cognitive scale***

Cognitive abnormalities affect typical cognitive domains such as: attention, executive functions, visuo-spatial functions, memory and language
(excluding prominent aphasia)

Absence of Major Depression

Absence of delirium

There are no other features that make the diagnosis uncertain or suggest other conditions or diseases as causes of mental impairment (diagnosis of
probable vascular dementia)

If all items are checked, the diagnosis is probable PDD

If item 2 and/or item 5, and/or item 6, and/or item 7, and/or item or 8 are not checked, the diagnosis is possible PDD
*Based on specific diagnostic criteria; **According to any method of functional assessment; ***Based on population normative levels, with scores adjusted for schooling level and other
factors (age, sex, etc.) if necessary.

Studies with Brazilian PD patients have used several
instruments to assess functional abilities, including the
Pfeffer Functional Activities Questionnaire (FAQ),
the Disability Assessment for Dementia (DAD),
the Informant Questionnaire on Cognitive Decline
in the Elderly (IQCODE), Pill questionnaire, the phone
call test, and the Direct Assessment of Functional
Abilities (DAFA)15,33-37. Two studies evaluated the PFAQ
accuracy to detect functional impairment in patients
with PD33,37. Oliveira et al. proposed that a score >2
had 23% sensitivity and 74% specificity to predict
abnormal performance on a global cognitive test33.
In turn, Almeida et al. defined a score >3 as the best
cutoff for a modified version of the PFAQ (mPFAQ)
to diagnose PDD (47% sensitivity and 88% specificity).
In this modified version, the authors suppressed items 5
(make coffee) and 6 (prepare a meal) from the original
version to minimize the possible effects of motor
symptoms that affect the interpretation of the patient’s
functional assessment37. The authors used the IQCODE
as a reference to diagnose functional impairment with
the cutoff score of 3.27, the same defined for the cross-
cultural adaptation of the scale for Brazilian patients
with Alzheimer’s disease dementia37.
Baldivia et al. used DAD to assess functional
impairment in patients with PD with the cutoff score
of 94.6, the same previously defined for diagnosis of
Alzheimer’s disease dementia in Brazilian patients15.
In turn, Breder et al. used a modified version of DAD
to evaluate patients with PD. The authors did not
evaluate a disability but the dependence in activities
of daily living (ADL). They classified the patient
as dependent if he needed assistance for over half
of the time on at least one activity evaluated due
to cognitive impairment 35. Oliveira et al. showed
that close informants usually overestimate patients’
instrumental abilities in ADL. In some patients,
therefore, the assessment of functional loss might only
be considered reliable with direct assessment tools.
The direct assessment of functional abilities might

Parmera JB, et al.   Brazilian consensus on Parkinson’s disease dementia.   75

 Dement Neuropsychol 2022 September;16(3 Suppl. 1):69-82
better predict impairment on a global cognitive scale
than questionnaires33.
These studies show a lack of validated instruments
to accurately assess functional abilities in Brazilian PD
patients. Further studies should focus on developing
these instruments. We recommend that despite the
functional assessment tool used, the examiner should
always be sure that other PD symptoms, such as motor
symptoms, are not interfering with the patient’s ability
to carry out activities. For clinical practice, though the
pill questionnaire seems to be an interesting procedure
for screening, it should be complemented by other
functional assessments or a clinical interview aimed
at functional status. For clinical research studies,
authors must precisely define the methods used
to assess the functional abilities of patients with PD.
Regarding global cognitive assessment, we suggest
using other global cognitive scales besides the Mini-
Mental State Examination (MMSE). The MDS has
proposed the MMSE as a first-line assessment tool
for global cognitive efficiency in PD because of the
instrument’s simplicity and wide use in dementia.
However, other studies, including some with Brazilian
populations, showed that the MMSE had lower
sensitivity than other scales to detect cognitive
abnormalities in PD patients34,35,38. Moreover, MMSE
cutoff scores adjusted for schooling level from normative
studies performed in the Brazilian population were
more accurate for diagnosis of PDD15,34. Other cognitive
scales should also consider schooling level.
Table 4. Clinical Brazilian research studies with brief global cognitive instruments in Parkinson’s disease dementia.
Study Sample characteristics
79 PD patients
Median age 63 years (28-81)
Sobreira et al. 201543 Median schooling
time 6.5 years (1-20)
36% male
70 PD patients
Mean age 64.1 years (SD= 9.3)
Rocha et al. 201438 Mean schooling time 5.9 years
(SD= 3.4)
57.1% male
76   Brazilian consensus on Parkinson’s disease dementia.   Parmera JB, et al.
Diagnostic accuracy also depends on the quality of
evidence for normative data of cognitive scales in the
Brazilian population. Therefore, a less precise approach
to define cutoff scores for PDD diagnosis relies on scale-
assessment studies to distinguish between PD without
dementia and PDD. Souza et al. proposed using the
interlocking finger test (ILFT) to screen PD patients for
dementia39. ILFT is a simple test in which the patient
is asked to imitate four meaningless bimanual gestures.
The authors showed that a score <3 (each gesture
earned one point) presented 61% sensitivity and
85% specificity to diagnose PDD, indicating ILFT as
a practical bedside test to assess cognitive impairment
in patients with PD39.
The Montreal Cognitive Assessment (MoCA) and the
Addenbrooke’s Cognitive Examination-Revised (ACE-R)
are other brief global cognitive instruments that have
been used in PD and DLB. They have already been
translated and validated for Brazilian populations40-42.
Some studies suggest that these instruments may be
more effective than the MMSE to detect dementia in
PD patients35,36,38,43,44. However, most studies showed
inadequate accuracy to evaluate PD-MCI43. A previous
study evaluating the MoCA subtests showed that
PD patients with low schooling level might have
difficulty completing the tests, contributing to poor
diagnostic accuracy and affecting the detection
of MCI45. Table 4 summarizes the findings and cutoff
scores applied with brief global cognitive instruments
in Brazilian PD patients.
Diagnosis of dementia Results
The area under the ROC curve for the MoCA dementia
diagnosis was 0.86 (95%CI= 0.76-0.95). The best cutoff
score for MoCA to differentiate patients with PDD from
According to level II of the the others was <21 (sensitivity of 94%, specificity of 68%).
MDS diagnostic criteria The area under the ROC curve for the ACE-R was 0.84
(95%CI= 0.74-0.94). The best cutoff score for ACE-R
to differentiate patients with PDD from the others was <76
(sensitivity of 88%, specificity of 68%).
The area under the ROC curve for the MMSE was 0.88
(95% CI: 0.78-0.97). The best cutoff score for MMSE
to differentiate patients with PDD from the others was ≤24,
According to level II of the (sensitivity of 78.5%, specificity of 96.4%).
MDS diagnostic criteria The area under the ROC curve for the ACE-R was 0.93
(95% CI: 0.86-0.98). The best cutoff score for ACE-R
to differentiate patients with PDD from the others was ≤72
(sensitivity of 89.3%, specificity of 84.6%)
Continue...

Table 4. Continuation.
Study Sample characteristics
101 PD patients
Mean age 62.5 years
(SD= 12.1)
Souza et al, 201639
Mean schooling time 5.2 years
(SD= 4.1)
42.5% male
89 PD patients
Mean age 59 years
Almeida et al, 2019 36
Mean education 8.4 years
53.9% male
50 PD patients
Mean age 69.28 (SD= 11.41)
Camargo et al, 201644
Mean schooling time 6.9 years
64% male
PD: Parkinson’s disease; PDD: Parkinson’s disease dementia; MDS: Movement Disorders Society; ILFT: interlocking finger test.
Studies conducted in Brazil have assessed the cognitive
profile of patients with PD using comprehensive and
formal neuropsychological tests, such as the Mattis
Dementia Rating Scale (MDRS), Scales for Outcomes in
Parkinson’s Disease-Cognition (SCOPA-COG), Wisconsin
Card Sorting Test (WCST), Frontal Assessment Battery
(FAB), Verbal Fluency Tests27,46, and Trail Making tests47.
A study applying a comprehensive neuropsychological
battery showed cognitive impairment in 56.7% of PD
patients in a waiting list for deep brain stimulation (DBS)
implantation according to FAB scores and in 76.7% of them
according to MoCA, showing the importance of a formal
cognitive evaluation in this group of candidates to DBS48.
Moreover, another study showed that the Consortium
to Establish a Registry for Alzheimer’s Disease (CERAD)
neuropsychological battery could effectively assess
cognitive deficits in PD patients49.
Based on the available data, we recommend clinicians
to apply at least one brief cognitive instrument,
such as MMSE and preferably the MoCA or ACE-R,
to investigate PDD and DLB – especially since we
found no Brazilian studies or samples concerning
neuropsychological profiles of the latter. However,
for a tertiary center and other treatment strategies such
as DBS, a comprehensive neuropsychological evaluation
is more appropriate if suitable.
Ancillary investigation and biomarkers
Besides analyzing the clinical history and conducting
neurological examination with brief cognitive
instruments, we also recommend applying ancillary
Dement Neuropsychol 2022 September;16(3 Suppl. 1):69-82
Diagnosis of dementia Results
The area under the ROC curve for the ILFT was 0.761The best
cutoff score for ILFT to differentiate patients with PDD from
According to MDS
the others was <3 (sensitivity of 61%, specificity of 85%).
criteria but did say if
The area under the ROC curve for the MMSE was 0.841. The best
level I or II
cutoff score for MMSE to differentiate patients with PDD from the
others was <25 (sensitivity of 80.5%, specificity of 73%).
The best cutoff score for MoCA to differentiate patients with
According to level II of the
PDD from those with PD-MCI was <18 (sensitivity of 85.5%,
MDS diagnostic criteria
specificity of 81.6%).
The MoCA test showed an AUC=0.906 area under the
According to MDS ROC curve with a cutoff score of ≤19 points (sensitivity
criteria but did not of 87.80%, specificity of 88.89%). The MMSE had an 0.936
indicate if level I or II area under the curve with a cutoff score of ≤26 points
(specificity of 66.67%, sensitivity of up to 90.24%).
tests to confirm the PDD and DLB diagnoses. Routine
screening tests are recommended to exclude other
causes of cognitive impairment. We suggest conducting
a complete blood count, as suggested in article one,
and using structural imaging such as magnetic resonance
imaging (MRI) or computed tomography (CT) scans to
exclude other causes for dementia syndromes, such as
vascular dementia, stroke, and brain tumors.
The PDD and DLB biomarkers do not define the
presence of alpha-synuclein in vivo, but seek to reflect
the repercussions of the pathophysiological process.
Specifically for PDD, the current diagnostic criteria do not
recommend structural, functional, or electrophysiological
studies for routine diagnostic purposes in differentiating
PD from PDD due to the lack of specificity1. Nevertheless,
the current MDS criteria for PD diagnosis21 has included
ancillary diagnostic tests.
123I-Meta-iodo-benzylguanidine scintigraphy
(123I-MIBG) is a method that provides a functional analysis of
the sympathetic postganglionic pathway, evaluating in vivo
the cardiac noradrenergic neurotransmission. 123I-MIBG
scintigraphy documenting cardiac sympathetic denervation
is a supportive criterion for PD diagnosis, having over
80% specificity to distinguish PD from other parkinsonian
conditions21. A study by Leite et al. showed that this
method identified cardiac sympathetic neurotransmission
impairment in Brazilian de novo PD patients without
clinically defined dysautonomia50. The DLB consortium
criteria also classifies 123I-MIBG as an indicative biomarker,
showing good sensitivity (69%) and specificity (87%)
values for discriminating probable DLB from probable AD51.
Parmera JB, et al.   Brazilian consensus on Parkinson’s disease dementia.   77
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):69-82

Moreover, normal functional neuroimaging of biomarker for DLB diagnosis. Dopamine Transporter
the presynaptic dopaminergic system is currently (DAT) imaging has well-established utility in
considered an absolute exclusion criterion for the MDS distinguishing DLB from AD, with 78% of sensitivity and
PD criteria. However, the task force mentioned that PD 90% of specificity52. DAT imaging does not distinguish,
diagnosis does not require dopaminergic functional however, between degenerative parkinsonian
imaging21. Reduced dopamine transporter uptake in syndromes, such as progressive supranuclear palsy,
basal ganglia demonstrated by Single Photon Emission corticobasal syndrome, frontotemporal dementia
Computed Tomography (SPECT) or Positron Emission with parkinsonism, among others. Figure 2 shows
Tomography (PET) imaging is another indicative TRODAT-SPECT images in PD patients.

Dopamine transporter uptake in basal ganglia demonstrated by TRODAT-1 SPECT imaging. The superior row shows a normal uptake in the caudate and putamen. The medium row shows an asymmetric
uptake in a PD patient. The lower row shows a bilateral minimal uptake in a DLB patient. (Reproduced with permission from Dr. Artur Coutinho, Nuclear Medicine Center – Inrad – HC-FMUSP).
Figure 2. Dopamine transporter uptake in basal ganglia shown by SPECT or PET.

PSG is the third indicative biomarker for DLB association between global cognitive performance
diagnosis. It aims to confirm the clinical suspicion and wakefulness after sleep onset and the number of
of RBD, showing the loss of atony in the REM sleep stage2. sleep stage changes53.
A study by Sobreira et al. examined the association S u p p o r t i v e b i o m a r k e r s fo r D L B i n c l u d e :
between cognitive status and presence of sleep the relative preservation of medial temporal lobe
disorders in PD patients by PSG, finding a significant structures on CT/MRI scans since patients with

78   Brazilian consensus on Parkinson’s disease dementia.   Parmera JB, et al.

 Dement Neuropsychol 2022 September;16(3 Suppl. 1):69-82

AD show greater atrophy of medial temporal lobe
structures; the generalized low uptake on SPECT/PET
perfusion/metabolism scan, which shows reduced
occipital activity; and the posterior cingulate island
sign on FDG-PET imaging. Figure 3 shows FDG-PET
images in a DLB patient54. MCI in Parkinson’s Disease
presents a similar typical pattern of hypometabolism,
mainly in the posterior regions of the brain.
Therefore, the absence of this typical pattern hints
at an alternative diagnosis, including depression or
an atypical parkinsonian syndrome55.
Furthermore, a prominent posterior slow-wave EEG
activity with periodic fluctuations in the pre-alpha/theta
range is a supportive biomarker for DLB diagnosis56.
Some Brazilian studies have investigated the quantitative
EEG changes concerning cognitive decline in PD patients,
showing increased posterior theta and delta amplitude in
patients with MCI-PD or PDD57,58 and differences in EEG
power and coherence in AD and PDD59,60.
Recommendation for primary and secondary care
Figure 4 presents a flowchart of the approach to patients
with parkinsonism and dementia.

Upper row – Images on the left with standard axial view and images on the right with [18F]FDG-PET 3D-stereotactic surface projection (3D-SSP, Cortex ID Suite software,
GE Healthcare):occipital lobe metabolism is typically preserved in AD. Hypometabolism in AD usually occurs in bilateral temporoparietal regions. Lower row – Images on the left with
standard axial view and images on the right with [18F]FDG-PET 3D-stereotactic surface projection (3D-SSP, Cortex ID Suite software, GE Healthcare): DLB shows occipital hypometabolism.
Relative preservation of the posterior cingulate region, representing the “cingulate island sign”.
(Reproduced with permission from Dr. Artur Coutinho, Nuclear Medicine Center – Inrad – HC-FMUSP).
Figure 3. [18F]FDG-PET images in Alzheimer’s disease (AD) and Dementia with Lewy Bodies (DLB).

Parmera JB, et al.   Brazilian consensus on Parkinson’s disease dementia.   79

 Dement Neuropsychol 2022 September;16(3 Suppl. 1):69-82

PD patients Probable/possible DLB

Risk factors:
Cognitive impairment and one of the following features:
Old age
Visual hallucinations
Low schooling
Fluctuating cognition (Spontaneous alertness and
Worse motor performance
concentration impairment; excessive daytime sleepiness)
Visual hallucinations
Primary care

Parkinsonism (one sign only)

Memory complaints
REM sleep behavior Disorders
Visuospatial dysfunction

Cognitive and functional

assessment (MMSE; FAQ)

Request neuroimage (brain CT or MRI) and screening blood test

Refer to secondary care

Clinical features and ancillary diagnostic test confirm diagnosis No

Secondary care

Start specific therapy Expand cognitive assessment (ACE-R; MoCA)

Assessment of RDB (specific questionnaires)

Persistence of diagnostic or clinical follow up difficulties. Refer to tertiary care

Tertiary care

Consider performing: Neuropsychological evaluation: More specific

FDG-PET Mattis scale therapeutic adjustment
TRODAT-SPECT SCOOPA-Cog
EEG RAVLT
Polysomnography NPI

Figure 4. Flowchart of the approach to patients with parkinsonism and dementia.

ACKNOWLEDGEMENTS
PC, LCS and RN are funded by CNPq, Brazil (bolsa de
produtividade em pesquisa).
Authors’ contributions. JBP, VT, HBF, MS, MTB, RMC,
NAFF, JS, BJAPB, LPS: concept; JBP, VT, HBF, MS,
MTB, RMC, NAFF: drafting the manuscript; BJAPB,
FACV, JS, LCS, LPS, MLFB, MLFC, NAFF, PC, PHFB, RN,
SMDB: critical revision of the manuscript for important
intellectual content.

REFERENCES
1. Emre M, Aarsland D, Brown R, Burn DJ, Duyckaerts C, Mizuno Y, et al.
Clinical diagnostic criteria for dementia associated with Parkinson’s
disease. Mov Disord. 2007;22(12):1689-707. doi:10.1002/mds.21507.
2. McKeith IG, Boeve BF, Dickson DW, Halliday G, Taylor J, Weintraub D,
et al. Diagnosis and management of dementia with Lewy bodies: Fourth
consensus report of the DLB Consortium. Neurology. 2017;89(1):88-100.
doi:10.1212/WNL.0000000000004058.
3. Carod-Artal FJ, Mesquita HM, Ziomkowski S, Martinez-Martin P. Burden
and health-related quality of life among caregivers of Brazilian Parkinson’s
disease patients. Parkinsonism Relat Disord. 2013;19(11):943-8.
doi:10.1016/j.parkreldis.2013.06.005.
4. Nascimento ER, Barbosa MA, Brasil VV, Sousa ALL, Amaral GF,
Jácomo PJ. Qualidade de vida de quem cuida de portadores de demência
com corpos de Lewy. J Bras Psiquiatr. 2013;62(2):144-52. doi:10.1590/
S0047-20852013000200008
5. Barbosa MT, Caramelli P, Maia DP, Cunningham MCQ, Guerra HL,
Lima-Costa MF, et al. Parkinsonism and Parkinson’s disease in the elderly:
A community-based survey in Brazil (the Bambuí Study). Mov Disord.
2006;21(6):800-8. doi:10.1002/mds.20806.
6. Vale TC, Barbosa MT, Resende EPF, Maia DP, Cunningham MCQ,
Guimarães HC, et al. Parkinsonism in a population-based study of

80   Brazilian consensus on Parkinson’s disease dementia.   Parmera JB, et al.


individuals aged 75+ years: The Pietà study. Parkinsonism Relat Disord.
2018;56:76-81. doi:10.1016/j.parkreldis.2018.06.030.
7. Herrera E Jr, Caramelli P, Silveira ASB, Nitrini R. Epidemiologic
survey of dementia in a community-dwelling Brazilian population.
Alzheimer Dis Assoc Disord. 2002;16(2):103-8. doi:10.1097/00002093-
200204000-00007.
8. Bottino CMC, Azevedo D Jr, Tatsch M, Hototian SR, Moscoso MA,
Folquitto J, et al. Estimate of dementia prevalence in a community sample
from São Paulo, Brazil. Dement Geriatr Cogn Disord. 2008;26(4):291-9.
doi:10.1159/000161053.
9. Takada LT, Caramelli P, Radanovic M, Anghinah R, Hartmann APBJ,
Guariglia CC, et al. Prevalence of potentially reversible dementias in
a dementia outpatient clinic of a tertiary university-affiliated hospital
in Brazil. Arq Neuropsiquiatr. 2003;61(4):925-9. doi:10.1590/
s0004-282x2003000600007.
10. Souza RKM, Barboza AF, Gasperin G, Garcia HDBP, Barcellos PM,
Nisihara R. Prevalence of dementia in patients seen at a private hospital
in the Southern Region of Brazil. Einstein (Sao Paulo). 2019;18:eAO4752.
doi:10.31744/einstein_journal/2020AO4752.
11. Correa Ribeiro PC, Souza Lopes C, Alves Lourenço R. Prevalence of
dementia in elderly clients of a private health care plan: A study of the
FIBRA-RJ, Brazil. Dement Geriatr Cogn Disord. 2013;35(1-2):77-86.
doi:10.1159/000345984.
12. Camargo CHF, Retzlaff G, Justus FF, Resende M. Patients with dementia
syndrome in public and private services in southern Brazil. Dement e
Neuropsychol. 2015;9(1):64-70. doi:0.1590/S1980-57642015DN91000010
13. Vieira RT, Barros NM, Caixeta L, Machado S, Silva AC, Nardi AE. Clinical
diagnosis of 80 cases of dementia in a university hospital TT. J Bras
Psiquiatr. 2013;62(2):139-43. doi:10.1590/S0047-20852013000200007.
14. Suemoto CK, Ferretti-Rebustini REL, Rodriguez RD, Leite REP,
Soterio L, Brucki SMD, et al. Neuropathological diagnoses and clinical
correlates in older adults in Brazil: A cross-sectional study. PLoS Med.
2017;14(3):e1002267. doi:10.1371/journal.pmed.1002267.
15. Baldivia B, Brucki SMD, Batistela S, Esper JC, Augusto CD, Rocha MSG.
Dementia in parkinson’s disease: a Brazilian sample. Arq Neuropsiquiatr.
2011;69(5):733-8. doi:10.1590/s0004-282x2011000600002.
16. Tedrus GMAS, Fonseca LC, Letro GH, Bossoni AS, Samara AB. Dementia
and mild cognitive impairment in Parkinson’s disease. Arq Neuropsiquiatr.
2009;67(3-B):957-9. doi:10.1590/S0004-282X2009000600038.
17. Camargo CHF, Jobbins VA, Serpa RA, Berbetz FA, Sabatini JS,
Teive HAG. Association between olfactory loss and cognitive deficits
in Parkinson’s disease. Clin Neurol Neurosurg. 2018;173:120-3.
doi:10.1016/j.clineuro.2018.08.018.
18. Dubois B, Burn D, Goetz C, Aarsland D, Brown RG, Broe GA,
et al. Diagnostic procedures for Parkinson’s disease dementia:
recommendations from the movement disorder society task force.
Mov Disord. 2007;22(16):2314-24. doi:10.1002/mds.21844.
19. McKeith IG, Ferman TJ, Thomas AJ, Blanc F, Boeve BF, Fujishiro H, et al.
Research criteria for the diagnosis of prodromal dementia with Lewy bodies.
Neurology. 2020;94(17):743-55. doi:10.1212/WNL.0000000000009323.
20. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical
diagnosis of idiopathic Parkinson’s disease: A clinico-pathological
study of 100 cases. J Neurol Neurosurg Psychiatry. 1992;55(3):181-4.
doi:10.1136/jnnp.55.3.181.
21. Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, et al.
MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord.
2015;30(12):1591-601. doi:10.1002/mds.26424.
22. Litvan I, Goldman JG, Tröster AI, Schmand BA, Weintraub D, Petersen RC,
et al. Diagnostic criteria for mild cognitive impairment in Parkinson’s
disease: Movement Disorder Society Task Force guidelines. Mov Disord.
2012;27(3):349-56. doi:10.1002/mds.24893.
23. Walker Z, Possin KL, Boeve BF, Aarsland D. Lewy body dementias. Lancet.
2015;386(10004):1683-97. doi:10.1016/S0140-6736(15)00462-6.
24. Barbosa ER, LeFèvre BH, Comerlatti LR, Scaff M, Canelas HM.
Neuropsychologic dysfunctions in Parkinson’s disease: a study of 64
cases. Arq Neuropsiquiatr. 1987;45(2):109-18. doi:10.1590/S0004-
282X1987000200003.
25. Oliveira FF, Machado FC, Sampaio G, Marin SM, Chen ES, Smith MC,
et al. Contrasts Between Patients With Lewy Body Dementia Syndromes
and APOE-ε3/ε3 Patients With Late-onset Alzheimer Disease Dementia.
Neurologist. 2015;20(2):35-41. doi:10.1097/nrl.000000000000004.
26. Pena MCS, Sobreira EST, Souza CP, Oliveira GN, Tumas V, Vale FAC.
Visuospatial cognitive tests for the evaluation of patients with Parkinson’s
disease. Dement Neuropsychol. 2008;2(3):201-5. doi:10.1590/
S1980-57642009DN20300007.
27. Machado FC, Oliveira FF, Marin SMC, Sampaio G, Bertolucci PHF.
Correlates of neuropsychiatric and motor tests with language assessment
in patients with lewy body dementia. Rev Psiquiatr Clin. 2020;47(3):75-81.
doi:10.1590/0101-60830000000236.
Parmera JB, et al.   Brazilian consensus on Parkinson’s disease dementia.   81
Dement Neuropsychol 2022 September;16(3 Suppl. 1):69-82
27. Olchik MR, Ayres A, Ghisi M, Schuh AFS, Rieder CRM. The impact of
cognitive performance on quality of life in individuals with Parkinson’s
disease. Dement Neuropsychol. 2016;10(4):303-9. doi:10.1590/
S1980-5764-2016DN1004008.
28. Pena-Pereira MA, Sobreira-Neto MA, Sobreira E, Chagas MHN,
Oliveira DS, Rodrigues GR, et al. Validation of the brazilian Portuguese
version of the rapid eye movement sleep behavior disorder screening
questionnaire (RBDSQ-BR). Arq Neuropsiquiatr. 2020;78(10):629-37.
doi:10.1590/0004-282X20200125.
29. Schelp AO, Mendes-Chiloff CL, Bazan R, Paduan VC, Pioltini AB.
Metabolic syndrome and dementia associated with Parkinson’s disease:
impact of age and hypertension. Arq Neuropsiquiatr. 2012;70(2):114-8.
doi:10.1590/S0004-282X2012000200008.
30. Aarsland D, Cummings JL, Larsen JP. Neuropsychiatric differences
between Parkinson’s disease with dementia and Alzheimer’s
disease. Int J Geriatr Psychiatry. 2001;16(2):184-91. doi:10.1002/
1099-1166(200102)16:2<184::aid-gps304>3.0.co;2-k.
31. Oliveira FF, Machado FC, Sampaio G, Marin SMC, Naffah-Mazzacoratti MG,
Bertolucci PHF. Neuropsychiatric feature profiles of patients with Lewy
body dementia. Clin Neurol Neurosurg. 2020;194:105832. doi:10.1016/
j.clineuro.2020.105832.
32. Kummer A, Harsányi E, Dias FMV, Cardoso F, Caramelli P, Teixeira AL.
Depression impairs executive functioning in parkinson disease patients
with low educational level. Cogn Behav Neurol. 2009;22(3):167-72.
doi:10.1097/WNN.0b013e3181b278f9.
33. Oliveira GSR, Bressan L, Balarini F, Jesuino e Silva RSJ, Brito MMCM,
Foss MP, et al. Direct and indirect assessment of functional abilities in
patients with parkinson’s disease transitioning to dementia. Dement
Neuropsychol. 2020;14(2):171-7. doi:10.1590/1980-57642020dn14-020011.
34. Oliveira GN, Souza CP, Foss MP, Tumas V. An analysis of the cognitive
items of the movement disorders society checklist for the diagnosis of
dementia in patients with Parkinson’s disease. Parkinsionism Relat Disord.
2015;21(10):1260-3. doi:10.1016/j.parkreldis.2015.08.005.
35. Breder R, Leite MAA, Pinto JA, Cavalcante IP, Pessoa BL, Neves MAO.
Low Sensitivity of the Mini-Mental State Examination for Cognitive
Assessment of Brazilian Patients with Parkinson Disease. J Geriatr
Psychiatry Neurol. 2017;30(6):311-5. doi:10.1177/0891988717731826.
36. Almeida KJ, Sá Carvalho LCL, Holanda Monteiro THOD, Gonçalves Júnior PCJ,
Campos-Sousa RN. Cut-off points of the Portuguese version of the
Montreal Cognitive Assessment for cognitive evaluation in Parkinson’s
disease. Dement Neuropsychol. 2019;13(2):210-5. doi:10.1590/
1980-57642018dn13-020010.
37. Almeida KJ, Macêdo LP, Lopes JLMLJ, Bor-Seng-Shu E, Campos-Sousa RN,
Barbosa ER. Modified Pfeffer Questionnaire for Functional Assessment
in Parkinson Disease. J Geriatr Psychiatry Neurol. 2017;30(5):261-6.
doi:10.1177/0891988717720298.
38. Rocha MSG, Bassetti EM, Oliveira MO, Kuark RGB, Estevam NM,
Brucki SMD. Addenbrooke’s Cognitive Examination-Revised is accurate
for detecting dementia in Parkinson’s disease patients with low
educational level. Dement Neuropsychol. 2014;8(1):20-5. doi:10.1590/
S1980-57642014DN81000004.
39. Souza CP, Oliveira GN, Foss MP, Tumas V. The interlocking finger test in
patients with Parkinson’s disease and healthy subjects. J Clin Neurosci.
2016;29:145-8. doi:10.1016/j.jocn.2015.09.026.
40. Amaral-Carvalho V, Caramelli P. Normative data for healthy middle-
aged and elderly performance on the Addenbrooke Cognitive
Examination-Revised. Cogn Behav Neurol. 2012;25(2):72-6. doi:10.1097/
WNN.0b013e318259594b.
41. César KG, Yassuda MS, Porto FHG, Brucki SMD, Nitrini R. Addenbrooke’s
cognitive examination-revised: normative and accuracy data for seniors
with heterogeneous educational level in Brazil. Int Psychogeriatr.
2017;29(8):1345-53. doi:10.1017/S1041610217000734.
42. Apolinario D, Santos MF, Sassaki E, Pegoraro F, Pedrini AVA, Cestari B,
et al. Normative data for the Montreal Cognitive Assessment (MoCA) and
the Memory Index Score (MoCA-MIS) in Brazil: Adjusting the nonlinear
effects of education with fractional polynomials. Int J Geriatr Psychiatry.
2018;33(7):893-9. doi:10.1002/gps.4866.
43. Sobreira E, Pena-Pereira MA, Eckeli AL, Sobreira-Neto MA, Chagas MHN,
Foss MP, et al. Screening of cognitive impairment in patients with
parkinson’s disease: Diagnostic validity of the Brazilian versions of
the montreal cognitive assessment and the addenbrooke’s cognitive
examination-revised. Arq Neuropsiquiatr. 2015;73(11):929-33.
doi:10.1590/0004-282X20150156.
44. Camargo CHF, Tolentino ES, Bronzini A, Ladeira MA, Lima R,
Schultz-Pereira GL, et al. Comparison of the use of screening tools for
evaluating cognitive impairment in patients with Parkinson’s disease.
Dement Neuropsychol. 2016;10(4):344-50. doi:10.1590/s1980-5764-
2016dn1004015.
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):69-82
45. Tumas V, Borges V, Ballalai-Ferraz H, Zabetian CP, Mata IF, Brito MMC,
et al. Some aspects of the validity of the Montreal Cognitive Assessment
(MoCA) for evaluating cognitive impairment in Brazilian patients with
Parkinson’s disease. Dement Neuropsychol. 2016;10(4):333-8.
doi:10.1590/S1980-5764-2016DN1004013.
46. Sobreira EST, Pena MCS, Silva Filho JH, Souza CP, Oliveira GN,
Tumas V, et al. Executive cognitive tests for the evaluation of patients
with Parkinson’s disease. Dement Neuropsychol. 2008;2(3):206-10.
doi:10.1590/S1980-57642009DN20300008.
47. Olchik MR, Ghisi M, Freiry AM, Ayres A, Schuh AFS, Rieder CRM, et al.
Comparison trail making test between individuals with parkinson’s disease
and health controls: Suggestions of cutoff point. Psychol Neurosci.
2017;10(1):77-82. doi:10.1037/pne0000076.
48. Machado FA, Rieder CR, Hilbig A, Reppold CT. Neuropsychological
profile of Parkinson’s disease patients selected for deep brain stimulation
surgery. Dement Neuropsychol. 2016;10(4):296-302. doi:10.1590/S1980-
5764-2016DN1004007.
49. Camargo CHF, Bronzini A, Tolentino ES, Medyk C, Schultz-Pereira GL.
Can the CERAD neuropsychological battery be used to assess cognitive
impairment in parkinson’s disease? Arq Neuropsiquiatr. 2018;76(3):145-9.
doi:10.1590/0004-282X20180003.
50. Leite MAA, Nascimento OJM, Pereira JS, Amaral C, Mesquita CT,
Azevedo JC, et al. Cardiac 123I-MIBG uptake in De novo Brazilian
patients with Parkinson’s disease without clinically defined dysautonomia.
Arq Neuropsiquiatr. 2014;72(6):430-4. doi:10.1590/0004-282x20140042.
51. Yoshita M, Arai H, Arai H, Arai T, Asada T, Fujishiro H, et al. Diagnostic
accuracy of123I-meta-iodobenzylguanidine myocardial scintigraphy
in dementia with lewy bodies: A multicenter study. PLoS One.
2015;10(3):e0120540. doi:10.1371/journal.pone.0120540.
52. McKeith I, O’Brien J, Walker Z, Tatsch K, Booij J, Darcourt J, et al.
Sensitivity and specificity of dopamine transporter imaging with 123I-FP-
CIT SPECT in dementia with Lewy bodies: a phase III, multicentre study.
Lancet Neurol. 2007;6(4):305-13. doi:10.1016/S1474-4422(07)70057-1.
82   Brazilian consensus on Parkinson’s disease dementia.   Parmera JB, et al.
53. Sobreira EST, Sobreira-Neto MA, Pena-Pereira MA, Chagas MHN,
Fernandes RMF, Eckeli AL, et al. Global cognitive performance is associated
with sleep efficiency measured by polysomnography in patients with
Parkinson’s disease. Psychiatry Clin Neurosci. 2019;73(5):248-53.
doi:10.1111/pcn.12819.
54. Higuchi M, Tashiro M, Arai H, Okamura N, Hara S, Higuchi S, et al. Glucose
hypometabolism and neuropathological correlates in brains of dementia
with Lewy bodies. Exp Neurol. 2000;162(2):247-56. doi:10.1006/
exnr.2000.7342.
55. Nobili F, Arbizu J, Bouwman F, Drzezga A, Agosta F, Nestor P, et al.
European Association of Nuclear Medicine and European Academy of
Neurology recommendations for the use of brain 18 F-fluorodeoxyglucose
positron emission tomography in neurodegenerative cognitive impairment
and dementia: Delphi consensus. Eur J Neurol. 2018;25(10):1201-1217.
doi:10.1111/ene.13728.
56. Schumacher J, Taylor JP, Hamilton CA, Firbank M, Cromarty RA,
Donaghy PC, et al. Quantitative EEG as a biomarker in mild cognitive
impairment with Lewy bodies. Alzheimers Res Ther. 2020;12(1):82.
doi:10.1186/s13195-020-00650-1.
57. Fonseca LC, Tedrus GMAS, Letro GH, Bossoni AS. Dementia, mild cognitive
impairment and quantitative EEG in patients with Parkinson’s disease. Clin
EEG Neurosci. 2009;40(3):168-72. doi:10.1177/155005940904000309.
58. Pereira JS, Pimentel MLV, Gomes PLH. Distúrbios cognitivos na doença
de Parkinson: correlações eletrencefalográficas. Arq Neuropsiquiatr.
1995;53(1):11-5. doi:10.1590/S0004-282X1995000100002.
59. Sandmann MC, Piana ER, Sousa DS, Bittencourt PRM. Digital EEG
with brain mapping in Alzheimer’s dementia and Parkinson’s disease:
a prospective controlled study. Arq Neuropsiquiatr. 1996;54(1):50-6.
doi:10.1590/S0004-282X1996000100009.
60. Fonseca LC, Tedrus GMAS, Carvas PN, Machado ECFA. Comparison of
quantitative EEG between patients with Alzheimer’s disease and those with
Parkinson’s disease dementia. Clin Neurophysiol. 2013;124(10):1970-4.
doi:10.1016/j.clinph.2013.05.001.
Dement Neuropsychol 2022 September;16(3 Suppl. 1):83-95 Consensus
https://doi.org/10.1590/1980-5764-DN-2022-S106EN

Treatment of dementia:
recommendations of the Scientific Department
of Cognitive Neurology and Aging of the
Brazilian Academy of Neurology
Paulo Caramelli1 , Valeska Marinho2 , Jerson Laks3,4 , Marcus Vinicius Della Coletta5 ,
Florindo Stella6,7 , Einstein Francisco Camargos8,9 , Jerusa Smid10 ,
Breno José Alencar Pires Barbosa10,11,12 , Lucas Porcello Schilling13,14,15 ,
Marcio Luiz Figueredo Balthazar16 , Norberto Anízio Ferreira Frota17,18 , Leonardo Cruz de Souza1 ,
Francisco Assis Carvalho Vale19 , Márcia Lorena Fagundes Chaves20,21 , Sonia Maria Dozzi Brucki10 ,
Ricardo Nitrini10 ,Helen Bedinoto Durgante22 , Paulo Henrique Ferreira Bertolucci23

1
Universidade Federal de Minas Gerais, Faculdade de Medicina, Departamento de Clínica Médica, Belo Horizonte MG, Brazil.
2
Universidade Federal do Rio de Janeiro, Instituto de Psiquiatria, Centro para Doença de Alzheimer, Rio de Janeiro RJ, Brazil.
3
Universidade Federal do Rio de Janeiro, Instituto de Psiquiatria, Programa de Pós-Graduação em Psiquiatria e Saúde Mental, Rio de Janeiro RJ, Brazil.
4
Universidade do Estado do Rio de Janeiro, Faculdade de Ciências Médicas, Rio de Janeiro RJ, Brazil.
5
Universidade do Estado do Amazonas, Manaus AM, Brazil.
6
Universidade Estadual Paulista, Instituto de Biociências, Campus de Rio Claro SP, Brazil.
7
Universidade de São Paulo, Faculdade de Medicina, Departamento e Instituto de Psiquiatria, Laboratório de Neurociências, São Paulo SP, Brazil.
8
Hospital Universitário de Brasília, Centro de Medicina do Idoso, Brasília DF, Brazil.
9
Universidade de Brasília, Faculdade de Medicina, Programa de Pós-Graduação em Ciências Médicas, Brasília DF, Brazil.
10
Universidade de São Paulo, Faculdade de Medicina, Departamento de Neurologia, Grupo de Neurologia Cognitiva e do Comportamento, São Paulo SP, Brazil.
11
Universidade Federal de Pernambuco, Centro de Ciências Médicas, Área Acadêmica de Neuropsiquiatria, Recife PE, Brazil.
12
Instituto de Medicina Integral Prof. Fernando Figueira, Recife PE, Brazil.
13
Pontifícia Universidade do Rio Grande do Sul, Escola de Medicina, Serviço de Neurologia, Porto Alegre RS, Brazil.
14
Pontifícia Universidade do Rio Grande do Sul, Instituto do Cérebro do Rio Grande do Sul, Porto Alegre RS, Brazil.
15
Pontifícia Universidade do Rio Grande do Sul, Programa de Pós-Graduação em Gerontologia Biomédica, Porto Alegre RS, Brazil.
16
Universidade Estadual de Campinas, Departamento de Neurologia, Faculdade de Ciências Médicas, Campinas SP, Brazil.
17
Hospital Geral de Fortaleza, Serviço de Neurologia, Fortaleza CE, Brazil.
18
Universidade de Fortaleza, Fortaleza CE, Brazil.
19
Universidade Federal de São Carlos, Centro de Ciências Biológicas e da Saúde, Departamento de Medicina, São Carlos SP, Brazil.
20
Hospital de Clínicas de Porto Alegre, Serviço de Neurologia, Porto Alegre RS, Brazil.
21
Universidade Federal do Rio Grande do Sul, Faculdade de Medicina, Departamento de Medicina Interna, Porto Alegre RS, Brazil.
22
Universidade Federal de Pelotas, Pelotas RS, Brazil.
23
Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Neurologia e Neurocirurgia, São Paulo SP, Brazil
Correspondence: Paulo Caramelli; Email: caramelli@ufmg.br.
Conflict of interest: PC: Participation as principal investigator in clinical trials for Novo Nordisk and Roche laboratories. Participation in advisory boards for Aché,
Biogen, EMS, Nutricia and Roche laboratories. Development of continuing medical education materials and participation as speaker in symposia sponsored by
Aché, Nutricia, Libbs, Roche, Sandoz, Torrent and Zodiac laboratories; VM: Development of continuing medical education materials and participation as speaker in
symposia sponsored by Biogen, Sandoz and Torrent laboratories; JS: Participation as speaker in symposia sponsored by Roche laboratory; LPS: Participation in
advisory boards for Biogen. Participation as speaker in symposia sponsored by Aché, Apsen and Biogen laboratories; MLFB: Participation in advisory boards for
Biogen. Development of continuing medical education materials and participation as speaker in symposia sponsored by EMS and Torrent laboratories; PHFB:
Participation in advisory boards for Biogen and Novo Nordisk laboratories. Supervision of training activities for Biogen, Janssen-Cilag and Novo Nordisk laboratories
and for Quintiles. Participation as speaker in symposia sponsored by Apsen, Nutricia, Roche and Sandoz laboratories; LCS: Participation in advisory board for Biogen.
Participation as speaker in symposia sponsored by Biogen; RN: Participation in advisory board for Biogen; JL, MVDC, FS, EFC, BJAPB, NAFF, FACV, MLFC, SMDB,
HBD: No conflict of interest to declare.
Received on February 20, 2022; Received in its final form on April 27, 2022; Accepted on April 27, 2022.

Caramelli P, et al.   Dementia care.   83

 Dement Neuropsychol 2022 September;16(3 Suppl. 1):83-95

ABSTRACT. There is currently no cure for neurodegenerative or vascular dementias, but some pharmacological and non-pharmacological interventions may
contribute to alleviate symptoms, slow disease progression and improve quality of life. Current treatment approaches are based on etiology, symptom profile
and stage of dementia. This manuscript presents recommendations on pharmacological and non-pharmacological treatments of dementia due to Alzheimer’s
disease, vascular cognitive impairment, frontotemporal dementia, Parkinson’s disease dementia, and dementia with Lewy bodies.
Keywords: Dementia; Drug Therapy; Behavior; Cognition.

TRATAMENTO DA DEMÊNCIA: RECOMENDAÇÕES DO DEPARTAMENTO CIENTÍFICO DE NEUROLOGIA COGNITIVA E DO ENVELHECIMENTO DA ACADEMIA

BRASILEIRA DE NEUROLOGIA
RESUMO. Atualmente não há tratamento curativo para as demências neurodegenerativas ou para a demência vascular, mas algumas intervenções
farmacológicas e não farmacológicas podem contribuir para aliviar os sintomas, retardar a progressão da doença e melhorar a qualidade de vida.
As abordagens terapêuticas atuais são baseadas na etiologia, no perfil dos sintomas e no estágio da demência. Neste artigo apresentamos recomendações
sobre os tratamentos farmacológicos e não farmacológicos da demência devida à doença de Alzheimer, comprometimento cognitivo vascular, demência
frontotemporal, demência da doença de Parkinson e demência com corpos de Lewy.
Palavras-chave: Demência; Tratamento Farmacológico; Comportamento; Cognição.

INTRODUCTION an early deficit in cholinergic activity in mild to

R esearch estimates that by 2050 about 152 million

people will have dementia, or one new case every
three seconds, mostly from low- and middle-income
countries (LMIC). Currently, about two thirds of people
diagnosed with dementia (PwD) live in LMIC1, added to
a high estimate of underdiagnosed cases—approximate-
ly 800.000 people in Brazil—according to recent data2.
Dementia is one of the leading causes of disability in
older adults, with significant impacts on the autonomy and
quality of life (QoL) of PwD and their families. Neurode-
generative diseases and cerebrovascular disorders are the
main causes of dementia, with Alzheimer’s disease (AD)
accounting for more than half of the cases3. In Brazil,
AD ranked among the top ten causes of deaths in 20194.
Other degenerative causes include frontotemporal demen-
tia (FTD), Parkinson’s disease (PD) dementia (PDD) and
dementia with Lewy bodies (DLB).
Although we currently lack a cure for neurodegen-
erative or vascular dementias, some pharmacological
and non-pharmacological interventions can contribute
to alleviate symptoms, slow disease progression and
improve QoL5. Therapeutic approaches are based on
etiology, symptom profile and stage of dementia. Thus,
this manuscript presents updated information and rec-
ommendations on current available treatments in Brazil
for dementia due to AD, vascular cognitive impairment
(VCI), FTD, PDD and DLB.
TREATMENT OF DEMENTIA DUE TO AD
Pharmacological treatment
Degeneration of basal forebrain cholinergic neurons
precedes clinical manifestations in AD, thus implying
moderate stages of dementia due to AD6. Cholines-
terase inhibitors (ChEI) donepezil, galantamine, and
rivastigmine inhibit the ChE enzyme and increase
acetylcholine availability in the brain. These drugs are
approved for treating mild and moderate AD dementia,
but have also shown positive effects in severe stages7.
For moderate-to-severe AD dementia, studies recom-
mend combining ChEI with the glutamatergic NMDA
receptor antagonist memantine.
Despite modest effects, use of ChEI and meman-
tine have shown improvement in disease symptoms
or slower progression when compared with placebo.
Clinical benefits can be seen in cognitive, behavioral,
and functional domains5,7. Despite conflicting evidence,
research shows that all ChEI may reduce AD mortality
and galantamine may reduce the risk of conversion to
severe dementia8.
When prescribing these drugs, physicians must
clarify to PwD and caregivers that the expected clinical
effects are usually modest, sometimes characterized
only by stabilization or slower worsening. Therapy
should begin with the lowest dosage to avoid adverse
events (AEs) and be increased at least every four weeks
for ChEI and one week for memantine. Regarding ChEI,
usage should reach the therapeutic doses, i.e., 5-10mg
for donepezil, 16-24 mg for galantamine, 6-12mg for
oral rivastigmine and 9.5mg for rivastigmine patch
(the 13.3mg patch is also available and can be pre-
scribed for selected cases). Ideally, the highest dose
within the therapeutic range of each drug should be
targeted, given the greater potential for clinical ben-
efits. Figure 1 illustrates the dose regimen for drug
therapy of AD dementia.

84   Dementia care.   Caramelli P, et al.


4 weeks
Donepezil Donepezil
tablet 5mg 1x/d tablet 10mg 1x/d
Galantamine Galantamine
capsule 8mg 1x/d capsule 16mg 1x/d
Rivastigmine Rivastigmine
capsule 1.5mg 2x/d or capsule 3mg 2x/d or
patch 4.6mg 1x/d patch 9.5mg 1x/d
Memantine2 Memantine
1 week
5mg 1x/d 5mg 2x/d
1
In case of improvement or stabilization, the highest dose of rivastigmine patch can be postponed; 2memantine is indicated for treating moderate or severe AD dementia.
Figure 1. Overview of pharmacological treatment for AD dementia.
Common AEs consist of nausea, vomiting, diarrhea,
headache and insomnia, and are less likely to occur
if medication is taken after a meal. Donepezil should
be administered at bedtime; in case of insomnia or
nightmares, it can be taken in the morning. Less com-
mon, but more serious AEs are bradyarrhythmia and
syncope. Treatment effects and duration vary from
person to person, and any positive effect may be lost
over time. No research has confirmed the superiority of
one ChEI over the others, despite some specificities on
the mechanisms of action and frequency/types of AEs.
Switching to another ChEI is encouraged, particularly
when no clinical benefit is observed after a few months
of follow-up or in case of AEs that do not resolve. With
progression to moderate dementia, the association
with memantine is indicated5,9,10. Memantine is usually
well tolerated; the most common AEs are drowsiness,
dizziness and headache5,7.
Practical issues for prescribing and discontinuing ChEI
and memantine
• ChEI increase vagal tone and are contraindicated
in patients with baseline bradycardia or known
cardiac conduction system disorder (i.e., atrio-
ventricular block > 1st degree). Caution is required
when any of the three ChEI are used in combina-
tion with drugs that induce bradycardia or alter
atrioventricular conduction (e.g., beta blockers or
calcium channel blockers);
Dement Neuropsychol 2022 September;16(3 Suppl. 1):83-95
4 weeks 4 weeks
Galantamine
capsule 24mg 1x/d
Rivastigmine
capsule 6mg 2x/d
Rivastigmine
capsule 4.5mg 2x/d
Rivastigmine
patch 9.5mg 1x/d1
Memantine Memantine
1 week 1 week
2x/d – 10mg and 5mg 10mg 2x/d or 20mg 1x/d
Treatment of comorbidities
Non-phamacological interventions
• Caution is required when prescribing ChEI to
individuals with chronic obstructive pulmonary
disease or asthma;
• Discontinuation or switching (in the case of ChEI)
shall be considered when there is no clinical ben-
efit or in case of relevant AEs;
• Avoid abrupt discontinuation of ChEI or memantine;
• In the case of AEs with higher doses, dose reduc-
tion may be considered, noting whether there is
a decrease in AEs as well as changes in cognitive,
functional, or neuropsychiatric symptoms;
• Discontinue medication in the absence of clinical
benefits or if AEs persist.
Pharmacological treatment of neuropsychiatric symptoms
Neuropsychiatric symptoms may precede the cogni-
tive symptoms in AD, becoming more common at the
second half of the mild dementia stage, increasing
along the moderate stage and usually decreasing at
severe stage.
Clinical trials specifically addressing neuropsychi-
atric symptoms in AD have been disappointing. The
benefits of ChEI tend to favor specific neuropsychiatric
symptoms, such as depression, anxiety, dysphoria,
and apathy11. For depression, which may be present in
more than half of AD patients, there is some evidence
for the indication of sertraline or mirtazapine as the
best antidepressant options12. A recent clinical trial,
Caramelli P, et al.   Dementia care.   85
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):83-95
however, observed a trend to increased mortality with
mirtazapine used to treat agitation in AD dementia13.
Aggressiveness is a common neuropsychiatric
symptom which may contribute to agitation and in-
creased caregiver burden. Treatment encompasses both
pharmacological and non-pharmacological interven-
tions (see next session). Specific AD drugs (i.e., ChEI
and memantine) might have modest but significant
effects on these symptoms and even if there is a good
initial effect, it may be lost after some time. Given the
absence of approved pharmacological treatment for
neuropsychiatric symptoms in AD dementia, a sequence
of drugs may be considered for treatment of agitation
and aggressiveness14. According to this algorithm14,
first-line treatment would be atypical antipsychotics,
the first choice being risperidone, followed by aripip-
razole or quetiapine. If these drugs fail or are offset by
AEs, carbamazepine may be an option. In case of a new
failure the next step would be citalopram, followed by
gabapentin and prazosin. Citalopram is a good thera-
peutic option for agitation. Benzodiazepines must be
avoided in dementia due to AD.
Another common neuropsychiatric symptom is
sleep disorder. The first step to a successful treat-
ment of sleep disorder in AD is to ask why and how
it occurs. A sleep disorder may be the consequence
of a sleep wake cycle inversion, and in this case sleep
hygiene and non-pharmacological interventions may
be helpful. For pain or another discomfort, the cause
should be addressed; issues related to sundowning,
fragmented sleep or difficulty in starting sleep should
be addressed. The sleep may be interrupted by de-
lusions and hallucinations, when an antipsychotic,
particularly with sedative effects (e.g., quetiapine)
may be useful. There is no evidence that hypnotics
or mirtazapine have positive effects. Trazodone
might improve sleep, although the effects are usually
modest15. A recent Brazilian study has shown that
short-term use (i.e., 14 days) of zopiclone or zolp-
idem may be clinically helpful in treating insomnia
in AD dementia16.
Delusions and hallucinations may be present in up to
one third of AD patients and indicate poorer prognosis,
with increased functional impairment and higher mor-
tality. Treatment of these neuropsychiatric symptoms
includes avoiding typical antipsychotics, due to AEs and
cognitive worsening. There is evidence of a modest effect
of ChEI, but often there is a need of using antipsychotics,
and in this case the evidence is stronger for risperidone
and olanzapine, while for quetiapine the evidence is
86   Dementia care.   Caramelli P, et al.
scanter. Studies with brexpiprazole are ongoing, but
evidence of efficacy and safety has not been definitively
established to date17. Although some studies suggest
that cannabinoids may have potential positive effects in
neurodegenerative diseases, there is no current evidence
to support their clinical use in dementia18.
Pharmacological treatment for AD-related conditions
AD may have associated complications. Parkinson-
ism may be present in 9% to 70%, depending on the
disease stage. There are differences with typical PD,
with tremor being mild or absent, and usually pre-
senting symmetrical bradykinesia and rigidity from
the start. Levodopa may be tried, but response is less
likely than in PD.
Between 10% and 20% of AD patients will have at
least one seizure. Newer anticonvulsants (e.g., lamo-
trigine or levetiracetam) are first-line treatments for
epilepsy in PwD19.
Non-pharmacological treatments for AD:
cognitive symptoms
Cognitive stimulation therapy (CST)
Recommended treatment according to the National
Institute for Health and Clinical Excellence of the
United Kingdom20 to stimulate language, memory,
executive functions; approved by the Alzheimer’s
Disease International and used in many countries21.
CST was shown to improve cognition, QoL, neuropsy-
chiatric symptoms in PwD from LMIC22,23. CST and its
implementation manual have been adapted for use in
Brazil24 and the intervention was found to be feasible
and beneficial to improve mood in PwD in a recent
clinical trial25.
Multicomponent/multidisciplinary cognitive rehabilitation
program (MCRP)
MCRP includes cognitive rehabilitation, stimulation and
computer-assisted therapy, physical training, physio-
therapy, reading and games. This program may decrease
depressive symptoms and improve QoL indicators of
PwD/caregivers. However, MCRP effects on cognition
are questionable23,26.
Reality orientation (RO)
Neurosensory stimulation to reorient daily activities may
improve cognition and adherence to pharmacological
treatment in mild-moderate AD dementia27,28. Results for
neuropsychiatric symptoms are inconclusive29.

Non-pharmacological treatments for AD:
neuropsychiatric symptoms
To increase the chance of success with a non-pharma-
cological treatment it is essential to adopt an individu-
alized approach that considers:
• When and how the neuropsychiatric symptom
started? (Was there a trigger?)
• How did it evolve? (Are there associated symptoms?)
• How did it end?
• What are the associated worsening and improving
factors?
Psychosocial/psychoeducational interventions
These are group or person-centered approaches to in-
form the management and care of dementia, including
emotional and social stimulation of PwD/caregivers.
Face-to-face or technology-based multicomponent
psychoeducational and Cognitive-Behavioral Therapy
approaches (cognitive reframing, self-monitoring,
mood management techniques, mindfulness-based
training) may improve neuropsychiatric symptoms
(agitation, restlessness, anxiety, sleep disturbances),
delay the progression of cognitive impairment, and
benefit caregiver confidence, self-efficacy, burden,
depression, stress levels, and QoL of the dyad30-33. Posi-
tive Psychology practices are recommended for mental
health promotion of PwD/caregivers according to the
Alzheimer’s Association Psychosocial Measurement
Workgroup 33 and the European INTERDEM Social
Health Taskforce34,35.
Reminiscence therapy (RT)
RT is a group-based intervention to recall autobiograph-
ical memories. It is used for mild-moderate dementia
with modest evidence to improve depressive symptoms,
mood, cognition22, and well-being36. Lacking theoretical
basis and methodological systematization make RT
effects questionable37.
Music therapy (MT)/dancing
Significant positive effects were found of MT on mem-
ory38, emotional/mood22 and neuropsychiatric symp-
toms27. Dancing may also lead to beneficial effects on
cognition and psychical health20.
Physical-related/lifestyle-related interventions
Repetitive transcranial magnetic stimulation (rTMS)
and acupuncture seem to improve cognitive functions,
whereas acupuncture, exercise and light therapy pre-
sented potential to enhance functional performance22
and cognition 39,40 . Long-term exercise improves
Dement Neuropsychol 2022 September;16(3 Suppl. 1):83-95
blood flow, hippocampal volume, neurogenesis, also
neuropsychiatric symptoms41. Occupational therapy
(error-reduction techniques)42 and physiotherapy43,44
tend to enhance functioning and delay physical
decline; results are inconclusive for improvement
in cognition. Early interventions targeting lifestyle
modifiable risk factors (arterial hypertension, di-
abetes, obesity, physical inactivity, high alcohol
consumption, smoking, social isolation), clinical
conditions (hearing loss and depression), and poor
nutrient intake, may work as protective measures for
reducing AD risk1,10,45,46.
TREATMENT OF VASCULAR COGNITIVE IMPAIRMENT
The general principles of approach and treatment for VCI
are the same as for dementia due to AD. They encompass
the treatment of comorbidities, including neuropsychiat-
ric symptoms, providing information and support to PwD
and caregivers, and maintaining independence.
Primary and secondary prevention
The multidisciplinary team should focus primarily on
controlling the main risk factors for new cerebrovascular
events and cognitive impairment in VCI. Although we
recognize risk factors for post-stroke dementia, such as
low education and diabetes mellitus47, factors for stroke
itself have long been known and controllable, including
smoking, arterial hypertension, diabetes mellitus and
dyslipidemia (notably high LDL-cholesterol levels)48.
However, in recent decades several studies have
proposed measuring the weight of these risk factors on
the appearance of new strokes, on post-stroke cognition
and functionality, often with conflicting results. Based
on these observations we recommend:
• Blood pressure control: There is strong evidence
that increased blood pressure levels are associated
with stroke48. There are still no studies that have
confirmed the impact of blood pressure control on
worsening cognitive impairment. Intensive blood
pressure control (systolic pressure of 120 versus
140 mmHg) does not show a reduction in the
incidence of dementia (all etiologies). In frail
older adults, with symptoms of orthostatic hy-
potension and increased risk of falls, individu-
alize blood pressure targets to avoid symptoms
of hypotension;
• Glycemic control: There is strong evidence that
increased blood glucose levels are associated
with stroke 48. However, there is no evidence
that strict glycemic control in older adults
Caramelli P, et al.   Dementia care.   87
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):83-95
prevents cardiovascular events. Studies have
shown that tight blood glucose control in older
adults was associated with greater frailty and
mortality, with no benefit in the evolution of
dementia49,50. Acceptable fasting glycemic values​​
in individuals with VCI should be around up
to 150 mg/dL and postprandial < 180 mg/dL,
as well as glycated hemoglobin targets should
be less stringent (e.g., < 8%)51;
• Antiplatelet agents: There is strong evidence
to support using these agents for secondary
prevention of non-embolic stroke, either ace-
tylsalicylic acid (81 to 100mg/day) or clopi-
dogrel (75mg/day)52. In cases of VCI without
evidence of previous stroke, therapy should
be individualized 53, especially in individuals
with significant risk of falls. In recent years,
no studies have been published providing sup-
port for the benefits of antiaggregants in the
evolution of VCI54;
• Statins: Statins are of interest in the secondary
prevention of cerebrovascular disease due to both
their lipid-lowering and pleiotropic effects on
vascular function, combining to inhibit athero-
sclerosis. There is good evidence that statins given
late in life to people at risk for vascular disease
do not prevent cognitive decline or dementia55.
For individuals with VCI and a history of ischemic
(non-embolic) stroke, statin use should follow
secondary prevention recommendations with
individual risk analysis. The use of statins in older
adults and subjects with vascular risk factors is
not recommended for the sole purpose of primary
prevention or treatment of dementia;
• Multidisciplinary interventions: In a system-
atic review of 15 prospective studies with over
30,000 individuals without dementia, involve-
ment in at least one physical activity of minimal
to moderate intensity was associated with a 35%
reduction in the relative risk of cognitive decline
in one to 12 years of follow-up56. In another study
with 639 older adults without disability and with
cerebral white matter changes, physical activity
reduced the risk of cognitive and functional defi-
cits, regardless of the severity of white matter
changes or other risk factors57. Hence, practice
of physical activity at mild to moderate intensity
should be strongly recommended to all individuals
at the primary care level as a means of primary and
secondary prevention of VCI. On the other hand,
evidence that physical rehabilitation reduces post-
stroke cognitive loss is still insufficient58;
88   Dementia care.   Caramelli P, et al.
• Diet and supplements: A balanced diet, rich in
vegetables and fruits, impacts many organ systems.
One recent systematic review with metanalysis has
shown that high adherence to the Mediterranean
diet reduced the risk of global cognitive decline in
non-demented older adults59. The use of vitamin
and mineral supplements should only be indicated
in cases with insufficiency. It is not recommended
to use vitamin supplements for the prevention or
treatment of VCI.
Pharmacological treatment
ChEI and memantine
The pharmacological treatment commonly prescribed
in VCI, particularly vascular dementia, is mainly based
on ChEI and memantine. These medications are rou-
tinely used in clinical practice to treat cognitive decline,
functionality changes and neuropsychiatric symptoms.
However, randomized controlled clinical trials have
shown limited efficacy of these drugs.
Randomized, placebo-controlled studies demon-
strate little efficacy of ChEI in pure vascular demen-
tia60,61. There is a statistically significant but clini-
cally slight cognitive benefit for cognitive functions,
mainly processing speed and executive functions62.
In general, there is a slight attenuation of cognitive
decline compared to placebo61. Some studies report
favorable results regarding functional performance,
but the gain is not consistent. Improvement of neuro-
psychiatric symptoms, when present, is also limited.
On the other hand, agitation has been observed as an
AE of ChEI and memantine63,64.
Favorable results of ChEI seem more evident in
mixed dementia (vascular + AD) compared to ‘pure’
vascular dementia65. Galantamine is approved in Brazil
for treatment of mild to moderate AD dementia with
concomitant significant cerebrovascular disease and has
shown positive effects on cognitive speed and QoL of
individuals with mixed dementia in a controlled clini-
cal trial in the country66. Possible benefits of ChEI in
mixed dementia, although limited, are attributed to the
reduction of cholinergic depletion caused by concomi-
tant AD60,65,66. There is insufficient clarity regarding the
differences in efficacy of ChEI, as well as memantine,
between multiple infarcts and subcortical vascular
dementia64,67-69. Initiation of ChEI treatment in patients
with severe dementia is not recommended.
Among the AEs of ChEI already described above,
bradycardia and arterial hypotension are the main
conditions associated that require special attention in
patients with vascular dementia62,65,67-71.

In current clinical practice, memantine is com-
monly added to ChEI in subjects with moderate or
severe vascular dementia. However, the benefits of
memantine are very limited or controversial for con-
trolling cognitive and neuropsychiatric symptoms,
as well as for slowing cognitive or functional decline61.
For this reason, the drug has not been approved for
treatment of vascular dementia. The few randomized,
placebo-controlled studies report that memantine is
well-tolerated and that drowsiness has been the AE
of major concern72.
Treatment of neuropsychiatric symptoms in VCI
Overall, the neuropsychiatric symptoms in VCI are
like those observed in AD, and the treatment is sim-
ilar 14,73-75. The non-pharmacological interventions
include occupational therapy, cognitive stimulation,
art therapy, involvement in social interaction activ-
ities, physical activity, and psychological support for
PwD and caregivers.
Regarding pharmacological interventions, general
recommendations follow the commentaries made
above (AD section), namely, to avoid benzodiazepines,
to prescribe antipsychotics in low doses and for strict-
ly necessary periods, antidepressants for depression,
anxiety, panic and mild agitation, and anticonvulsants
when indicated.
The pharmacological treatment of patients with
vascular dementia should be regularly monitored for
cardiovascular signs and symptoms.
TREATMENT OF FRONTOTEMPORAL DEMENTIA
(BEHAVIORAL AND LANGUAGE VARIANTS)
Frontotemporal dementia (FTD) encompasses different
clinical syndromes associated with progressive behav-
ioral/personality deterioration or language disorders,
and is considered the second most frequent cause of
young-onset dementia76.
Treatment of behavioral variant frontotemporal dementia
The clinical syndrome associated with behavioral and
personality changes called behavioral variant (bvFTD)
is the most common clinical presentation and specific
diagnostic criteria are available for clinical use77.
There are no approved treatments for bvFTD, either
disease-modifying drugs or symptomatic treatments
to ameliorate disturbing symptoms. Only a few small
studies have shown benefits of symptomatic pharma-
cological approaches78.
Dement Neuropsychol 2022 September;16(3 Suppl. 1):83-95
Considering that there are no specific treatments,
care should focus on managing behavioral symptoms
and disability, and reducing caregiver burden that is
high in bvFTD. In a recent Brazilian study including
20 bvFTD and 30 AD individuals, Lima-Silva et al.
found out that bvFTD subjects presented higher levels
of neuropsychiatric symptoms and that their caregivers
experienced higher levels of distress than AD caregivers.
Moreover, bvFTD caregiver’s distress and burden were
related to cognitive and functional impairment79.
Multidisciplinary management may be needed
throughout the disease process, but this has not been
specifically established for bvFTD treatment. A mul-
tidisciplinary team may offer a more comprehensive
care management and seems to be an essential
tool for dealing with other degenerative diseases80.
However, the needs in bvFTD may be more specific
and studies regarding their management should be
conducted. Social, financial, psychological counseling
may be required to address specific issues and more
knowledge on those topics should be gathered to help
services’ organization. For instance, the emergence
of swallowing problems during dementia progression
may require specialized evaluation. Problems with
inappropriate eating speed, passivity, coughing, and
choking beginning in the mild stages and following
the worsening cognitive and behavioral declines were
recently reported and add information about specific
treatment needs81.
Regarding pharmacological approaches, a recent
systematic review gathered information aiming to
identify pharmacological interventions that could
be used to treat the more troublesome behaviors in
bvFTD. Trieu et al.78 found 23 studies (11 randomized
controlled trials, eight open-label studies, one proof-
of-concept study, and three case series) involving a
sample of 573 individuals. Sixteen out of the 23 stud-
ies used pharmacological interventions, resulting
in benefits, as measured by the Neuropsychiatric
Inventory, for trazodone, citalopram, rivastigmine,
paroxetine, ameliorating symptoms such as disinhi-
bition, hyperorality, and depression.
Two reviews82,83 published by Brazilian authors re-
port that most studies have small sample sizes, short
duration of treatment, and non-uniform measures while
evaluating efficacy and tolerability.
Portugal et al.82 conducted a systematic review and
reported better results for drugs with serotonergic
action, such as selective serotonin reuptake inhibi-
tors or SSRIs (paroxetine, citalopram, fluvoxamine)
and trazodone to treat behavioral symptoms, but not
cognition. Authors suggest that using SSRIs as the
Caramelli P, et al.   Dementia care.   89
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):83-95
first-line treatment seems to be the best practice
until better data on evidence-based strategies to rely
upon are available.
In a narrative review aiming to guide clinical prac-
tice, Gambogi et al.83 conducted a literature search
on bvFTD treatment. According to drug class, ChEI
and memantine do not have significant therapeutic
actions. Antidepressants (SSRIs and trazodone) im-
proved behavioral symptoms with better tolerability;
antipsychotics reduced agitation (quetiapine, risperi-
done, aripiprazole), improper behaviors (risperidone
and aripiprazole), and scores on the Neuropsychiatric
Inventory (olanzapine) in uncontrolled cases series
and clinical reports. However, mortality issues related
to antipsychotic use in dementia, cardiovascular risks,
and motor AEs limit their use in bvFTD. Psychostim-
ulants for apathy and anticonvulsants for abnormal
behaviors were investigated, but must be used with
caution due to AEs. In a symptom-focused approach,
authors suggest SSRIs or trazodone as the first option
for disinhibition, compulsive/perseverative behaviors,
stereotyped behaviors, and hyperorality. Psychostimu-
lants may be an option for apathy and antipsychotics
should be used with care and reserved to manage
challenging and hazardous behaviors.
In summary, several low-quality reports are fo-
cusing on symptomatic treatment for bvFTD and
no specific treatment proved to be effective to date.
ChEI and memantine should not be used as they
have not shown any significant therapeutic action.
SSRIs or trazodone seem the best practice to manage
behavioral problems as a first step, and the use of
second-generation antipsychotics should be reserved
for the management of psychotic manifestations,
troublesome or hazardous behaviors.
Treatment of primary progressive aphasias
Primary progressive aphasia (PPA) refers to clinical syn-
dromes characterized by an insidious and progressive
loss of language abilities associated with neurodegen-
erative diseases. The three variants differ in anatomic,
phenotypic presentation, and underlying pathology84.
The non-fluent/agrammatic variant PPA (nfvPPA)
is associated with atrophy of left frontal lobe, insula,
and supplementary motor areas, and progressive,
effortful, non-fluent speech, with syntactic deficits,
grammatical errors, and omissions. The semantic
variant PPA (svPPA) is associated with left anterior
temporal lobe atrophy and fluent speech with deficits
in lexical retrieval, naming, and word comprehension.
The logopenic variant PPA (lvPPA) presents AD as the
pathological substrate in most cases and is associated
90   Dementia care.   Caramelli P, et al.
with left posterior temporal/parietal atrophy, and slow
speech with long-word finding pauses, anomia,
and repetition deficits84.
Up to this moment, there are no disease-modify-
ing agents approved for these language syndromes
associated with neurodegenerative diseases. Symp-
tomatic treatments aiming to improve language dis-
orders have been shown to enhance oral and written
naming abilities85. Language training therapies im-
prove naming accuracy for trained items at short- and
long-term follow-up and are considered the standard
treatment for PPA85,86.
There are very few studies on PPA treatment in
Brazil and Latin-America, with small sample sizes,
demonstrating the lack of local information about
language therapies in PPA87. Notwithstanding, an im-
portant piece of information was gathered by a Brazil-
ian systematic review organized by Carthery-Goulart
et al.88. The literature on evidence-based strategies of
language rehabilitation in PPA was summarized and
the language behavioral treatments classified into
impairment-directed and functional interventions.
The results suggest, as a practical option, the rec-
ommendations for the use of impairment-directed
therapies aimed at naming and lexical retrieval in
svPPA. In relation to nfvPPA and lvPPA, the small
number of studies limits conclusions about the best
therapeutic option for such variants88.
While impairment-directed intervention targets
the remediation or slowing the progression of specific
language and speech impairments, the functional inter-
ventions focus on communication, including environ-
mental modifications. The functional interventions key
components rely on building communication strategies
and practicing the strategies with a communication
partner. However, the frequency and dosage of such
interventions using rigorous outcomes is an unmet need
up to this moment89.
The maintenance of therapy gains, in the absence of
continuous training, is more evident in the short-term
than long-term in all PPA variants and is influenced by
treatment length and session frequency. Generalization
to untreated items varies following each PPA subtype and
occurs more often in nfvPPA and lvPPA than in svPPA90.
Language therapies usually focus on enhancing
abilities in trained activities or tasks and such training
may limit benefits to the practiced domains86,88. Recent
reviews have shown a potential benefit for non-invasive
brain stimulation combined with language therapies in
improving oral or written naming accuracy for trained
and untrained items85,86.

As a practical orientation cognitive-linguistic
interventions targeting impairment and aiming at
remediation and symptoms’ improvement seem the
best practice. In this sense, a recent Brazilian study
investigated the short- and mid-term effects of four
training programs directed to language and speech defi-
cits in 18 PPA individuals (different subtypes) carried
out during four months (two weekly sessions). All cases
improved performance on trained items during the ac-
tive phase of treatment. Statistically significant clinical
benefits were observed in 13 individuals, while for five,
the results were maintained. However, generalization to
untrained items or to other tasks were observed only
in two individuals91.
TREATMENT OF PARKINSON’S DISEASE
DEMENTIA AND DEMENTIA WITH LEWY BODIES
PD and DLB are neurodegenerative disorders that share
some common features such as dopaminergic deple-
tion and movement disorders92. Lewy body inclusions
throughout the cortex ensue the typical triad of the
dementia syndrome in DLB: dementia, complex visual
hallucinations and parkinsonism. PDD, in turn, starts
with a dysexecutive syndrome93,94.
DLB may show parkinsonism later in the course
of the disease, whereas complex visual hallucinations
appear early, together with delirium without other
clinical causes. PD first symptoms, on the other hand,
encompass asymmetric bradykinesia, tremor and
muscle rigidity95. Memory complaints are not the first
symptoms in DLB or in PDD, as usually observed in
dementia due to AD and VCI. PDD typically presents
with a frontal dysexecutive syndrome95,96.
The identification of the disease which is causing
dementia is important to identify drugs that should
and should not be prescribed when neuropsychiatric
symptoms occur. Antipsychotics should be avoided
in DLB, as there is a hypersensitivity to neuroleptic
malignant syndrome and because they may aggravate
parkinsonism, regardless of the dose prescribed. When
psychosis exists in PDD, levodopa and other antipar-
kinsonian drugs should be re-evaluated, before pre-
scribing any antipsychotics to deal with the behavioral
and mood symptoms97,98.
Cognitive and neuropsychiatric symptoms in
PDD and DLB are treated with rivastigmine, the only
approved ChEI for these indications98,99. Memantine
appears to be associated with some improvement in
behavioral aspects, but studies have not reported ben-
efits for cognition in these individuals98,99. Memantine
has not been approved for treatment of DLB or PDD.
Dement Neuropsychol 2022 September;16(3 Suppl. 1):83-95
As for treatment of neuropsychiatric symptoms and
syndromes, stimuli regulation should be tried before
any medication is applied. Excessive stimulation, or the
lack of proper stimulation, can worsen orientation and
behavior. Room light, physical exercise, cognitive stim-
ulation, calm environment and maintenance of clinical
status can help control behavioral problems before
medication comes into place100. Even if medication is
needed, all these measures should be enforced.
The clinical diagnosis, differentiating PDD from
DLB, can be a challenge, even for the specialist, since
the two conditions seem to be different spectra of the
same pathological family, being mainly differentiated
by the clinical course.
The cortical and subcortical distribution of Lewy
bodies will lead to different clinical presentations.
Although it seems somewhat theoretical, this distinc-
tion is essential in some details of the medication man-
agement inherent to each situation. Diagnostic criteria
for PDD and DLB have been published before96,97.
Lewy body diseases spectrum
Due to the inherent characteristics of PDD and DLB,
several clinical-pathological correlation studies include
the two conditions as different spectra of the same patho-
logical process. In the present consensus, we consider the
two diseases from this viewpoint, i.e., different involve-
ments of a common pathological substrate. In PDD, the
accumulation of Lewy bodies is mainly concentrated in
subcortical areas, while in DLB the pathological process
affects cortical areas (Figure 2) 101-103.
Lewy body diseases
DLB PD PDD
Cortical Nigral
Figure 2. Topographic distribution pattern of Lewy bodies in dementia
with Lewy bodies (DLB), Parkinson’s disease (PD) and dementia
associated with Parkinson’s disease (PDD).
Management of DLB
There is no specific disease-modifying treatment for DLB.
Non-pharmacological and pharmacological interventions
can be used in symptomatic management. There are no
specific non-pharmacological interventions in DLB100,104.
Caramelli P, et al.   Dementia care.   91
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):83-95
Motor symptoms
Levodopa is the drug of choice to treat motor symp-
toms. Slow titration is important to achieve some mo-
tor response with minimal psychiatric AEs. Response
to levodopa in DLB can be limited, especially in the
later stages, due to the predominance of levodopa
non-responsive symptoms. Dopamine agonists are not
recommended due to the risk of worsening hallucina-
tions. Anticholinergics are contraindicated97-99,105,106.
Neuropsychiatric symptoms
The use of antipsychotics must be done very judiciously,
due to the high sensitivity of these patients, with im-
portant paradoxical reactions107. Typical antipsychotics
are contraindicated. Atypical antipsychotics, specifically
quetiapine and clozapine, can be used, always under
close supervision, to detect AEs97,99,108. Of special note,
clozapine may cause neutropenia in about 3% of cases,
which demands weekly monitoring of blood cell count
within the first 18 weeks of treatment.
As for ChEI (mainly rivastigmine), besides the cog-
nitive benefits several studies have shown positive ef-
fects on neuropsychiatric symptoms, particularly visual
hallucinations, delusions, and apathy. It is essential to
be aware that the withdrawal of ChEI, for any reason,
may be associated with cognitive deterioration99,109-111.
CONCLUSIONS
Although current treatments for neurodegenerative
and vascular dementias are only symptomatic, several
evidenced-based therapies are available and may provide
benefits to Pwd and to their caregivers. The clinician
must combine the best pharmacological options with
the best available non-pharmacological interventions,
taking into consideration the underlying etiology,
REFERENCES
1. Mukadam N, Sommerlad A, Huntley J, Livingston G. Population attributab-
le fractions for risk factors for dementia in low-income and middle-income
countries: an analysis using cross-sectional survey data. Lancet Glob
Health. 2019;7(5):e596-603. doi:10.1016/S2214-109X(19)30074-9.
2. Nakamura AE, Opaleye D, Tani G, Ferri CP. Dementia underdiag-
nosis in Brazil. Lancet. 2015;385(9966):418-9. doi:10.1016/S0140-
6736(15)60153-2.
3. Nitrini R, Bottino CM, Albala C, Custodio Capuñay NS, Ketzoian C, Llibre
Rodriguez JJ, et al. Prevalence of dementia in Latin America: a collaborative
study of population-based cohorts. Int Psychogeriatr. 2009;21(4):622-30.
doi:10.1017/S1041610209009430.
4. Institute of Health Metrics [homepage on the Internet]. Brazil. 2018 [cited
2022 Aug 22]. Available from: http://www.healthdata.org/brazil
5. Engelhardt E, Brucki SMD, Cavalcanti JLS, Forlenza OV, Laks J, Vale FAC.
Treatment of Alzheimer’s Disease: recommendations and suggestions
of the Scientific Department of Cognitive Neurology and Aging of the
Brazilian Academy of Neurology. Arq Neuropsiquiatr. 2005;63(4):1104-12.
doi:10.1590/S0004-282X2005000600035.
92   Dementia care.   Caramelli P, et al.
symptoms profile and severity of the dementia syn-
drome, as well as the clinical and personal history of
each individual.
It is important to inform the PwD and their families
about the potential expected benefits of the overall
treatment, as well as the possible AEs of the prescribed
drugs. Regular follow-up is critical (ideally every three
to four months in the beginning of treatment and
around every six months later on) to evaluate the clini-
cal effects and whether adjustments (e.g., drug dosing,
additional pharmacological and non-pharmacological
interventions) are needed.
Given that the modest effects of the available treat-
ments and the lack of approved disease-specific drug
therapies, prevention of dementia is a key principle.
Several modifiable risk factors have been identified
and lifestyle and clinical interventions (e.g., adequate
control of hypertension and diabetes, regular phys-
ical activity, diet programs, cognitive stimulation
activities) shall be recommended for middle-age and
older adults to reduce the risk of cognitive impair-
ment and dementia, thus contributing to mitigate the
personal, socioeconomic and public health impacts of
these devastating disorders.45
ACKNOWLEDGEMENTS
PC, JL, LCS and RN are funded by CNPq, Brazil (bolsa
de produtividade em pesquisa).
Authors’ contributions. PC, VM, JL, MVDC, FS, EFC, JS,
BJAPB, LPS, HBD, PHFB: concept; PC, VM, JL, MVDC,
FS, EFC, HBD, PHFB: drafting of the manuscript;
BJAPB, FACV, JS, LCS, LPS, MLFB, MLFC, NAFF, PC,
PHFB, RN, SMDB: critical revision of the manuscript
for important intellectual content.
6. Bartus RT. On neurodegenerative diseases, models, and treatment stra-
tegies: lessons learned and lessons forgotten a generation following the
cholinergic hypothesis. Exp Neurol. 2000;163(2):495-529. doi:10.1006/
exnr.2000.7397.
7. Small G, Bullock R. Defining optimal treatment with cholinesterase
inhibitors in Alzheimer’s disease. Alzheimers Dement. 2011;7(2):177-84.
doi:10.1016/j.jalz.2010.03.016.
8. Xu H, Garcia-Ptacek S, Jönsson L, Wilmo A, Nordström P, Eriks-
dotter M. Long-term effects of cholinesterase inhibitors on cognitive
decline and mortality. Neurology. 2021;96(e):2220-30. doi:10.1212/
WNL.0000000000011832.
9. Ministério da Saúde (BR). Secretaria de Atenção à Saúde. Portaria Con-
junta nº 13, de 28 de novembro de 2017. Aprova o Protocolo Clínico e
Diretrizes Terapêuticas da Doença de Alzheimer. Diário Oficial da União.
2017 Dec 8;1:201.
10. Pais M, Martinez L, Ribeiro O, Loureiro J, Fernandez R, Valiengo L, et al.
Early diagnosis and treatment of Alzheimer’s disease: New definitions and
challenges. Braz J Psychiatry. 2020;42(4):431-41. doi:10.1590/1516-
4446-2019-0735.

11. Vale FAC, Corrêa Neto Y, Bertolucci PHF, Machado JCB, Silva DJ, Allam N,
et al. Treatment of Alzheimer’s disease in Brazil: II. Behavioral and psycho-
logical symptoms of dementia. Dement Neuropsychol. 2011;5(3):189-97.
doi:10.1590/S1980-57642011DN05030006.
12. He Y, Li H, Huang J, Huang S, Bai Y, Li Y, et al. Efficacy of antidepres-
sant drugs in the treatment of depression in Alzheimer disease patients:
A systematic review and network meta-analysis. J Psychopharmacol.
2021;35(8):901-9. doi:10.1177/02698811211030181.
13. Banerjee S, High J, Stirling S, Shepstone L, Swart AM, Telling T,
et al. Study of mirtazapine for agitated behaviours in dementia
(SYMBAD): a randomised, double-blind, placebo-controlled trial. Lancet.
2021;398(10310):1487-97. doi:10.1016/S0140-6736(21)01210-1.
14. Davies SJ, Burhan AM, Kim D, Gerretsen P, Graff-Guerrero A, Woo VL,
et al. Sequential drug treatment algorithm for agitation and aggression in
Alzheimer’s and mixed dementia. J Psychopharmacol. 2018;32(5):509-23.
doi:10.1177/0269881117744996.
15. Camargos EF, Louzada LL, Quintas JL, Naves JO, Louzada FM, Nóbrega
OT. Trazodone improves sleep parameters in Alzheimer disease patients:
a randomized, double-blind, and placebo-controlled study. Am J Geriatr
Psychiatry. 2014;22(12):1565-74. doi:10.1016/j.jagp.2013.12.174.
16. Louzada LL, Machado FV, Quintas JL, Ribeiro GA, Silva MV, Mendonça-
-Silva DL, et al. The efficacy and safety of zolpidem and zopiclone to
treat insomnia in Alzheimer’s disease: a randomized, triple-blind, pla-
cebo-controlled trial. Neuropsychopharmacology. 2022;47(2):570-9.
doi:10.1038/s41386-021-01191-3.
17. Caraci F, Santagati M, Caruso G, Cannavò D, Leggio GM, Salomone S,
et al. New antipsychotic drugs for the treatment of agitation and psychosis
in Alzheimer’s disease: focus on brexpiprazole and pimavanserin. F1000Res.
2020;9:F1000 Faculty Rev-686. doi:10.12688/f1000research.22662.1.
18. Brucki SMD, Adoni T, Almeida CMO, Andrade DC, Anghinah R, Barbosa
LM, et al. Cannabinoids in Neurology – Position paper from Scientific
Departments from Brazilian Academy of Neurology. Arq Neuropsiquiatr.
2021;79(4):354-69. doi:10.1590/0004-282X-ANP-2020-0432.
19. Frederiksen KS, Cooper C, Frisoni GB, Frölich L, Georges J, Kramber-
ger MG, et al. A European Academy of Neurology guideline on medical
management issues in dementia. Eur J Neurol. 2020;27(10):1805-20.
doi:10.1111/ene.14412.
20. York Health Economics Consortium. NICE: Overview of Systematic Re-
views of Non-pharmacological Interventions for Dementia [Internet]. Final
Report. Heslington: University of York; 2017 [cited 2022 Aug 22]. Available
from: https://www.nice.org.uk/guidance/ng97/evidence/appendix-o-yhe-
c-report-pdf-174697045530
21. Aguirre E, Spector A, Orrell M. Guidelines for adapting cognitive stimulation
therapy to other cultures. Clin Interv Aging. 2014;9:1003-7. doi:10.2147/
CIA.S61849.
22. Meyer C, O’Keefe F. Non-pharmacological interventions for people with
dementia: A review of reviews. Dementia (London). 2020;19(6):1927-54.
doi:10.1177/1471301218813234.
23. Stoner CR, Lakshminarayanan M, Durgante H, Spector A. Psychosocial
interventions for dementia in low- and middle-income countries (LMICs):
a systematic review of effectiveness and implementation readiness. Aging
Ment Health. 2021;25(3):408-19. doi:10.1080/13607863.2019.1695742.
24. Bertrand E, Naylor R, Laks J, Marinho V, Spector A, Mograbi DC. Cog-
nitive stimulation therapy for Brazilian people with dementia: examination
of implementation’ issues and cultural adaptation. Aging Ment Health.
2019;23(10):1400-4. doi:10.1080/13607863.2018.1488944.
25. Marinho V, Bertrand E, Naylor R, Bomilcar I, Laks J, Spector A, et al.
Cognitive stimulation therapy for people with dementia in Brazil (CST-Bra-
sil): Results from a single blind randomized controlled trial. Int J Geriatr
Psychiatry. 2021;36(2):286-93. doi:10.1002/gps.5421.
26. Madureira BG, Pereira MG, Avelino PR, Costa HS, Menezes KKP. Efeitos
de programas de reabilitação multidisciplinar no tratamento de pacientes
com doença de Alzheimer: uma revisão sistemática. Cad Saude Coletiva.
2018;26(2):222-32. doi:10.1590/1414-462x201800020446.
27. Cammisuli DM, Danti S, Bosinelli F, Cipriani G. Non-pharmacological inter-
ventions for people with Alzheimer’s disease: A critical review of the scien-
tific literature from the last ten years. Eur Geriatr Med. 2016,7(1):57-64.
doi:10.1016/j.eurger.2016.01.002.
28. Carrion C, Folkvord F, Anastasiadou D, Aymerich M. Cognitive therapy
for dementia patients: a systematic review. Dement Geriatr Cogn Disord.
2018;46(1-2):1-26. doi:10.1159/000490851.
29. Chiu H-Y, Chen P-Y, Chen Y-T, Huang H-C. Reality orientation therapy
benefits cognition in older people with dementia: A meta-analysis. Int J
Nurs Stud. 2018;86:20-8. doi:10.1016/j.ijnurstu.2018.06.008.
30. Alves GS, Casali ME, Veras AB, Carrilho CG, Bruno Costa E, Rodri-
gues VM, et al. A systematic review of home-setting psychoeducation
interventions for behavioral changes in dementia: some lessons for the
Dement Neuropsychol 2022 September;16(3 Suppl. 1):83-95
COVID-19 Pandemic and post-pandemic assistance. Front Psychiatry.
2020;11:577871. doi:10.3389/fpsyt.2020.577871.
31. Duan Y, Lu L, Chen J, Wu C, Liang J, Zheng Y, et al. Psychosocial
interventions for Alzheimer’s disease cognitive symptoms: a Bayesian
network meta-analysis. BMC Geriatr. 2018;18(1):175. doi:10.1186/
s12877-018-0864-6.
32. Piersol CV, Canton K, Connor SE, Giller I, Lipman S, Sager S. Effectiveness
of interventions for caregivers of people with Alzheimer’s Disease and
related major neurocognitive disorders: a systematic review. Am J Occup
Ther. 2017;71(5):7105180020p1-p10. doi:10.5014/ajot.2017.027581.
33. Shim M, Tilley JL, Im S, Price K, Gonzalez A. A systematic review of mind-
fulness-based interventions for patients with mild cognitive impairment or
dementia and caregivers. J Geriatr Psychiatry Neurol. 2021;34(6):528-54.
doi:10.1177/0891988720957104.
34. Gaugler JE, Bain LJ, Mitchell L, Finlay J, Fazio S, Jutkowitz E & Alzhei-
mer’s Association Psychosocial Measurement Workgroup. Reconsidering
frameworks of Alzheimer’s dementia when assessing psychosocial out-
comes. Alzheimers Dement. 2019;5:388-97. https://doi.org/10.1016/
j.trci.2019.02.008.
35. Dröes RM, Chattat R, Diaz A, Gove D, Graff M, Murphy K. Social health
and dementia: a European consensus on the operationalization of the
concept and directions for research and practice. Aging Ment Health.
2017;21(1):4-17. doi:10.1080/13607863.2016.1254596.
36. Oksnebjerg L, Diaz-Ponce A, Gove D, Moniz-Cook E, Mountain G, Chattat
R, et al. Towards capturing meaningful outcomes for people with dementia
in psychosocial intervention research: a pan-European consultation. Health
Expect. 2018;21(6):1056-65. doi:10.1111/hex.12799.
37. Arroyo-Anlló EM, Díaz-Marta JP, Chamorro Sánchez J. Técnicas de
rehabilitación neuropsicológica en demencias: hacia la ciber-rehabilitación
neuropsicológica. Pensam Psicol. 2012;10(1):107-27.
38. Moreira SV, Reis Justi FR, Moreira M. Can musical intervention im-
prove memory in Alzheimer’s patients? Evidence from a systematic
review. Dement Neuropsychol. 2018;12(2):133-42. doi:10.1590/
1980-57642018dn12-020005.
39. Jia RX, Liang JH, Xu Y, Wang YQ. Effects of physical activity and exercise
on the cognitive function of patients with Alzheimer disease: a meta-a-
nalysis. BMC Geriatr. 2019;19(1):181. doi:10.1186/s12877-019-1175-2.
40. Wang LY, Pei J, Zhan YJ, Cai YW. Overview of meta-analyses of five
non-pharmacological interventions for Alzheimer’s Disease. Front Aging
Neurosci. 2020;12:594432. doi:10.3389/fnagi.2020.594432.
41. Meng Q, Lin MS, Tzeng IS. Relationship between exercise and Alzhei-
mer’s disease: a narrative literature review. Front Neurosci. 2020;14:131.
doi:10.3389/fnins.2020.00131.
42. Smallfield S, Heckenlaible C. Effectiveness of occupational therapy
interventions to enhance occupational performance for adults with Alzhei-
mer’s Disease and related major neurocognitive disorders: a systematic
review. Am J Occup Ther. 2017;71(5):7105180010p1-p9. doi:10.5014/
ajot.2017.024752.
43. Marques CLS, Borgato MH, Moura Neto E, Bazan R, Luvizutto GJ. Phy-
sical therapy in patients with Alzheimer’s disease: a systematic review of
randomized controlled clinical trials. Fisioter Pesqui. 2019;26(3):311-21.
doi:10.1590/1809-2950/18037226032019.
44. Zhu XC, Yu Y, Wang HF, Jiang T, Cao L, Wang C, et al. Physiotherapy
intervention in Alzheimer’s disease: systematic review and meta-analysis.
J Alzheimers Dis. 2015;44(1):163-74. doi:10.3233/JAD-141377.
45. Kivipelto M, Mangialasche F, Snyder HM, Allegri R, Andrieu S, Arai H,
et al. World-Wide FINGERS Network: A global approach to risk reduction
and prevention of dementia. Alzheimers Dement. 2020;16(7):1078-94.
doi:10.1002/alz.12123.
46. Moreira SC, Jansen AK, Silva FM. Dietary interventions and cognition
of Alzheimer’s disease patients: a systematic review of randomized
controlled trial. Dement Neuropsychol. 2020;14(3):258-82. doi:10.1590/
1980-57642020dn14-030008.
47. Pendlebury ST, Rothwell PM. Prevalence, incidence, and factors asso-
ciated with pre-stroke and post-stroke dementia: a systematic review
and meta-analysis. Lancet Neurol. 2009;8(11):1006-18. doi:10.1016/
S1474-4422(09)70236-4.
48. Boehme AK, Esenwa C, Elkind MSV. Stroke risk factors, geneti-
cs, and prevention. Circ Res. 2017;120(3):472-95. doi:10.1161/
CIRCRESAHA.116.308398.
49. ADVANCE Collaborative Group; Patel A, MacMahon S, Chalmers J, Neal
B, Billot L, et al. Intensive blood glucose control and vascular outcomes
in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560-72.
doi:10.1056/NEJMoa0802987.
50. Launer LJ, Miller ME, Williamson JD, Lazar RM, Gerstein HC, et al.
Effects of intensive glucose lowering on brain structure and function in
people with type 2 diabetes (ACCORD MIND): a randomised open-label
Caramelli P, et al.   Dementia care.   93
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):83-95
substudy. Lancet Neurol. 2011;10(11):969-77. doi:10.1016/S1474-
4422(11)70188-0.
51. Costa e Forti A, Pires AC, Pittito BA, Gerchman F, Oliveira JEP, Zajden-
verg L, et al. Diretrizes da Sociedade Brasileira de Diabetes: 2019-2020.
São Paulo: Clannad; 2019.
52. Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI, Ezekowitz
MD, et al. Guidelines for the prevention of stroke in patients with stroke
and transient ischemic attack. Stroke. 2014;45(7):2160-236. doi:10.1161/
STR.0000000000000024.
53. Smith EE, Saposnik G, Biessels GJ, Doubal FN, Fornage M, Gorelick PB,
et al. Prevention of stroke in patients with silent cerebrovascular disease: a
scientific statement for healthcare professionals from the American Heart
Association/American Stroke Association. Stroke. 2017;48(2):e44-71.
doi:10.1161/STR.0000000000000116.
54. Davis KAS, Bishara D, Molokhia M, Mueller C, Perera G, Stewart RJ.
Aspirin in people with dementia, long-term benefits, and harms: a sys-
tematic review. Eur J Clin Pharmacol. 2021;77(7):943-54. doi:10.1007/
s00228-021-03089-x.
55. McGuinness B, Craig D, Bullock R, Malouf R, Passmore P. Sta-
tins for the prevention of dementia. Cochrane Database Syst Rev.
2014;(7):CD007514. doi:10.1002/14651858.CD007514.pub3.
56. Sofi F, Valecchi D, Bacci D, Abbate R, Gensini GF, Casini A, et al. Physical
activity and risk of cognitive decline: a meta-analysis of prospective studies.
J Int Med. 2011;269(1):107-17. doi:10.1111/j.1365-2796.2010.02281.x.
57. Verdelho A, Madureira S, Ferro JM, Baezner H, Blahak C, Poggesi A, et al.
Physical activity prevents progression for cognitive impairment and vascu-
lar dementia: results from the LADIS (Leukoaraiosis and Disability) study.
Stroke. 2012;43(12):3331-5. doi:10.1161/STROKEAHA.112.661793.
58. Gillespie DC, Bowen A, Chung CS, Cockburn J, Knapp P, Pollock A.
Rehabilitation for post-stroke cognitive impairment: an overview of re-
commendations arising from systematic reviews of current evidence. Clin
Rehabil. 2015;29(2):120-8. doi:10.1177/0269215514538982.
59. Coelho-Júnior HJ, Trichopoulou A, Panza F. Cross-sectional and longitu-
dinal associations between adherence to Mediterranean diet with physical
performance and cognitive function in older adults: A systematic review
and meta-analysis. Ageing Res Rev. 2021;70:101395. doi:10.1016/
j.arr.2021.101395.
60. Brucki SMD, Ferraz AC, Freitas GR, Massaro AR, Radanovic M, Schultz
RR. Treatment of vascular dementia. Recommendations of the Scientific
Department of Cognitive Neurology and Aging of the Brazilian Academy
of Neurology. Dement Neuropsychol. 2011;5(4):275-87. doi:10.1590/
S1980-57642011DN05040005.
61. Smith EE, Barber P, Field TS, Ganesh A, Hachinski V, Hogan DB, et al.
Canadian Consensus Conference on Diagnosis and Treatment of Dementia
(CCCDTD) 5: Guidelines for management of vascular cognitive impairment.
Alzheimers Dement (N Y). 2020;6(1):e12056. doi:10.1002/trc2.12056.
62. Dichgans M, Markus HS, Salloway S, Verkkoniemi A, Moline M, Wang
Q, et al. Donepezil in patients with subcortical vascular cognitive im-
pairment: a randomised double-blind trial in CADASIL. Lancet Neurol.
2008;7(4):310-8. doi:10.1016/S1474-4422(08)70046-2.
63. Black S, Román GC, Geldmacher DS, Salloway S, Hecker J, Burns A,
et al. Efficacy and tolerability of donepezil in vascular dementia: positive
results of a 24-week, multicenter, international, randomized, placebo-
-controlled clinical trial. Stroke. 2003;34(10):2323-30. doi:10.1161/
01.STR.0000091396.95360.E1.
64. Orgogozo JM, Rigaud AS, Stöffler A, Möbius HJ, Forette F. Efficacy
and safety of memantine in patients with mild to moderate vascular
dementia: a randomized, placebo-controlled trial (MMM 300). Stroke.
2002;33(7):1834-9. doi:10.1161/01.str.0000020094.08790.49.
65. Erkinjuntti T, Kurz A, Gauthier S, Bullock R, Lilienfeld S, Damaraju CV.
Efficacy of galantamine in probable vascular dementia and Alzheimer’s
disease combined with cerebrovascular disease: a randomised trial.
Lancet. 2002;359(9314):1283-90. doi:10.1016/S0140-6736(02)08267-3.
66. Caramelli P, Laks J, Palmini AL, Nitrini R, Chaves ML, Forlenza OV, et al.
Effects of galantamine and galantamine combined with nimodipine on cog-
nitive speed and quality of life in mixed dementia: a 24-week, randomized,
placebo-controlled exploratory trial (the REMIX study). Arq Neuropsiquiatr.
2014;72(6):411-7. doi:10.1590/0004-282x20140055.
67. Ballard C, Sauter M, Scheltens P, He Y, Barkhof F, Straaten EC, et al.
Efficacy, safety and tolerability of rivastigmine capsules in patients with
probable vascular dementia: the VantagE study. Curr Med Res Opin.
2008;24(9):2561-74. doi:10.1185/03007990802328142.
68. Román GC, Salloway S, Black SE, Royall DR, Decarli C, Weiner MW, et al.
Randomized, placebo-controlled, clinical trial of donepezil in vascular de-
mentia: differential effects by hippocampal size. Stroke. 2010;41(6):1213-
21. doi:10.1161/STROKEAHA.109.570077.
69. Moretti R, Torre P, Antonello RM, Cazzato G, Pizzolato G. Different res-
ponses to rivastigmine in subcortical vascular dementia and multi-infarct
94   Dementia care.   Caramelli P, et al.
dementia. Am J Alzheimers Dis Other Demen. 2008;23(2):167-76.
doi:10.1177/1533317507312558.
70. Auchus A, Brashear HR, Salloway S, Korczyn A, De Deyn PP, Gass-
mann-Mayer C; GAL-INT-26 Study Group. Galantamine treatment of
vascular dementia: a randomized trial. Neurology. 2007;69(5):448-58.
doi:10.1212/01.wnl.0000266625.31615.f6.
71. Narasimhalu K, Effendy S, Sim C, Lee JM, Chen I, Hia SB, et al. A rando-
mized controlled trial of rivastigmine in patients with cognitive impairment
no dementia because of cerebrovascular disease. Acta Neurol Scand.
2010;121(4):217-24. doi:10.1111/j.1600-0404.2009.01263.x.
72. Wilcock G, Möbius HJ, Stöffler A; MMM 500 group. A double-blind, place-
bo-controlled multicentre study of memantine in mild to moderate vascular
dementia (MMM500). Int Clin Psychopharmacol. 2002;17(6):297-305.
doi:10.1097/00004850-200211000-00005.
73. Reus VI, Fochtmann LJ, Eyler AE, Hilty DM, Horvitz-Lennon M, Jibson MD,
et al. The American Psychiatric Association practice guideline on the use
of antipsychotics to treat agitation or psychosis in patients with dementia.
Am J Psychiatry. 2016;173(5):543-6. doi:10.1176/appi.ajp.2015.173501.
74. Kales HC, Lyketsos CG, Miller EM, Ballard C. Management of behavioral
and psychological symptoms in people with Alzheimer’s disease: an
international Delphi consensus. Int Psychogeriatr. 2019;31(1):83-90.
doi:10.1017/S1041610218000534.
75. Oliveira LF, Camargos EF, Martini LLL, Machado FV, Novaes MRCG. Use of
psychotropic agents to treat agitation and aggression in Brazilian patients
with Alzheimer’s disease: A naturalistic and multicenter study. Psychiatry
Res. 2021;295:113591. doi:10.1016/j.psychres.2020.113591.
76. Onyike CU, Diehl-Schmid J. The epidemiology of frontotemporal de-
mentia. Int Rev of Psychiatry. 2013;25(2):130-7. doi:10.3109/0954026
1.2013.776523.
77. Rascovsky K, Hodges JR, Knopman D, Mendez MF, Kramer JH, Neuhaus
J, et al. Sensitivity of revised diagnostic criteria for the behavioural variant
of frontotemporal dementia. Brain. 2011;134(Pt 9):2456-77. doi:10.1093/
brain/awr179.
78. Trieu C, Gossink F, Stek ML, Scheltens P, Pijnenburg YAL, Dols A.
Effectiveness of pharmacological interventions for symptoms of behavioral
variant frontotemporal dementia: a systematic review. Cogn Behav Neurol.
2020;33(1):1-15. doi:10.1097/WNN.0000000000000217.
79. Lima-Silva TB, Bahia VS, Carvalho VA, Guimarães HC, Caramelli P, Balthazar
ML, et al. Neuropsychiatric symptoms, caregiver burden and distress in
behavioral-variant frontotemporal dementia and Alzheimer’s disease. Dement
Geriatr Cogn Disord. 2015;40(5-6):268-75. doi:10.1159/000437351.
80. Wylie MA, Shnall A, Onyike CU, Huey ED. Management of frontotemporal
dementia in mental health and multidisciplinary settings. Int Rev Psychiatry.
2013;25(2):230-6. doi:10.3109/09540261.2013.776949.
81. Marin SMC, Mansur LL, Oliveira FF, Marin LF, Wajman JR, Bahia VS, et al.
Swallowing in behavioral variant frontotemporal dementia. Arq Neuropsi-
quiatr. 2021;79(1):8-14. doi:10.1590/0004-282X20200060.
82. Portugal MG, Marinho V, Laks J. Pharmacological treatment of fron-
totemporal lobar degeneration: systematic review. Braz J Psychiatry.
2011:33(1):81-90. doi:10.1590/s1516-44462011000100016.
83. Gambogi LB, Guimarães HC, Souza LC, Caramelli P. Treatment
of the behavioral variant of frontotemporal dementia: a narrative
review. Dement Neuropsychol. 2021;15(3):331-8. doi:10.1590/
1980-57642021dn15-030004.
84. Gorno-Tempini ML, Hillis AE, Weintraub S, Kertesz A, Mendez M, Cappa
SF, et al. Classification of primary progressive aphasia and its variants.
Neurology. 2011;76(11):1006-14. doi:10.1212/WNL.0b013e31821103e6.
85. Cotelli M, Manenti R, Ferrari C, Gobbi E, Macis A, Cappa SF. Effectiveness
of language training and non-invasive brain stimulation on oral and written
naming performance in Primary Progressive Aphasia: A meta-analysis
and systematic review. Neurosci Biobehav Rev. 2020;108:498-525.
doi:10.1016/j.neubiorev.2019.12.003.
86. Nissim NR, Moberg PJ, Hamilton RH. Efficacy of noninvasive brain sti-
mulation (tDCS or TMS) paired with language therapy in the treatment
of primary progressive aphasia: an exploratory meta-analysis. Brain Sci.
2020;10(9):597. doi:10.3390/brainsci10090597.
87. Beber BC, Brandão L, Chaves MLF. A warning to the Brazilian Speech-
-Language Pathology and Audiology community about the importance
of scientific and clinical activities in primary progressive aphasia. CoDAS.
2015;27(5):505-8. doi:10.1590/2317-1782/20152015081.
88. Carthery-Goulart MT, Silveira AC, Machado TH, Mansur LL, Parente
MAMP, Senaha MLH, et al. Nonpharmacological interventions for cognitive
impairments following primary progressive aphasia: A systematic review
of the literature. Dement Neuropsychol. 2013;7(1):122-31. doi:10.1590/
S1980-57642013DN70100018.
89. Volkmer A, Spector A, Meitanis V, Warren JD, Beeke S. Effects of func-
tional communication interventions for people with primary progressive
aphasia and their caregivers: A systematic review. Aging Ment Health.
2020;24(9):1381-93. doi:10.1080/13607863.2019.1617246.

90. Cadório I, Lousada M, Martins P, Figueiredo D. Generalization and
maintenance of treatment gains in primary progressive aphasia (PPA):
A systematic review. Int J Lang Commun Disord. 2017;52(5):543-60.
doi:10.1111/1460-6984.12310.
91. Machado TH, Carthery-Goulart MT, Campanha AC, Caramelli P. Cognitive
intervention strategies directed to speech and language deficits in primary
progressive aphasia: practice-based evidence from 18 cases. Brain Sci.
2021;11(10):1268. doi:10.3390/brainsci11101268.
92. Aarsland D. Cognitive impairment in Parkinson’s disease and dementia
with Lewy bodies. Parkinsonism Relat Disord. 2016;22(Suppl 1):S144-8.
doi:10.1016/j.parkreldis.2015.09.034.
93. Burn DJ. Cortical Lewy body disease and Parkinson’s disease
dementia. Curr Opin Neurol. 2006;19(6):572-9. doi:10.1097/01.
wco.0000247607.34697.a2.
94. Outeiro TF, Koss DJ, Erskine D, Walker L, Kurzawa-Akanbi M, Burn D,
et al. Dementia with Lewy bodies: an update and outlook. Mol Neurode-
gener. 2019;14(1):5. doi:10.1186/s13024-019-0306-8.
95. Jellinger KA. Dementia with Lewy bodies and Parkinson’s disease-de-
mentia: current concepts and controversies. J Neural Transm (Vienna).
2018;125(4):615-50. doi:10.1007/s00702-017-1821-9.
96. Emre M, Aarsland D, Brown R, Burn DJ, Duyckaerts C, Mizuno Y, et al.
Clinical diagnostic criteria for dementia associated with Parkinson’s
disease. Mov Disord. 2007;22(12):1689-707. doi:10.1002/mds.21507.
97. McKeith IG, Boeve BF, Dickson DW, Halliday G, Taylor JP, Weintraub D,
et al. Diagnosis and management of dementia with Lewy bodies: Fourth
consensus report of the DLB Consortium. Neurology. 2017;89(1):88-100.
doi:10.1212/WNL.0000000000004058.
98. Broadstock M, Ballard C, Corbett A. Latest treatment options for Alzhei-
mer’s disease, Parkinson’s disease dementia and dementia with Lewy
bodies. Expert Opin Pharmacother. 2014;15(13):1797-810. doi:10.1517
/14656566.2014.936848.
99. Stinton C, McKeith I, Taylor JP, Lafortune L, Mioshi E, Mak E, et al. Phar-
macological management of Lewy body dementia: a systematic review
and meta-analysis. Am J Psychiatry. 2015;172(8):731-42. doi:10.1176/
appi.ajp.2015.14121582.
100. Connors MH, Quinto L, McKeith I, Brodaty H, Allan L, Bamford C,
et al. Non-pharmacological interventions for Lewy body dementia:
Dement Neuropsychol 2022 September;16(3 Suppl. 1):83-95
a systematic review. Psychol Med. 2018;48(11):1749-58. doi:10.1017/
S0033291717003257.
101. Dugger BN, Boeve BF, Murray ME, Parisi JE, Fujishiro H, Dickson DW,
et al. Rapid eye movement sleep behavior disorder and subtypes in autop-
sy-confirmed dementia with Lewy bodies. Mov Disord. 2012;27(1):72-8.
doi:10.1002/mds.24003.
102. Ohma E, Ikuta F. Parkinson’s disease: distribution of Lewy bodies and
monoamine neuron system. Acta Neuropathol. 1976;34(4):311-9.
doi:10.1007/BF00696560.
103. Hughes AJ, Daniel SE, Blankson S, Lees AJ. A clinicopathological study
of 100 cases of Parkinson’s disease. J Neurol Neurosurg Psychiatry.
1992;55(3):181-4. doi:10.1136/jnnp.55.3.181.
104. Rongve A, Aarsland D. Management of Parkinson’s disease de-
mentia: practical considerations. Drugs Aging. 2006;23(10):807-22.
doi:10.2165/00002512-200623100-00004.
105. Caviness JN, Lue L, Adler CH, Walker DG. Parkinson’s disease dementia
and potential therapeutic strategies. CNS Neurosci Ther. 2011;17(1):32-44.
doi:10.1111/j.1755-5949.2010.00216.x.
106. Gauthier S. Pharmacotherapy of Parkinson disease dementia and
Lewy body dementia. Front Neurol Neurosci. 2009;24:135-9.
doi:10.1159/000197892.
107. Garcia-Ptacek S, Kramberger MG. Parkinson disease
and dementia. J Geriatr Psychiatry Neurol. 2016;29(5):261-70.
doi:10.1177/0891988716654985.
108. Sezgin M, Bilgic B, Tinaz S, Emre M. Parkinson’s disease demen-
tia and Lewy body disease. Semin Neurol. 2019;39(2):274-82.
doi:10.1055/s-0039-1678579.
109. Taylor JP, McKeith IG, Burn DJ, Boeve BF, Weintraub D, Bamford C, et al.
New evidence on the management of Lewy body dementia. Lancet Neurol.
2020;19(2):157-69. doi:10.1016/S1474-4422(19)30153-X.
110. Velayudhan L, Ffytche D, Ballard C, Aarsland D. New therapeutic strate-
gies for Lewy body dementias. Curr Neurol Neurosci Rep. 2017;17(9):68.
doi:10.1007/s11910-017-0778-2.
111. Rolinski M, Fox C, Maidment I, McShane R. Cholinesterase inhibitors
for dementia with Lewy bodies, Parkinson’s disease dementia and cog-
nitive impairment in Parkinson’s disease. Cochrane Database Syst Rev.
2012;(3):CD006504. doi:10.1002/14651858.CD006504.pub2.
Caramelli P, et al.   Dementia care.   95
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):96-115 Consensus
https://doi.org/10.1590/1980-5764-DN-2022-S107EN

Management in severe dementia:

recommendations of the Scientific Department
of Cognitive Neurology and Aging of the
Brazilian Academy of Neurology
Sonia Maria Dozzi Brucki1 , Ivan Aprahamian2,3,4 , Wyllians Vendramini Borelli5 ,
Victor Calil da Silveira6,7 , Ceres Eloah de Lucena Ferretti1 , Jerusa Smid1 ,
Breno José Alencar Pires Barbosa1,8,9 , Lucas Porcello Schilling10,11,12 ,
Márcio Luiz Figueiredo Balthazar13 , Norberto Anízio Ferreira Frota14,15 ,
Leonardo Cruz de Souza16 , Francisco Assis Carvalho Vale17 , Paulo Caramelli16 ,
Paulo Henrique Ferreira Bertolucci18 , Márcia Lorena Fagundes Chaves19,20 ,
Ricardo Nitrini1 , Rodrigo Rizek Schultz21,22 , Lilian Schafirovits Morillo23

1
Universidade de São Paulo, Faculdade de Medicina, Departamento de Neurologia, Grupo de Neurologia Cognitiva e do Comportamento, São Paulo SP, Brazil.
2
Faculdade de Medicina de Jundiaí, Departamento de Medicina Interna, Divisão de Geriatria, Grupo de Investigação sobre Multimorbidade e Saúde Mental no
Envelhecimento, Jundiaí SP, Brazil.
3
University of Groningen, University Medical Center Groningen, Department of Psychiatry, Groningen, The Netherlands.
4
Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, Serviço de Geriatria, Laboratorio de Investigação Médica em Envelhecimento, São Paulo SP, Brazil.
5
Hospital de Clínicas de Porto Alegre, Departamento de Neurologia, Porto Alegre RS, Brazil.
6
Instituto D’Or de Pesquisa e Ensino, Rio de Janeiro RJ, Brazil.
7
Hospital Glória D’Or, Rio de Janeiro RJ, Brazil.
8
Universidade Federal de Pernambuco, Centro de Ciências Médicas, Área Acadêmica de Neuropsiquiatria, Recife PE, Brazil.
9
Instituto de Medicina Integral Prof. Fernando Figueira, Recife PE, Brazil.
10
Pontifícia Universidade do Rio Grande do Sul, Escola de Medicina, Serviço de Neurologia, Porto Alegre RS, Brazil.
11
Pontifícia Universidade do Rio Grande do Sul, Instituto do Cérebro do Rio Grande do Sul, Porto Alegre RS, Brazil.
12
Pontifícia Universidade do Rio Grande do Sul, Programa de Pós-Graduação em Gerontologia Biomédica, Porto Alegre RS, Brazil.
13
Universidade Estadual de Campinas, Faculdade de Ciências Médicas, Departamento de Neurologia, Campinas SP, Brazil.
14
Hospital Geral de Fortaleza, Serviço de Neurologia, Fortaleza CE, Brazil.
15
Universidade de Fortaleza, Fortaleza CE, Brazil.
16
Universidade Federal de Minas Gerais, Departamento de Clínica Médica, Belo Horizonte MG, Brazil.
17
Universidade Federal de São Carlos, Centro de Ciências Biológicas e da Saúde, Departamento de Medicina, São Carlos SP, Brazil.
18
Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Neurologia e Neurocirurgia, São Paulo SP, Brazil.
19
Hospital de Clínicas de Porto Alegre, Serviço de Neurologia, Porto Alegre RS, Brazil.
20
Universidade Federal do Rio Grande do Sul, Faculdade de Medicina, Departamento de Medicina Interna, Porto Alegre RS, Brazil.
21
Associação Brasileira de Alzheimer, São Paulo SP, Brazil.
22
Universidade Santo Amaro, Departamento de Neurologia, São Paulo SP, Brazil.
23
Universidade de São Paulo, Hospital das Clínicas, Serviço de Geriatria, São Paulo SP, Brazil.
Correspondence: Sonia Brucki; Email: sonia.brucki@gmail.com.
Conflict of interest: JS: Participation as speaker in symposia sponsored by the Roche laboratory; LPS: Participation in advisory boards for Biogen. Participation
as speaker in symposia sponsored by the Aché, Apsen, and Biogen laboratories; MLFB: Participation in advisory boards for Biogen. Development of material for
continuous medical education and participation as speaker in symposia sponsored by the EMS and Torrent laboratories; PC: Participation as principal investigator
in clinical trials for the Novo Nordisk and Roche laboratories. Participation in advisory boards for the Aché, Biogen, EMS, Nutricia, and Roche laboratories. Development
of material for continuous medical education and participation as speaker in symposia sponsored by the Aché, Nutricia, Libbs, Roche, Sandoz, Torrent, and Zodiac
laboratories; PHFB: Participation in advisory boards for the Biogen and Novo Nordisk laboratories. Supervision of training activities for the Biogen, Janssen-Cilag,
and Novo Nordisk laboratories and for Quintiles. Participation as speaker in symposia sponsored by the Apsen, Nutricia, Roche, and Sandoz laboratories; LCS:
Participation in advisory board for Biogen. Participation as speaker in symposia sponsored by Biogen; RN: Participation in advisory board for Biogen; SMDB, IP,
WVB, VC, CELF, BJAPB, NAFF, FACV, MLFC, RRS, LSM: There is no conflict of interest to declare.
Received on August 08, 2021; Received in its final form on October 04, 2021; Accepted on April 27, 2022.

96   Management in severe dementia.   Brucki SMD, et al.

 Dement Neuropsychol 2022 September;16(3 Suppl. 1):96-115

ABSTRACT. Alzheimer’s disease (AD) and other neurodegenerative dementias have a progressive course, impairing cognition, functional capacity, and behavior.
Most studies have focused on AD. Severe dementia is associated with increased age, higher morbidity-mortality, and rising costs of care. It is fundamental
to recognize that severe dementia is the longest period of progression, with patients living for many years in this stage. It is the most heterogeneous phase
in the process, with different abilities and life expectancies. This practice guideline focuses on severe dementia to improve management and care in this stage
of dementia. As it is a long period in the continuum of dementia, clinical practice should consider non-pharmacological and pharmacological approaches.
Multidisciplinary interventions (physical therapy, speech therapy, nutrition, nursing, and others) are essential, besides educational and support to caregivers.
Keywords: Dementia; Palliative Care; Behavior; Cognition.

MANEJO DAS DEMÊNCIAS EM FASE AVANÇADA: RECOMENDAÇÕES DO DEPARTAMENTO CIENTÍFICO DE NEUROLOGIA COGNITIVA E DO ENVELHECIMENTO
DA ACADEMIA BRASILEIRA DE NEUROLOGIA
RESUMO. A doença de Alzheimer (DA) e outras demências neurodegenerativas têm um curso progressivo com comprometimento da cognição, capacidade
funcional e comportamento. A maioria dos estudos enfocou a DA. A demência grave está associada ao aumento da idade, maior morbimortalidade e aumento
dos custos de cuidados. É fundamental reconhecer que a demência grave é o período mais longo de progressão, com o paciente vivendo muitos anos
nesta fase. É a fase mais heterogênea do processo, com diferentes habilidades e expectativa de vida. Esta diretriz de prática concentra-se na demência
grave para melhorar o manejo e o cuidado nessa fase da demência. Como um longo período no continuum da demência, as abordagens não farmacológicas
e farmacológicas devem ser consideradas. Intervenções multidisciplinares (fisioterapia, fonoaudiologia, nutrição, enfermagem, entre outras) são essenciais,
além de educacionais e de apoio aos cuidadores.
Palavras-chave: Demência; Cuidados Paliativos; Comportamento; Cognição.

INTRODUCTION This practice guideline focuses on severe dementia

A lzheimer’s disease (AD) and other neurodegenerative

dementias have a progressive course, impairing
cognition, functional capacity, and behavior. Most studies
have focused on AD. Severe dementia is associated
with increased age, higher morbidity-mortality,
and rising costs of care. Severe stages could account for
70 to 80% of total treatment expenses1,2. Degenerative
dementias slowly and progressively worsen. In its severe
stage, patients show a higher dependency for all basic
activities of daily living and incapacity for instrumental
activities of daily living.
Around 30 to 60% of patients with dementia (PWD)
and 90% of individuals residing in long-term care
facilities are in its moderate-late stage3-5.
The progression of dementia is associated with
a progressive dependency on caregivers, with loss
of capacity to provide self-care in basic activities of daily
living. Usually, severe AD patients will score below ten
on mini mental examination (MMSE) and moderately
severely with 10 to 155. Severe dementia could cause
complications such as immobility, swallowing disorders,
malnutrition, and fragility. This situation can increase
the risk of pneumonia, which has been found as
a common cause of death in PWD5-9.
It is fundamental to recognize that severe dementia
is the longest period of progression, with patients living
for many years in this stage. It is the most heterogeneous
phase in the process, with different abilities and life
expectancies7. Around 17% of PWD older than 75 years
are living with a very severe stage of dementia8.
to improve management and care in this stage
of the disease. As a long period in the continuum
of dementia, clinical practice should consider non-
pharmacological and pharmacological approaches.
Multidisciplinary interventions (physical therapy,
speech therapy, nutrition, nursing, and others)
are essential, besides educational and support
to caregivers. Primary, secondary, and tertiary care
center professionals could use this practice guideline .
STAGING SEVERE DEMENTIA
We find many different situations and stages of severe
dementia. A bedridden patient with dysphagia is different
from a walking and dependent but communicative and
without dysphagia patient.
The Clinical Dementia Rating (CDR) permits
rating the severity of AD and other dementias on
a five-point scale from 0 (normal) to 3 (severe stage)10.
The final score is obtained after interviews with PWD
and informants. It evaluates memory, orientation,
judgment, problem solving, community affairs, home,
hobbies, self-care. Chaves et al.11 validated this study
for Brazilian Portuguese.
The Alzheimer Disease Cooperative Study of activities
of daily living (ADCS-ADL sev) is a good measure of
activities of daily living (ADL) which strongly correlates
with cognition and severity of dementia in moderate
to severe AD. Its scores vary from 0 to 54 points,
divided into 19 items12.

Brucki SMD, et al.   Management in severe dementia.   97

 Dement Neuropsychol 2022 September;16(3 Suppl. 1):96-115

A simple scale that assesses gradual severity and
progression of the disability during follow-up is
the Global Deterioration Scale (GDS) 13. This scale
has seven global stages, from normality to severe
impairment; stage 6 represents severe dementia,
and stage 7, very severe13.
The Functional Assessment Staging (FAST)
assesses decline from normal (stage 1) to severe stages
(stage 7); the latter is subdivided into seven situations
(A to G) (Box 1)14.
In advanced dementia, we observe impairment
to basic daily activities. The Katz Scale is often
used to measure performance in bathing, dressing,
toileting, transferring, continence, and feeding;
characterizing severe dementia. Table 1 summarizes
all these instruments.

Box 1. Functional Assessment Staging (FAST).

1 No difficulty either subjectively or objectively.

2 Complains of forgetting location of objects. Subjective work difficulties.

3 Decreased job functioning evident to co-workers. Difficulty in traveling to new locations. Decreased organizational capacity.

Decreased ability to perform complex tasks, e.g., planning dinner for guests, handling personal finances (such as forgetting to pay bills),
4
difficulty shopping, etc.

5 Requires assistance in choosing proper clothing.

6a Improperly puts on clothes without assistance.

6b Unable to properly bathe (shower) (e.g., difficulty adjusting bathwater (shower) temperature.

6c Inability to handle toileting mechanics.

6d Urinary incontinence.

6e Fecal incontinence.

Ability to speak limited to approximately a half a dozen intelligible different words or fewer in the course of an average day or in the course
7a
of an intensive interview.

7b Speech ability limited to the use of a single intelligible word in an average day or in the course of an interview.

7c Loss of ambulatory ability (unable to walk without personal assistance).

7d Unable to sit up without assistance.

7e Loss of ability to smile.

7f Loss of ability to independently hold up their head.

Table 1. Instruments to evaluate severe dementia.

Test Measure Score Answered by Comments

SMMSE Global cognition 0-30 points Patient Good for measuring cognition

0 none
Global State
0.5 questionable
Domains: memory, orientation, judgment,
CDR 1 mild Caregiver and patient Good for follow-up
problem solving, community affairs,
2 moderate
home and hobbies, and personal care
3 severe

0-100 points
SIB Global cognition Patient Allows to evaluate very severe patients
(<63 severe impairment)

ADL Allows to evaluate severe to very

ADCS-ADL 0-54 points Caregiver
19 ADL of moderate to severe dementia severe patients

Stages 6-7: divided into incapacity

FAST Functionality 1-7 Health professional
progression

98   Management in severe dementia.   Brucki SMD, et al.


COGNITIVE EVALUATION
Cognitive evaluation in advanced dementia is relevant
to measure pharmacologic and non-pharmacologic
management and interventions. MMSE is the most
frequently used instrument in brief cognitive evaluation
in dementia. However, for moderate-late stages,
we could observe a floor-effect, with few modifications
over time below 10 points. At this point, we must
consider other tests. The GDS described above could
be an instrument for cognitive evaluation but severe-
MMSE (SMMSE) or Severe Impairment Battery (SIB)15,16
could offer more detailed and objective assessments.
The SIB, consisting of 40 questions, evaluates
nine areas of cognition: social interaction, memory,
orientation, language, attention, praxis, visuospatial
ability, construction, and orientation to name. Scores
vary from 0 to 100.15
SMMSE is a brief test requiring minimal training
and no special materials, but educational attainment
influences it. Its scores vary from 0 to 30 and its
items are divided into autobiographical knowledge,
executive function, language, verbal f luenc y,
and spelling16, 17 (Table 1).
If only one physician monitors cognitive status, they
may ask the same questions to observe the progression
of deterioration, such as age, date of birth, names of
children or spouse, food or soccer team preferences.
TREATMENT OF BEHAVIOR AND THE
PSYCHOLOGICAL SYMPTOMS OF DEMENTIA
Behavior and psychological symptoms of dementia
(BPSD) comprehends the neuropsychiatric
manifestations besides cognition, affecting between
60 and 90% of people with dementia18. BPSD includes
a wide spectrum of conditions: apathy, depression,
anxiety, sleep disorders, psychosis, agitation, aggression,
wandering and motor manifestations, disinhibition,
and many others. Generally, BPSD prevalence increases
with disease severity although epidemiologic studies in
this topic mostly include small sample sizes, especially
among those with AD18,19. Moreover, severe forms
of BPSD like delusions, hallucinations, agitation,
aggression, and aberrant motor conditions are more
common in moderate and severe dementia20. Multiple
adverse outcomes have been associated with BPSD,
such as cognitive and functional impairment, caregiver
burnout, nursing home placement, and mortality21-25.
However, research has scarcely explored outcomes
in severe forms of dementia.
The occurrence and maintenance of BPSD relies
on three factors, namely patients (e.g., hunger, pain,
Dement Neuropsychol 2022 September;16(3 Suppl. 1):96-115
and acute medical conditions), caregivers (e.g., stress,
lack of politeness, and communication skills), and the
environment (e.g., under/overstimulation and lack of
routine and activities). Consequently, it is rational and
evidence-based that the first treatment step against
BPSD includes non-pharmacological measures 26 .
A systematic review and meta-analysis points to an
effect size at least equivalent to those of psychotropic
drugs, and it is safer26. However, in clinical practice,
non-pharmacological measures are yet to be fully
implemented due to several economic and cultural
reasons. The next session will better explore this
specific topic. Clinical practice recommends the
observation of BPSD symptoms at different hours,
with varying caregivers, and multiple environments.
Moreover, research has also suggested using BPSD
measurement instruments, such as the Neuropsychiatric
Inventory (including the clinician version or NPI-C)
and the BEHAVE-AD, due to multiple concurrent and
sometimes complex symptoms.
After non-pharmacological measures or concomitantly
to them, pharmacological treatment is possible and
common due to safety reasons or BPSD severity.
In general, response rates to different classes of
medications are heterogenous and of small therapeutic
effect. The overall evidence points to a small number
of psychotropic drugs which reasonably improve
BPSD. We recommend that these drugs be prescribed
at low doses and that clinicians avoid, if possible,
polypharmacotherapy. Table 2 summarizes our expert
consensus-based recommendation for the use of
psychotropic medication in BPSD associated with AD.
Treating cognitive impairment with cholinesterase
inhibitors and memantine shows slight improvement in
early and moderate stages of AD, according to a recent
systematic review and meta-analysis27. Effects are small
and benefits to which family members and caregivers
referred may amount to a placebo effect. The benefits
of these drugs for severe dementia are questionable but
may exist and thus, clinicians must weigh the decision
of maintaining or ceasing such treatment27. In moderate
to severe AD, low to insufficient evidence suggested
that cholinesterase inhibitors and add-on memantine
inconsistently improved cognition and global clinical
impression, compared to placebo. However, the evidence
is questionable and deserves further exploration in
clinical trials. Cholinesterase inhibitors and memantine
also slightly improve BPSD, especially in the early and
moderate stages of AD and include apathy, anxiety,
and depressive symptoms. In total, three systematic
reviews with meta-analysis28-30 have summarized this
evidence. In general, attending physicians may consider
Brucki SMD, et al.   Management in severe dementia.   99
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):96-115
prescribing and maximizing both cholinesterase
inhibitors and memantine to improve cognitive function
and BPSD before considering other psychotropic
medication. Nonetheless, we emphasize that evidence
is insufficient to decide in favor or against this position.
Citalopram and risperidone have produced favorable
evidence for agitation in AD. Citalopram improved
moderate agitation, if administered between 10-30mg
a day31. Other antidepressant agents, such as sertraline
and trazodone, improved agitation32. However, we must
stress their potential limitations as one review included
fewer patients with severe AD, still showing cognitive
performance and a prolonged QT interval in patients
receiving citalopram 30mg31. Ongoing S-CitAD, which
evaluates escitalopram for agitation, may show greater
safety and a better cognitive profile. Risperidone,
mostly at low doses (0.5-1mg), and selective serotonin
reuptake inhibitors (SSRI), as a class, alleviated
agitation in patients with dementia, according to a
systematic review and meta-analysis32-34.
The evidence for the use of antipsychotics for
BPSD is limited even for agitation and aggression.
Data from a systematic review showed that aripiprazole
was the safest and most effective antipsychotic
versus placebo, and it was associated with improved
outcomes on the NPI, the Brief Psychiatric Rating
Scale (BPRS), and the Cohen-Mansfield Agitation
Inventory (CMAI)35. Quetiapine improved outcomes on
the BPRS, and risperidone was associated with improved
outcomes on the CMAI. Differences between atypical
antipsychotics were insignificant for effectiveness,
death, or cardiovascular adverse events35.
Apathy is a common BPSD, especially in early-
stage dementia. The literature reports pooled evidence
Box 2. Overall recommendation for the non-pharmacological and pharmacological treatment of cognitive dysfunction and behavior and psychological
symptoms of dementia (BPSD) in severe Alzheimer’s dementia.
1. Consider withdrawing cholinesterase inhibitors and memantine in severe dementia in the absence of clear benefits to cognition or BPSD
2. Education and support for caregivers
3. Well established routine of daily care and activities
4. If possible, consider music therapy and any form of physical activity
5. Investigate causes for cognitive fluctuations or BPSD
6. Consider pain control before prescribing psychotropic agents
7. If agitated or aggressive, consider citalopram, sertraline or trazodone
8. If agitation or aggression persists with antidepressants, consider antipsychotics such as risperidone, aripiprazole or quetiapine
9. Always reevaluate withdrawing psychotropics for BPSD after symptom control
100   Management in severe dementia.   Brucki SMD, et al.
(small sample size from three studies) favoring the
use of methylphenidate to reduce this symptom in the
Apathy Evaluation Scale36. However, apathy is part of
the phenotype of more severe dementia, and the overall
cognitive decline summed with other bothersome BPSD
in this stage results in a questionable pharmacological
treatment of apathy.
A systematic review and meta-analysis 37 was
unable to recommend the use of antidepressants to
treat depression in BPSD based on its lack of efficacy
in respond to or reduce depressive symptomatology.
Benzodiazepines, anticonvulsants, and cannabidiols
are also ineffective in pharmacologically controlling
BPSD due to their lack of efficiency or adverse reactions,
including cognitive decline. Finally, dextromethorphan/
quinidine and prazosin showed evidence of improving
agitation in AD 38,39 and pimavanserin reduced
psychosis in AD 40 . However, these three agents
are unavailable in Brazil.
B ox 2 s ummar iz es our overall treatment
recommendation for cognitive dysfunction and BPSD.
In conclusion, taken together, current evidence shows
low certainty for prescribing cholinesterase inhibitors
and memantine in severe dementia. The use of agents
such as SSRIs, risperidone, and aripiprazole for
agitation, aggression, and psychosis also showed a small
or uncertain effect when we consider severe dementia.
Non-pharmacological measures, including activities
of daily living and care routines, proper feeding, pain
control, music therapy, physical therapies, and caregiver
education and support, seem to be safer and more
effective41. The use of pharmacological agents should
consist of single agents, in small doses, and for a short
period to control the targeted BPSD (Table 2).

Table 2. Consensus-based recommendation for the use of psychotropic medication in specific behavior and psychological symptoms of dementia (BPSD)
associated with severe Alzheimer’s dementia.
BPSD Suggested dose range*
Citalopram** 10-20mg/day, single dose
Sertraline 50-100mg/day, single dose
Agitation or
aggression Trazodone*** 25-100mg/day, single/partial doses
Risperidone 0.25-1mg/day, single dose
Risperidone 1-3mg/day, single dose
Psychosis
Quetiapine 100-200mg/day, single/ partial doses
Aripiprazole 10-30mg/day, single dose
*Doses are recommended based on clinical trials and personal experience, considering the pharmacological properties of these agents; **May consider escitalopram due to its greater
safety and better cognitive profile. It is also more commonly prescribed in Brazil than citalopram; ***Although it has less evidence than the other agents, this drug shows a good balance
between safety and effectiveness in clinical practice. Extended-release formulation is better during the day to avoid somnolence.
NON-PHARMACOLOGICAL TREATMENT
Nonverbal communication
“Perhaps it’s the most important part of caring. Because it
leads to reflection, because it provides the manifestation
of human nature, present in each of the professionals
involved with care. It is the deepest empathy and the need
to show affection, affection and, above all, respect for
the other. Holding the hands of someone who may have
their mind lost, in another dimension perhaps, gently
touching the thin skin of an already weakened body, looking
deeply into their eyes and letting the feelings present in
this exchange of glances lead to the understanding of what
is needed to do. It is the meeting of the human and bioethics,
a feeling of lightness and of certainty that the task is being
carried out with respect and with the dignity that every
human being deserves.” (Ceres Ferretti)
The literature is very rich in papers discussing
non-pharmacological approaches to psychological and
behavioral symptoms in dementia – BPSD, which arise
with the evolution of different dementia syndromes42,43.
However, unfortunately, the literature still lacks studies
discussing the possibilities and effectiveness of these
approaches in severe dementia, or even the difficulty
of conceptualizing and adequately treating people
with it44-46. Some behaviors are more prevalent in the
initial phase of the disease, others in its intermediate
phase and some in its severe phase. Its last phase
signals a possible combination of factors intrinsic
to patients (comorbidities) and caregivers (stress) and
extrinsic (environmental) ones, which require multi and
Dement Neuropsychol 2022 September;16(3 Suppl. 1):96-115
Side effects
nausea, diarrhea, headache, increased risk of falls
extrapyramidal side effects, weight gain, metabolic abnormalities,
hyperprolactinemia
extrapyramidal side effects, weight gain, metabolic abnormalities,
hyperprolactinemia
drowsiness, weight gain, metabolic abnormalities
nausea, weight gain, headache, somnolence, akathisia
interdisciplinary assessment and conduct to make the
best decision, case by case47.
Family doctors and multidisciplinar y teams
(previously trained by specialists) in primary health care
units can theoretically recognize the needs and monitor
patients with severe dementia who were discharged
from the secondary care service. However, professionals
working in this sector still face difficulties, related to
their knowledge to perform diagnoses and administer
pharmacological and non-pharmacological treatment,
especially in mild and severe AD phases48.
Due to the problems in the health, economic,
and social sectors in Brazil and the need for
biopsychosocial support (especially during this serious
health crisis49), reference and assistance centers have
created projects which aim to minimize the direct
and indirect social costs of PWD caregivers 50,51 .
These projects are in line with most guidelines from
international consensus meetings of associations52-57,
universities58,59, and scientific committees57,60.
A l l e x p e r t co n s e n s u s e s d i s c u s s t h e n e e d
for psychoeducational programs and sug gest
recommendations which contribute to the education
of caregivers about systematized and appropriate
models for different behavioral disorders. The great gap,
however, is still the approach to the severe phase
of AD. Knowing the causes of SCPD in this phase
is the objective, and solving them, or better yet,
preventing them is the goal 61. The starting point
is understanding possible social and more individual
family barriers to the construction and practice of these
models, those aimed at reducing these behaviors and,
Brucki SMD, et al.   Management in severe dementia.   101
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):96-115

consequently, the comfort and quality of life of patients
with severe dementia and their caregivers62.
Assessment Models
In Brazil, the nursing model in dementia care includes
all stages of disease evolution63. Research has shown
that the protocol is useful in its main objective,
which is to assess patients and their caregivers.
Composed of two stages, patients and caregivers focus
on patient-centered care models, in combination with
the caregiver-centered care model64.
Kales (2015)58 offers a review with an interesting
conceptual model of factors which require evaluation,
leading to the reflection on the union of disciplines
combining different areas of knowledge such
as neurology, geriatrics, psychiatry, and gerontology
in a multidisciplinary view (Figure 1). The same
review shows “DICE - Describe, Investigate, Create,
and Evaluate,” proposed by the University of Michigan
in partnership with the Johns Hopkins Alzheimer’s
Disease Research Center and the Center for Innovative
Care in Aging with guidelines to identify needs
for the practice of care58.
As mentioned above, clinical practice still lacks
a consensus on the definition of severe dementia,
sometimes confused with moderate dementia.
However, studies agree on possible causes that give
rise to common behaviors, such as agitation, apathy,
hallucinations, delusions, “unmotivated” crying,
fear, anxiety, contracted body, and resistance to care,
among others58,62.
Several studies report that most factors responsible
for SPCD in severe dementia originate from patients’
comorbidities, caregivers’ lack of knowledge and
stress, and the environment. The inability to verbally
communicate can lead to the behaviors in the same way
that the rapid recognition of any change in the pattern
of patients’ usual behavior can prevent progressing
of the SPCD and interfering with the quality of life of
both patients and caregivers (Table 3)58,65.

Neurodegeneration associated with dementia Greater vulnerability to stressors Psychological and Behavioral
Symptoms of Dementia (BPSD)

– Change in the ability to interact with others Caregiver-related factors Factors related to the environment
and environment;
– Disruption of brain neurocircuits – Stress, overload, depression – Overstimulation or understimulation
– Lack of education about dementia; – Lack of activity and structure
– Communication; – Lack os establishing routines
– Incompatibility of expectations
Factors related to patient
and severity of dementia
– Premorbid personality/psychiatric illnesses
– Acute medical problems
(ICU, pneumonia, dehydration, constipation)
– Unmet needs
(pain, sleep problems, fear...)

Figure 1. Depiction of a conceptual model for different interactions resulting in BPSD. Adapted from Kales (2015)58.

Table 3. Recognition and Management Recommendations for Psychological and Behavioral Symptoms in Severe Dementia. Adapted of Kales (2015)58.
In the patient In the caregiver In the environment Recommendations

Caregivers’ training;
Health education;
Lack of knowledge
Poor positioning Identification and elimination of causal factors in patients and the environment;
Health education
Pain Excessive noise Promotion of physical comfort;
Lack of education
Abrupt movements Information to the responsible physician and members of the health team;
in dementia
Elimination of excessive noise;
Gentle patient mobilization.

Continue...

102   Management in severe dementia.   Brucki SMD, et al.

 Dement Neuropsychol 2022 September;16(3 Suppl. 1):96-115

Table 3. Continuation.

In the patient In the caregiver In the environment Recommendations

Caregivers’ training;
Health education;
Urinary Lack of knowledge
Inadequate hygiene Optimization of fractional hydration (1.5-2L/day) or at medical discretion;
infection Stress
Double incontinence;
Hygiene, body, and environmental measures.

Dark, closed or dirty Caregivers’ training;

Respiratory
Lack of knowledge environment Preventive measures;
Infection
Cold temperature Passive exercises.

Adequate bathroom Training in hygiene measures and health education to caregivers;

Constipation Lack of knowledge hygiene, security, Medical and nutritional approach;
and privacy Fractioned hydration.

Inadequate
Refusal Environment Training of caregivers and health education;
communication
of care adaptation and care Caregivers must be careful with all stimulus and approaches.
and conducts

Lack of recognition
concerning pain,
Observation Training and health education;
Sleep hunger, coldness, heat,
Change in patients’ Adequacy of auditory environmental stimuli;
disturbances mobilization in bed,
behavioral patterns Medical evaluation.
and previous sleep
problems

* All caregivers must be trained in all activities proposed by the health team to offer their consent and understand the importance of each proposed intervention. Elaborated by Ferretti (2021).

Comorbidities in advanced dementia adults without this disease. These comorbidities impact
In general, older adults, and especially those with survival throughout patients’ later years74,75 (Table 4).
dementia, face exclusion from clinical trials on
pharmacological interventions and the medical
literature is scarce in good-quality data regarding Table 4. Conditions associated with higher mortality among subjects.
the advanced stages of dementia since the focus
Number of diagnoses
of guidelines and randomized, controlled studies
and intervention are aimed at premorbid, very mild, Male
and mild stages of dementias66,67. Age
Although research has suggested the possibility of
AD patients being healthier68, current evidence points Lung infections
to the opposite: people with dementia (PWD) show Parkinsonism
a significantly higher prevalence and medication use69-73.
Previous Stroke
Clinical diseases impact quality of life (by, for example,
worsening mobility) and patient survival regardless of Atrial fibrillation
dementia, both in institutionalized individuals and those Malignancy
who remain in the community, increasing the number
of searches for emergency rooms, hospitalizations,
hospital costs, and health expenditures69,70. As for the severity of dementia, results pointed
Older adults with dementia are three times more to a significantly lower two-year survival rate among
likely to have four or more concurrent chronic diseases most dependent patients, regardless of their number of
and annual expenses, up to 3.3 times higher than in older comorbidities. We find a positive correlation between

Brucki SMD, et al.   Management in severe dementia.   103

 Dement Neuropsychol 2022 September;16(3 Suppl. 1):96-115
number of comorbidities and dementia severity
independently but not the impact of the interaction
between them; the more advanced phases compete
with higher health expenditures73.
Schubert et al. highlight the possibility that the
lesser search for diagnoses and treating comorbidities
in PWD on an outpatient basis may be one of the
conditions responsible for its aggravation, showing
the need to search for advanced care units, which could
be avoided under a less nihilistic outlook72,76,77(Box 3).
Box 3. Chronic conditions most frequently associated in PWD.
• Heart failure
• Hypertension
• Diabetes mellitus
• Neoplasms
• Kidney failure
• Cerebral and coronary artery diseases
• Atrial fibrillation
• Lung diseases
Dementia in comorbidities
As previously mentioned, dementia directly impacts
the survival of individuals regardless of the presence
of comorbidities 75 . Dementia decreases survival
after acute myocardial infarction, with greater renal
decompensation, higher rate of acute lung edema,
showing the delay in hospitalization and the lesser
prescription of antiplatelet agents and beta-blockers
at hospital discharge77. Dementia also predicted higher
mortality in patients with heart failure78.
The frequent coexistence between Advanced
Dementia and Frailty syndrome could be one of the
ways to explain, at least partially, the worse prognosis
of comorbidities among PWD79. As it is known, although
the definition of frailty is still a matter of debate
in the current medical literature, frail individuals,
especially the elderly, have less functional reserve
of physiological organs and systems and less capacity
to face challenges and organic overload, having
greater difficulty in maintaining homeostasis when
faced with acute illnesses, interventions of any kind,
diagnostic or therapeutic80.
The management of comorbidities in dementia,
on the other hand, faces several difficulties regardless
of what has been exposed so far: starting with
making a diagnosis in these individuals, who, due to
104   Management in severe dementia.   Brucki SMD, et al.
the progressive impairment of language, memory,
and criticism the efficiency in reporting symptoms and
complaints is lower, less valued or commented upon
and dependent on a third party not always attentive
or accurate (the caregiver). Adherence to medication
and non-pharmacological guidelines is also erratic
and variable, by patients and caregivers69,81. Moreover,
once undiagnosed and addressed with an adequate
care plan at an outpatient level, such illnesses become
more complicated and patients end up being taken
to emergency rooms, wards, and Intensive Care Units,
often with treatments that are disproportionate to their
condition. advanced disease69,81.
Thus, often, despite having a high number of
comorbidities, patients with dementia are less
likely to have their health problems diagnosed and
treated, including those that may directly impact
their functionality, such as auditory and visual
sensory alterations71. Often, by the simple mention
of the diagnosis of dementia, especially if advanced
(albeit moderately), such individuals are deprived of
beneficial proportional treatments due to discrimination
since the diagnosis suggests that these patients would
fail to obtain the benefit of a certain procedure,
even though they might live long enough to experience
the complications of the disease, thus sometimes
imposing suffering which could have been avoided72,82.
The reduction in survival expectancy should limit
the administration of treatments unable to improve
patients’ symptoms or quality of life. Thus, clinical
practice should rethink primary preventive treatments
in light of the prognosis to avoid the unnecessary
use of medications and polypharmacy and control
diseases such as hypertension and diabetes mellitus,
and dyslipidemia. Moreover, other secondary prevention
measures must comply with current guidelines
indicating less strict goals for older adults with advanced
ages and those with lower survival expectations83.
Comorbidities of dementia
The more advanced stages of dementias, especially
in its terminal stages, induce the increase of morbid
conditions such as lung infections due to bronchial
aspiration or other causes, immobility, dysphagia,
urinary tract and skin infections, pressure injuries, falls,
malnutrition, and various dental problems84.
Maintaining patients’ dignity, regardless of their
cognitive status, treating and preventing reversible
complications (considering individual and family values),
and establishing, as early as possible, a plan to consistently
care for these patients with the best technical-scientific
knowledge, are the pillars to treat individuals with

any diagnosis, including dementia, whatever their etiology,
patients’ socioeconomic condition or stage81,82,84,85.
Cancer and dementia
Both cancer and dementia have increased prevalence
with age and lead to very complex health care needs
and worse outcomes in people suffering from these
diseases than those without these comorbidities86.
Estimates of the prevalence of the association between
the two diseases vary in the literature. An estimate
suggests that 7.5% of individuals over 75 years old live
with both diagnoses86,87. People living with this dual
diagnosis are less likely to receive screening, staging,
curative treatment, and adequate pain management
than cancer patients without dementia86,87. Moreover,
they have late diagnoses, a lower survival rate after it,
and a greater number of comorbidities than those living
only with cancer or dementia87.
Oncology services poorly identify dementia and
its patients often receive limited therapeutic options.
Oncology teams feel insecure about managing these
patients since dementia carries more complex decision-
making. Finally, studies highlight the important role
families play in promoting greater success in treating
and managing cancer in patients with dementia86.
Cancer diagnosis and treatment for patients in very
advanced stages of dementia refrain from administering
screening and very invasive measures. Even so, clinical
practice must establish a care plan to ensure quality
at the end of life for people who have aged with these
two diseases: pain management, prevention of avoidable
complications, and family support.
Approach to pain in advanced dementia
Older adults with dementia shown a 32-53% estimated
prevalence of pain, higher among those with diseases
known to cause pain, such as osteoarthritis, fractures,
peripheral arterial disease, and cancer. This prevalence
can reach 83%¨in those living in ILPIs. No study has
shown that dementia affects pain sensitivity; rather,
what it alters is individuals’ ability to report what
they are feeling88.
Research considers self-reports as the gold standard
in pain diagnosis. Patients with dementia show an
unacceptable underdiagnosis and undertreated pain88-90.
Among institutionalized older adults, 25% of those who
daily complained of pain had received no analgesics.
Among those with hip fractures and dementia, a student
found that the prescribed opioid was a third of the normal
dose and, therefore, insufficient 89,91.
Untreated pain manifests itself via secondary
symptoms in patients with dementia, such as sleep
Dement Neuropsychol 2022 September;16(3 Suppl. 1):96-115
disturbances, agitation, depression, weight loss,
and decreased mobility90. Studies have shown that
analgesics better control agitation in PWD and pain
than neuroleptics, especially in moderate-advanced
dementia. They also reduce aggressiveness and pain
without worsening patients’ cognition 91,92.
To optimize pain assessment in PWD and, therefore,
its identification, a study developed a specific pain
scale for severely demented patients, later validated
for Brazilian Portuguese90. The instrument (PAINAD)
evaluates five items: breathing; negative vocalizations;
facial expressions; body language; and comfortability,
observing the patient for five minutes in different
daily situations: during rest, in pleasurable activities
and moments of care; and 30 minutes after analgesic
medication. Multidisciplinary teams can use it after
training without impeding its complexity.
Thus, evaluating and treating pain in patients
with advanced dementia is a challenge that clinical
practice must face and, whenever suspected due
to its manifestations, approach and treat it.
Oral health
People with dementia have the same oral problems
as the general population. Good oral health positively
inf luences individuals’ overall health, dignity,
self-esteem, social integration, and nutrition. Studies
show the effects of oral problems in patients with
dementia with difficulty chewing due to missing dental
elements and consequent refusal to eat, behavioral
changes (such as withdrawal and aggressiveness
due to pain – as previously mentioned), and other
changes. The nature of dementia and its severity, social
functioning, behavioral aspects, adherence to oral cavity
care, and caregivers’ ability of caregivers to replace
them in this care may compromise the conditions
for maintaining oral health93 (Table 5).
Overall health and comfort are closely linked to oral
health in the terminal stages of neurodegenerative
diseases 94 (Table 6). Oral diseases worsen general
comfort, cause pain, affect cognition and behavior,
and alter quality and life expectancy of people with
dementia. The risk of aspiration pneumonia increases
in the presence of oral factors such as poor hygiene,
meager coronal and cer vical teeth, periodontal
disease, and the presence of microbes in saliva,
whereas a clean and healthy oral cavity significantly
reduces its occurrence95,96.
Caregivers play a central role in the oral health
of patients with advanced dementia. The quality
of hygiene care and the perception of problems
which may arise depend almost exclusively on them.
Brucki SMD, et al.   Management in severe dementia.   105
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):96-115
Studies have shown a poor understanding of the
importance of oral health and its subsequent problems,
such as patients’ (often aggressive) resistance further
complicate the adherence of caregivers to these demands.
Education, motivation, and the offer of strategies
was associated with improved oral hygiene in patients
with severe dementia97. Regular odonatological visits,
caregivers’ education and access to care facilities
in day centers, outpatient clinics, and home services are
strategies which can ensure better oral health for these
patients, benefitting their global health and quality
of life increasing their expectations of survival.
Table 5. The main changes seen in the oral cavity of patients with
dementia are:
• Poor hygiene
• Gingivitis with accumulation of bacterial plaque, calculi, and bleeding
• Caries
• Fractures with remaining roots and eventual infection
• Ulcers, gingival hyperplasia, and lack of taste due to psychotropic
drugs often used to control symptoms in these patients.
Table 6. Factors which negatively influence oral health93.
• The severity of dementia
• Previous dental history - care and diseases
• Ability to receive / consent to oral hygiene care by caregivers
or dental teams
• Knowledge of patients or their caregivers about the importance
of oral health
• Lack of patient/caregiver motivation
• Impacts of medications on the oral cavity (xerostomia)
• Lack of information on how to access teams
• Degree of knowledge/training of oral health teams regarding
dementia and aging
• Teams’ failure to develop strategies and long-term care plans.
• Scarcity of appropriate care facilities for small/medium
dental surgeries, day centers, and at home.
NUTRITIONAL ISSUES IN ADVANCED DEMENTIA
Undernutrition in advanced dementia
As dementia advances into a severe stage, feeding
difficulties become more common and bring about
important problems such as undernutrition and weight loss,
106   Management in severe dementia.   Brucki SMD, et al.
which are associated with more rapidly progressing
cognitive impairment and increased mortality 98.
Therefore, all PWD should receive routine assessments
of their nutritional problems. Several instruments
can identify whether patients are undernourished, such
as the Mini Nutritional Assessment (MNA) and the
Malnutrition Universal Screening Tool (MUST)99,100.
An unstructured evaluation is, however, also a useful
option, particularly under limited time, common in
Brazilian primary care consultations. These evaluations
should include anthropometric measurements (weight,
height, and body mass index) and questions about food
and fluid intake, dietary habits, and adversative feeding
behaviors. Laboratory tests are also helpful to better
evaluate patients’ nutritional status, including full
blood count, electrolytes, B12, urea, creatinine, glucose,
albumin, and ferritin.
Individuals with advanced dementia may show
adversative feeding behaviors that can importantly
contribute to undernutrition, such as refusal
to eat, wandering, and agitation 101. Research has
little evidence that interventions to modify mealtime
environments can improve food and fluid intake for
these patients102,103. However, given their favorable
risk-benefit and the possibility of improving patients’
quality of life, employing such measures is reasonable104.
Box 4 describes our suggested interventions.
Box 4. Measures to improve mealtime environment in advanced dementia.
Refrain from rushing; good interaction between patients
and caregivers increases food intake
Offer food patients like
If possible, the same caregiver should always be responsible
for assisting patient’s meals
Try to set a pleasant, homelike environment with improved lighting
and familiar music
Although it is useful to maintain a routine, it is advisable to wait until
patients are calm before offering them food and fluids.
Use high-contrast colored tableware
Consider offering regular snacks and small meals
Oral Nutritional Supplements (ONS) can increase
macronutrient intake and avoid undernutrition in older
adults, including persons with advanced dementia.
As a meta-analysis shows, ONS can increase weight in
persons with dementia, showing few gastrointestinal side
effects. Note, however, that the literature lacks enough
evidence to aclaimffirm that ONS decrease mortality
or cognitive deterioration among persons with dementia105.

Dysphagia in advanced dementia
Oropharyngeal dysphagia is a serious and common
problem in advanced dementia, as it may be an
important cause of undernutrition and increase the
risk of respiratory infections and death106. Early stages
of dementia may show subtle aspirations and even go
unnoticed by patients or caregivers107. Therefore, speech
and language therapists should take part in managing
PWD as early as possible, even in the absence of
swallowing complaints. The most important instrument
for diagnosing dysphagia on a day-to-day basis is the
Clinical Swallow Evaluation (CSE). it includes both
questionnaires on swallowing problems and a motor
and sensory examination of all oral structures involved
in bolus formation 108,109. More specific situations
(e.g., to diagnose more accurately aspiration) may
require employing an instrumental assessment, such as
videofluoroscopic swallow studies (VFSS) and fiberoptic
endoscopic evaluation of swallowing (FEES)108-110.
The use of thickeners to change the consistency
of fluids offered to patients with advanced dementia
can help to mitigate the consequences of dysphagia.
In 2018, a meta-analysis concluded that thickening
the fluids offered to patients with advanced dementia
may have an immediate positive effect on swallowing
and may decrease the three-month incidence of
pneumonia 111. It noted, however, that long-term
benefits are uncertain due to scarce evidence 111.
Research also lacks enough evidence to recommend
a specific thickness (i.e., nectar- or honey-thick) over the
other112. Adopting a chin-down posture while drinking
liquids is another useful intervention in dysphagia
and may be as effective as fluid thickening to decrease
the incidence of pneumonia, especially in individuals
with milder dysphagia112,113.
Tube feeding in advanced dementia
Usin g or w i t h hold ing t ub e fe e d ing re m a i n s
one of the most controversial topics in the management
of advanced dementia. Caregivers often misinterpret
the recommendation to not insert a percutaneous
endoscopic gastrostomy (PEG) as a recommendation
to withdraw all types of care, which might compromise
ongoing treatment and even harm the confidence
in healthcare providers. Of note, such recommendations
are based mostly on observational studies and not on
randomized controlled trials, as these are unavailable
due to ethical reasons114,115.
Most of the available evidence suggest that tube
feeding fails to benefit patients with advanced dementia
and may even harm them. The use of PEG tubes seems
Dement Neuropsychol 2022 September;16(3 Suppl. 1):96-115
to fail to improve mortality in individuals with advanced
dementia116-118, may lead to higher levels of discomfort119,
and its complications are responsible for almost half of
all emergency department visits among patients with
advanced dementia 120. Tube feeding also seems to
increase the risk of pressure ulcers and are unhelpful
to heal existing pressure ulcers121,122. Finally, enteral
feeding with a PEG tube fails to decrease caregivers’
burden121 and raise a perception of better end-of-life
care among relatives of individuals with advanced
dementia123. Current evidence still remains unclear,
however, on whether such adverse outcomes are related
to the late use of PEG tubes and if patients in less severe
stages of advanced dementia could benefit from it 117,124.
The decision to withhold tube feeding in advanced
dementia is ethical and based on current scientific
evidence but should not be viewed as a one-size-fits-all
way to approach the matter. The discussion should
include families and, whenever possible, patients,
and consider their social, cultural, and religious values.
In other words, the decision to use or withhold use
PEG tube feeding must be individualized. Whenever
tube feeding is contraindicated, assisted oral feeding is
encouraged. The concept of “comfort feeding only”125
is useful in such situations: it is based on feeding with
comfort as its main goal, i.e., focusing on satisfaction
and stopping whenever feeding is distressing.
END-OF-LIFE CARE IN DEMENTIA
People with advanced dementia may possibly include a
great part of the patients living with dementia in Brazil.
However, trustful estimates are still impossible due to
the lack of epidemiological data and the profile of this
population. Advanced dementia patients show a low
income, associated with a high disease burden profile,
often lacking the assistance of formal caregivers126.
Delivery of care to PWD is essentially provided by family
members in Brazil127, unlike European countries with
a public health system, such as the United Kingdom128.
Thus, unique characteristics of the Brazilian people and
its continental-size health system demand adapted
recommendations for appropriate end-of-life care
of people with dementia.
End-of-life care, or palliative care, is a therapeutic
strategy to maintain a person’s quality of life by
relieving discomfort or stress in a life-limiting condition.
This subtopic details a few steps to aid general
practitioners and primary care physicians: (1) accurately
identify the moment of defining end-of-life care,
(2) plan next steps with patients and their family
Brucki SMD, et al.   Management in severe dementia.   107
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):96-115
members, and (3) provide mental and physical assistance
to patients with terminal illness.
Identifying the moment of end-of-life caring
Recognizing individuals with dementia in advanced
disease stage is a cornerstone to provide adequate
strategies. In Brazil, almost 80% of individuals
with dementia are still undiagnosed129. A sensitive,
accurate feeling that forgetfulness may not be solely
associated with the aging process is the first step
to provide proper care of patients with severe dementia.
Ideally, the moment of discussing palliative care is
as early as dementia is diagnosed, focusing on patients’
wishes. Family members are essentially involved in
deliberating decisions when individuals no longer may
take complex decisions130.
Primary care physicians should have a high suspicion
of dementia even in patients without cognitive
complaints131. Once they identify the cognitive decline,
the next step is defining its stage. Clinical features vary
in severe stage dementia, including mutism, impaired
per os, and severe gait disturbances. Recurrent hospital
admissions or demanding frequent medical assistance
may be early signs of end-of-life disease, especially
involving a recent diagnosis of cancer, heart failure
or chronic obstructive pulmonary disease. Primary
healthcare professionals should also pay attention
to mental status of patients in home care appointments,
as a great number of individuals were home assisted,
lacking appropriate follow-up132.
Planning the approach to patients and their families
The Brazilian public healthcare system has a major infra-
structure to provide an interdisciplinary approach to
families with patients in the end-of-life dementia stage.
Primary care facilities are strategically located close to
the local community, which increases confidence and
access to healthcare. However, most public facilities lack
psychologists, physical therapists, speech therapists
or social workers.
Once the diagnosis of end-of-life dementia
is established, the next priority is to discuss an
interdisciplinary approach to provide optimal assistance
to loved ones. Only a minority of older adults have
access to long-term care institutions 133. Although
interdisciplinary care is essential to mitigate end-of-life
discomforts involving different healthcare professionals,
Clinical practice should implement a broad care for
those with access to private physical, occupational,
psychological, and speech therapy.
For most patients with limited access to these
services, we must discuss a few points. Firstly, family
108   Management in severe dementia.   Brucki SMD, et al.
members must immediately increase awareness
of end-of-life care. They should raise a community
spirit, reach local policies, and increase their voice
on a nationwide level. Philanthropic institutions
such as “Associação Brasileira de Alzheimer” (ABraz)
may provide information about local hospices or
low-cost services, though they often have limited
regional actions. All levels of care should also address
spiritual needs, as sect leaders should aid planning
at the time of diagnosis134.
Providing mental and physical assistance for patients
(and caregivers)
Assisting people with terminal dementia should consider
several levels of care135. The relatively weak healthcare
structure for patients with terminal diseases compels
families to establish a plan of care for persons with
dementia. The whole primary care team should perform
timely planning discussions, including stratifying care
demanded by both patients (when cognitively able
to take decisions) and caregivers136.
Ideally, they shall create a plan of care whenever
patients receive a diagnosis of end-of-life dementia.
They must assess patients’ understanding and
judgement to evaluate their wishes; if impossible,
this decision should involve their families or caregivers.
Patients with end-of-life dementia benefit from
care levels divided into five stages, ranging from critical
care including invasive procedures to supportive care
and comfort measures only137,138 . Care level must
consider patients’ wishes regarding invasive procedures
in general, including orotracheal tube, central venous
catheter, cardiopulmonary resuscitation, and ICU
admission (Table 7). Caring should be individualized
and performed together with families.
Education for caregivers and family members is
a fundamental point that must be thoroughly discussed.
Instructions such as available sources of information
about end-of-life dementia, where to ask for help,
when to ask for assistance (or be taken to the ER),
and what is expected and what is not. Assistant physicians
may provide adequate end-of-life care, including
adequate management of pain, agitation/aggression,
risk of aspiration, and need for a feeding tube,
dyspnea, and pneumonia139.
Caregivers’ mental health must also be addressed.
Since they usually are a family member, they often show
a psychological distress associated with the caregivers’
burden 140,141. Caregiver assistance should focus on
providing a better quality of life for the entire family.
Avoiding psychological distress should be a priority,
and we must suggest them to perform rotation shifts
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):96-115

between caregivers (other family members or half-time
support caregivers). Mental health hotlines have also
been progressively implemented to assist those with
psychological needs in Brazil142, especially after the
COVID-19 pandemic143.
Thus, end-of-care dementia demands unique,
individualized strategies which assistant physicians
should recognize. Early identification, conjoint
planning with families, and with level of care staging
are cornerstones of adequate dementia care.

Table 7. Medical Orders for Scope of Treatment (MOST), in Portuguese, adapted to patients with end-of-life dementia stage. Staging must consider wishes
to admission in a critical care unit, orotracheal intubation and cardiac resuscitation.
Plan demanded by the patient Medical record Plan of care Level of care

I want my life to be preserved using

ICU admission, including orotracheal
all measures of care available, Full intensive care
intubation and CPR
when indicated

I want my life to be preserved,

except when my heart stops.
I accept ICU admission and all
measures, including intubation,
except CPR if my heart stops.
I want my life to be preserved,
except when my heart stops.
I accept ICU admission and all
measures, except CPR if my heart
stops or in case of intubation.
Intensive care without CPR
Intensive care without
orotracheal intubation or
CPR
Critical care:
ICU admission.
- Attempt to support life with
Excluding:
artificial measures in ICUs.
Defibrillation and CPR
- These orders in general are
not used in case of natural
end-of-life outcomes.
ICU admission
Non-invasive ventilation and high-flow O2
Excluding:
Intubation, defibrillation, and CPR

I want to be treated for reversible

causes but without measures of
artificial life support.
If I show an irreversible condition,
I want to receive the treatment
available, except for invasive
procedures (intubation or CPR).
I want to receive this care
in this ward.
I understand death as a natural,
expected event. I accept receiving
care to decrease pain or other
symptoms. I would like to receive
this set of care whenever available.
Advanced ward care
Basic ward care
Ward care, including treatment for
reversible causes.
Excluding: ICU admission, intubation or CPR Ward care:
- Support artificial measures
will not be initiated if patients’
heart or breathing stops
(i.e., intubation or CPR)
Exclusive symptoms management
and comfort measures

ETHICAL AND LEGAL ASPECTS
Countless ethical and legal issues arise and evolve
regarding the stage and severity of neurodegenerative
diseases. These disorders compromise the psychological
well-being and behavior of patients, impacting their
quality of life, and physically and emotionally harming
their families. Dementias generate loss of autonomy
and inability to make decisions, pillars of medical
ethics which support the management of diagnostic
or therapeutic medical approaches144.
In its advanced stage, PWD are unable to care for
themselves145. Advance care planning (ACP) involves
a dynamic process based on a dialogue between
individuals, close ones, and healthcare providers
and concern future preferences about their medical
treatment. Although referring to advanced dementia
and contemplating favorable intentions, they are
unable to predict all possible scenarios for the most
appropriate decision-making. Patients have their own
characteristics; diseases have different courses, and the
future is unpredictable146.
Over the past few years, several countries have
implemented laws regulating care for the dying. Without
a doubt, the issue is controversial, especially regarding
shortening patients’ life; colorful debates address
euthanasia, though very timidly in Brazil. In patients

Brucki SMD, et al.   Management in severe dementia.   109

 Dement Neuropsychol 2022 September;16(3 Suppl. 1):96-115
with severe dementia, the situation becomes more
complex due to patients’ inability to make decisions and
report their feelings and suffering147.
The literature on severe dementia is significantly
reduced, containing few studies with reliable indicators
and guidelines directing healthcare providers in this
moment of innumerable doubts and uncertainties.
The lack of scientific evidence predisposes the prescription
of aggressive therapies without concern for their
insignificance, especially in intercurrent diseases, such as
the lack of results showing the effectiveness of artificial
nutrition and hydration. Thus, to avoid procedures
incompatible with the dignity of the human life, we need
to advance concepts such as which prognostic criteria best
fit survival, how to assess suffering and quality of life in
this special population, and for how long the medications
available could prolong life148.
In this sense, evoking the Hippocratic maxim
of “primum non nocere,” i.e., above all do no harm,
is always an appropriate judgment145.
It is essential to reflect on the development of
technologies that prolong life. Clinical practice may
falsely perceive that this has been accompanied by
an improvement in the quality of life. Living longer
fails to necessarily mean patients have had an adequate
quality of life, as the opposite is more often the case149.
Therefore, when questioned, people claim that living
with quality of life is more relevant than living longer
but the measures adopted in many assistance services
may be incompatible with this desire. Living without
a minimum of quality is unacceptable for a considerable
portion of the cognitively competent population.
In severe dementia, cardiopulmonary resuscitation
and other life support measures may seem futile and
should be carefully evaluated according to the patients’
previous wishes. Refusal to eat and dysphagia are late
manifestations and uncomfortable ethical dilemmas for
doctors who care for older adults. The decision to insert
food via an alternative route is complex and dependent
on a multidimensional understanding144.
In the end, our approach must be proportional
to patients’ needs and based on bioethical principles.
A bioethical perspective that studies life not only from
a biological point of view but also from a biographical
one, with the maintenance of life as a right rather
than obligation149.
Decision-making capacity
Ethically, screening and evaluating individuals for skills
such as decision-making capacity (DMC) should be
patient-centered and based on a functional assessment,
rather than on expectations from an instrument or scale
110   Management in severe dementia.   Brucki SMD, et al.
and its quantitative analyses. In dementia, substitute
decision makers (SDM) are authorized to have frank
conversations to predict and document patients’ desire
prior to their disability. Even when a SDM is appointed
to provide legally effective consent or refusal, this fails
to render patients’ preferences ethically irrelevant150.
In accordance with the DMC issue, doctors must
understand legal consequences, as they are responsible
for patients and will always be asked, when necessary,
to report information officially attesting the disease,
as well as briefly describing patients’ conditions
within expectations. One of these situations is the
possibility of a guardianship procedure for individuals
with dementia, depriving them of the legal capacity
to make decisions and manage their assets. The Brazilian
judicial determination of disability (a legal institution
provided for in the legislation) finds only a small number
of interdicted patients at an advanced stage of dementia.
The main intention of the interdiction is to protect
individuals with a legally significant disability. The Civil
Procedure Code regulates these guardianship processes,
“interdiction” in the Brazilian legal language. This means
that Brazil faces a significant lack of legal responsibility
in severe dementia, probably resulting in numerous
inappropriate measures which fial to reflect patients’
real needs and interests151.
Topics to deal with ethical dilemmas in the advanced
stages of chronic diseases such as dementias
The concept called “Jonsen’s 4-topic” is a practical
approach and structure used by many ethics committees
to resolve clinical ethical dilemmas. It includes
a categorization into four similarly weighted quadrants
composed of information, facts, and descriptions
(Box 5)144,145,151,152.
In conclusion, the general approach to patients
with advanced dementia is, as can be seen from the
above, quite complex. The range of information,
difficulties in diagnosis, peculiarities in treatments,
and the mandatory inclusion of family members
in decision-making impose extensive and frequent
care to guarantee these individuals the best care based
on the best evidence and, in the absence of such,
the best experience and common sense available.
To this end, we suggest that patients and their caregivers
are evaluated very closely, at least every three or four
months, to maintain their best possible functionality
and maximum comfort, and that the following aspects
receive attention. Respectful care, based on the best
evidence, individual and family values, ​​and the search
to clarify any remaining doubts should guide the medical
practice before patients and their loved ones.

Box 5. Bioethical topics.
Medical indication
benefits X harms/favoring patients
It refers to the practice of doing good and benefiting others against acts
which may be harmful, helping health professionals choose available
treatments and examining how each alternative raises the possibility of
success and favors patients.
Quality of life
Dignity/safety and comfort
The various treatments available should provide a better quality of life (QOL).
Dimensioning QOL is complex and unique for everyone, even with the help
of family members’ judgment, care must be taken not to prolong life with
suffering. Dignity, safety, and comfort must prevail.
ACKNOWLEDGEMENTS
PC, LCS and RN are funded by CNPq, Brazil (bolsa de
produtividade em pesquisa).
Authors’ contributions. SMDB, IA, WVB, VC, CELF, RRS,
LSM, JS, BJAPB, LPS: concept; SMDB, IA, WVB, VC,
REFERENCES
1. Wimo A, Ljunggren G, Winblad B. Costs of dementia and dementia
care: a review. Int J Geriatr Psychiatry. 1997;12(8):841-56. doi:10.1002/
(SICI)1099-1166(199708)12:8<841::AID-GPS652>3.0.CO;2-R.
2. Ferretti C, Sarti FM, Nitrini R, Ferreira FF, Brucki SMD. An assessment of
direct and indirect costs of dementia in Brazil. PLoS ONE. 2018;13(3):1-15.
doi:10.1371/journal.pone.0193209.
3. Canadian Study of Health and Aging. Study methods and prevalence
of dementia. Can Med Assoc J. 1994;150:899-913.
4. Schmitt FA, Wichems CH. A systematic review of assessment and
treatment of moderate to severe Alzheimer’s disease. J Clin Psychiatry.
2006;8(3):158-59. doi:10.4088/pcc.v08n0306.
5. Herrmann N, Gauthier S. Diagnosis and treatment of dementia:
6. Management of severe Alzheimer’s disease. Can Med Assoc J.
2008;179(12):1279-87. doi:10.1503/cmaj.070804.
6. Feldman HH, Woodward M. The staging and assessment of moderate
to severe Alzheimer disease. Neurology. 2005;65(6suppl3):S10-7.
doi:10.1212/WNL.65.6_suppl_3.S10.
7. Volicer L. Management of Alzheimer’s Disease and End-of-life issues. Clin
Geriatr Med. 2001;17(2):377-91. doi:10.1016/S0749-0690(05)70074-4.
8. Voisin T, Vellas B. Diagnosis and treatment of patients with Severe
Alzheimer’s disease. Drugs Aging. 2009;26:135-44. doi:10.2165/
0002512-200926020-00005.
9. Arrighi HM, Neumann PJ, Lieberburg IM, Townsend RJ. Lethality of
Alzheimer’s disease and its impact on nursing home placement. Alzheimer
Dis Assoc Disord. 2010;24(1):90–5. doi:10.1097/WAD.0b013e31819fe7d1.
10. Morris, JC. The Clinical Dementia Rating (CDR): current version and scoring
rules. Neurology. 1993;43(11):2412-14. doi:10.1212/wnl.43.11.2412-a.
11. Chaves MLF, Camozzato AL, Godinho C, Kochhann R, Schuh A,
Almeida VL, et al. Validity of clinical dementia rating scale for the detection
and stasging dementia in Brazilian patients. Alzheimer Dis Assoc Disord.
2007;21(3):210-17. doi:10.1097/WAD.0b013e31811ff2b4.
Dement Neuropsychol 2022 September;16(3 Suppl. 1):96-115
Patient preference
principle of autonomy/honor and respect the patients’ wishes
It applies the ethical principle of autonomy and examines patients’ previously
expressed or assumed beliefs and preferences. It aims to honor and respect
patients’ wishes as much as possible within acceptable limits. In severe
dementia, it would be supported by an advance directive, with the need
for a SDM as a family member or friend to help with decision-making.
In the absence of advanced directives, it is essential to request the presence
of an SDM. This enables caregivers to determine how patients would like
to be cared for if they were able to decide, whatever it may be. It would
involve their morals, hopes, aspirations, values, principles, and spirituality.
Therefore, sensitivity of those responsible is paramount, which is practically
the current rule in Brazil.
Contextual features
socio-economic factors/political and religious preferences
This last quadrant refers to the exacerbation of ethical dilemmas due
to socio-economic, political, cultural, and religious factors that frequently
appear in advanced dementia and are reflected in care and decision-making.
CELF, RRS, LSM: drafting the manuscript; BJAPB,
FACV, JS, LCS, LPS, MLFB, MLFC, NAFF, PC, PHFB, RN,
SMDB: critical revision of the manuscript for important
intellectual content.
12. Galasko D, Schmitt F, Thomas R, Jin S, Bennett D, Ferris S. Detailed
assessment of activities of daily living in moderate to severe Alzheimer’s
disease. J Int Neuropsychol Soc. 2005;11(4):446-53. doi:10.1017/
S1355617705050502.
13. Reisberg B, Ferris SH, Leon MJ, Crook T. The Global deterioration scale
(GDS) for assessment of primary degenerative dementia. Am J Psychiatry.
1982;139(9): 1136-39. doi:10.1176/ajp.139.9.1136.
14. Reiberg B. Functional Assessment Staging (FAST). Psychopharmacol Bull.
1988;24(4):653-59.
15. Saxton J, McGonigle-Gibson KL, Swihart AA, Miller VJ, Boller F.
Assessment of the severely impaired patient: description and validation of
a new neuropsychological test battery. Psychol Assess. 1990;2(3):298-303.
doi:10.1037/1040-3590.2.3.298.
16. Harrel LE, Marson D, Chatterjee A, Parrish JA. The Severe Mini-Mental
State Examination: a new neuropsychologic instrument for the bedside
assessment of severely impaired patients with Alzheimer disease.
Alzheimer Dis Assoc Disord. 2000;14(3):168-75. doi:10.1097/
00002093-200007000-00008.
17. Wajman JR, Bertolucci PHF: Comparison between neuropsychological
evaluation instruments for severe dementia. Arq Neuropsiquiatr.
2006;64(3b): 736-40. doi:10.1590/S0004-282X2006000500007.
18. Lyketsos CG, Steinberg M, Tschanz JT, Norton MC, Steffens DC,
Breitner JC. Mental and behavioral disturbances in dementia: findings
from the Cache County Study on Memory in Aging. Am J Psychiatry.
2000;157(5):708-14. doi:10.1176/appi.ajp.157.5.708.
19. Fossey J, Ballard C, Juszczak E, James I, Alder N, Jacoby R, Howard R.
Effect of enhanced psychosocial care on antipsychotic use in nursing
home residents with severe dementia: cluster randomised trial. Br Med J.
2006;332(7544):756-61. doi:10.1136/bmj.38782.575868.7C.
20. Selbaek G, Kirkevold Ø, Engedal K. The prevalence of psychiatric
symptoms and behavioural disturbances and the use of psychotropic drugs
in Norwegian nursing homes. Int J Geriatr Psychiatry. 2007;22(9),843-49.
doi:10.1002/gps.1749.
Brucki SMD, et al.   Management in severe dementia.   111
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):96-115
21. Siafarikas N, Selbaek G, Fladby T, Šaltyt BJ, Auning E, Aarsland D. Fre-
quency and subgroups of neuropsychiatric symptoms in mild cognitive
impairment and different stages of dementia in Alzheimer’s disease.
Int Psychogeriatr. 2018;30(1),103-13. doi:10.1017/S1041610217001879.
22. Cerejeira J, Lagarto L, Mukaetova-Ladinska EB. Behavioral and
psychological symptoms of dementia. Front Neurol. 2012;3(73):1-21.
doi:10.3389/fneur.2012.00073.
23. Toot S, Swinson T, Devine M, Challis D, Orrell M. Causes of nursing
home placement for older people with dementia: A systematic review
and meta-analysis. Int Psychogeriatr. 2017;29(2),195-208. doi:10.1017/
S1041610216001654.
24. Kamiya M, Sakurai T, Ogama N, Maki Y, Toba K. Factors associated with
increased caregivers’ burden in several cognitive stages of Alzheimer’s
disease. Geriatr Gerontol Int. 2014;14(52):45–55. doi:10.1111/ggi.12260.
25. Bränsvik V, Granvik E, Minthon L, Nordström P, Nägga K. Mortality in
patients with behavioural and psychological symptoms of dementia:
a registry-based study. Aging Ment Health. 2021;25(6):1101-9.
doi:10.1080/13607863.2020.1727848.
26. Brodaty H, Arasaratnam C. Meta-analysis of nonpharmacological
interventions for neuropsychiatric symptoms of dementia. Am J Psychiatry.
2012;169(9):946-53. doi:10.1176/appi.ajp.2012.11101529.
27. Fink HA, Linskens EJ, MacDonald R, Silverman PC, McCarten JR,
Talley KMC, et al. Benefits and Harms of Prescription Drugs and
Supplements for Treatment of Clinical Alzheimer-Type Dementia.
Ann Intern Med. 2020;172(10):656-68. doi:10.7326/M19-3887.
28. Kennedy RE, Cutter GR, Fowler ME, Schneider LS. Association of
Concomitant Use of Cholinesterase Inhibitors or Memantine With Cognitive
Decline in Alzheimer Clinical Trials: A Meta-analysis. JAMA Netw Open.
2018;1(7):1-10. doi:10.1001/jamanetworkopen.2018.4080.
29. Chen R, Chan PT, Chu H, Lin YC, Chang PC, Chen CY, Chou KR.
Treatment effects between monotherapy of donepezil versus combination
with memantine for Alzheimer disease: A meta-analysis. PLoS One.
2017;12(8):1-14. doi:10.1371/journal.pone.0183586.
30. Wang J, Yu JT, Wang HF, Meng XF, Wang C, Tan CC, Tan L.
Pharmacological treatment of neuropsychiatric symptoms in Alzheimer’s
disease: a systematic review and meta-analysis. J Neurol Neurosurg
Psychiatry. 2015;86(1):101-9. doi:10.1136/jnnp-2014-308112.
31. Trinh NH, Hoblyn J, Mohanty S, Yaffe K. Efficacy of cholinesterase inhibitors
in the treatment of neuropsychiatric symptoms and functional impairment
in Alzheimer disease: a meta-analysis. JAMA. 2003;289(2):210-6.
doi:10.1001/jama.289.2.210.
32. Porsteinsson AP, Drye LT, Pollock BG, Devanand DP, Frangakis C, Ismail Z,
et al. Effect of citalopram on agitation in Alzheimer disease: the CitAD
randomized clinical trial. JAMA. 2014;311(7):682-91. doi:10.1001/
jama.2014.93.
33. Henry G, Williamson D, Tampi RR. Efficacy and tolerability of
antidepressants in the treatment of behavioral and psychological
symptoms of dementia: a literature review of evidence. Am J Alzheimers
Dis Other Demen. 2011;26(3):169-83. doi:10.1177/1533317511402051.
34. Ehrhardt S, Porsteinsson AP, Munro CA, Rosenberg PB, Pollock BG,
Devanand DP, et al. Escitalopram for agitation in Alzheimer’s disease
(S-CitAD): Methods and design of an investigator-initiated, randomized,
controlled, multicenter clinical trial. Alzheimers Dement. 2019;15(11):1427-36.
doi:10.1016/j.jalz.2019.06.4946.
35. Kongpakwattana K, Sawangjit R, Tawankanjanachot I, Bell JS, Hilmer SN,
Chaiyakunapruk N. Pharmacological treatments for alleviating agitation
in dementia: a systematic review and network meta-analysis. Br J Clin
Pharmacol. 2018;84(7):1445-56. doi:10.1111/bcp.13604.
36. Yunusa I, Alsumali A, Garba AE, Regestein QR, Eguale T. Assessment of
Reported Comparative Effectiveness and Safety of Atypical Antipsychotics
in the Treatment of Behavioral and Psychological Symptoms of
Dementia: A Network Meta-analysis. JAMA Netw Open. 2019;2(3):1-14.
doi:10.1001/jamanetworkopen.2019.0828.
37. Ruthirakuhan MT, Herrmann N, Abraham EH, Chan S, Lanctôt KL.
Pharmacological interventions for apathy in Alzheimer’s disease. Cochrane
Database Syst Rev. 2018;5(5):CD012197. doi:10.1002/14651858.
CD012197.pub2.
38. Orgeta V, Tabet N, Nilforooshan R, Howard R. Efficacy of Antidepressants for
Depression in Alzheimer’s Disease: Systematic Review and Meta-Analysis.
J Alzheimers Dis. 2017;58(3):725-33. doi:10.3233/JAD-161247.
39. Cummings JL, Lyketsos CG, Peskind ER, Porsteinsson AP, Mintzer JE,
Scharre DW, et al. Effect of Dextromethorphan-Quinidine on Agitation in
Patients With Alzheimer Disease Dementia: A Randomized Clinical Trial.
JAMA. 2015;314(12):1242-54. doi:10.1001/jama.2015.10214.
112   Management in severe dementia.   Brucki SMD, et al.
40. Wang LY, Shofer JB, Rohde K, Hart KL, Hoff DJ, McFall YH, et al.
Prazosin for the treatment of behavioral symptoms in patients with
Alzheimer disease with agitation and aggression. Am J Geriatr Psychiatry.
2009;17(9):744-51. doi:10.1097/JGP.0b013e3181ab8c61.
41. Ballard C, Youakim JM, Coate B, Stankovic S. Pimavanserin in Alzheimer’s
Disease Psychosis: Efficacy in Patients with More Pronounced Psychotic
Symptoms. J Prev Alzheimers Dis. 2019;6(1):27-33. doi:10.14283/
jpad.2018.30.
42. Kales HC, Lyketsos CG, Miller EM, Ballard C. Management of behavioral
and psychological symptoms in people with Alzheimer’s disease:
an international Delphi consensus. Int Psychogeriatr. 2019;31(1):83-90.
doi:10.1017/S1041610218000534.
43. Bessey LJ, Walaszek A. Management of Behavioral and Psychological
Symptoms of Dementia. Curr Psychiatry Rep. 2019;21(8):66. doi:10.1007/
s11920-019-1049-5.
44. Reese TR, Thiel DJ, Cocker KE. Behavioral Disorders in Dementia:
Appropriate Nondrug Interventions and Antipsychotic Use. Am Fam
Physician. 2016;94(4):276-82.
45. Vellas B, Gauthier S, Allain H, Andrieu S, Aquino J-P, Berrut G, et al.
Consensus sur la démence de type Alzheimer au stade severe. Presse
Med 2005;34(20):1545-55. doi:10.1016/S0755-4982(05)84221-6.
46. Rongen S, Krammers C, O´mahony D, Feuth TB, Rikkert MGMO, Ahmed
AIA. Potentially inappropriate prescribing in older patients admitted
to psychiatric hospital. Int J Geriatr Psychiatry. 2016;31(2):137-45.
doi:10.1002/gps.4302.
47. McGilton KS, Rochon E, Sidani S, Shaw A, Ben-David BM, Saragosa M,
et al. Can we help care providers communicate more effectively with persons
having dementia living in long-term care homes? Am J Alzheimers Dis
Other Demen. 2017 Feb;32(1):41-50. doi:10.1177/1533317516680899.
48. Hickey JV. Neurological and Neurosurgical Nursing. 5th ed. Philadelphia:
Lippincott Williams & Wilkins, 2003: 1-816.
49. New hope for advancing neuropalliative care. Lancet Neurol.
2021;20(6):409. doi:10.1016/S1474-4422(21)00142-3.
50. Tsolaki M, Papaliagkas V, Anogeianakis G, Bernabei R, Emre M, Frolich L,
et al. Consensus statement on dementia education and training in Europe.
J Nutr Health Aging. 2010;14(2):131-35. doi:10.1007/s12603-009-0238-z.
51. Costa GD, Santos OG, Oliveira MAC. Knowledge, attitudes, and qualification
needs of primary health care professionals in the care of dementia. Rev Bras
Enferm. 2020;73(Suppl 3):1-9. doi:10.1590/0034-7167-2020-0330.
52. Keng A, Brown EE, Rostas A, Rajji TK, Pollock BG, Mulsant BH,
et al. Effectively Caring for Individuals with Behavioral and Psychological
Symptoms of Dementia During the Covid-19 Pandemic. Front Psychiatry.
2020;11:1-9. doi:10.3389/fpsyt.2020.573367.
53. Ferretti C, Nitrini R, Brucki SMD. Virtual Support in Dementia: A possible
viable strategy for caregivers. Front Neurol. 2021;12:1-7. doi:10.3389/
fneur.2021.662253.
54. Egan KJ, Pinto-Bruno AC, Bighelli I, Berg-Weger M, van Straten A,
Albanese E, et al. Online Training Support Programs Designed to Improve
Mental Health and Reduce Burden Among Caregivers of People With
Dementia: A Systematic Review. J Am Med Dir Assoc. 2018;19(3):200-6.
doi:10.1016/j.jamda.2017.10.023.
55. Reus VI, Forchtmann LJ, Eyler E, Hilty DM, Horvitz-Lennon M, Jibson MD,
et al. The American Psychiatric Association Practice Guideline on the Use
of Antipsychotics to Treat Agitation or Psychosis in Patients With Dementia.
Am J Psychiatry. 2016;173(5):543-6. doi: 10.1176/appi.ajp.2015.173501.
56. National Institute for Health and Care Excellence. Dementia: A NICE.
Suportting people with dementia and their carers.in health and social
care. Leicester (UK): British Psychological Society; 2012: 1-392.
57. International Psychogeriatric Association [Internet]. Milwalkee (WI): IPA;
2015 [citado 23 ago. 2022]. Disponível em: https://www.ipa-online.org/
58. American Geriatrics Society and American Association for Geriatric
Psychiatry. Consensus Statement on Improving the Quality of Mental
Health Care in U.S. Nursing homes: management of depression and
behavioral symptoms associated with dementia. J Am Geriatr Soc.
2003;51(9):1287-98. doi:10.1046/j.1532-5415.2003.51415.x.
59. American Medical Association, American Academy of Neurology
Institute and American Psychiatric Association. Dementia management
quality measurement set update [Internet]. Chicago (IL): American
Medical Association; 2018 [citado 23 ago. 2022]. Disponível em:
https://www.aan.com/siteassets/home-page/policy-and-guidelines/
quality/quality-measures/2018-dementia-management-measures.pdf
60. Ismail Z, Black SE, Camicioli R, Chertkow H, Herrmann N, Laforce R,
et al. Recommendations of the 5th Canadian Consensus Conference
on the diagnosis and treatment of dementia. Alzheimers Dement.
2020;16(8):1182-95. doi:10.1002/alz.12105.

61. Kales HC, Gitlin LN, Lyketsos CG. Assessment and management
of behavioral and psychological symptoms of dementia. Br Med J.
2015;350:1-16. doi:10.1136/bmj.h369.
62. Brodaty H, Arasaratnam C. Meta-Analysis of Non-Pharmacological
Interventions for Neuropsychiatric Symptoms of Dementia. Am J Psychiatry.
2012;169(9):946-53. doi:10.1176/appi.ajp.2012.11101529.
63. Livingston G, HuntleyJ, Sommerlad A, Ames D, Ballard C, Banerjee S,
et al. Dementia prevention, intervention, and care: 2020 report of
the Lancet Comission. Lancet. 2020;396:413-46. doi:10.1016/
S0140-6736(20)30367-6.
64. Caramelli P, Bottino CMC. Tratando os sintomas comportamentais e
psicológicos da demência (SCPD). Conferência Clínica. J Bras Psiquiatr.
2007;56(2):83-7. doi:10.1590/S0047-20852007000200002.
65. Eisenmann Y, Golla H, Schmidt H, Voltz R, Perrar KM. Palliative Care
in Advanced Dementia. Front Psychiatry. 2020;11:1-13. doi:10.3389/
fpsyt.2020.00699.
66. Ferretti CEL. Intervenções de Enfermagem nas Doenças Neurodegenerativas.
In: Koizume MS, Diccini S (orgs). Enfermagem em Neurociência:
Fundamentos para a prática clínica. São Paulo (SP): Atheneu; 2006: 1-672.
67. Bessey LJ, Walaszek A. Management of behavioral and psychological
symptoms of dementia. Curr Psychiatry Rep. 2019;21(8):66. doi:10.1007/
s11920-019-1049-5.
68. de Vugt ME, Stevens F, Aalten P, Lousberg R, Jaspers N, Winkens I,
et al. Do caregiver management strategies influence patient behavior?
Int J Geriatr Psychiatry. 2004;19(1):85-92. doi:10.1002/gps.1044.
69. Abreu W, Tolson D, Jackson GA, Staines H, Costa N. The relationship
between frailty, functional dependence, and healthcare needs among
community-dwelling people with moderate to severe dementia. Health
Soc Care Community. 2018;27(3):642-53. doi:10.1111/hsc.12678.
70. Aguero-Torres H, Fratiglioni L, Guo Z, Viitanen M, Winblad B. Prognostic
Factors in Very Old Demented Adults: A Seven-Year Follow-Up
From a Population-Based Survey in Stockholm. J Am Geriatr Soc.
1988;46(4):444-52. doi:10.1111/j.1532-5415.1998.tb02464.x.
71. Allen RS, Thorn BE, Fisher EF, Gerstle J, Quarles K, Bourgeois MS, et al.
Prescription and Dosage of Analgesic Medication in Relation to Resident
Behaviors in the Nursing Home. J Am Geriatr Soc. 2003;51(4):534-8.
doi:10.1046/j.1532-5415.2003.51164.x.
72. Bauer K, Schwarzkopf L, Graessel E, Holle R. A claims data-based
comparison of comorbidity in individual with and without dementia. BMC
Geriatrics. 2014;14(10):1-13. doi:10.1186/1471-2318-14-10.
73. Bynum JP, Rabins PV, Weller W, Niefeld M, Anderson GF, Wu AW.
The Relationship Between a Dementia Diagnosis, Chronic Ilness, Medical
Expenditures and Hospital use. J Am Geriatr Soc. 2004;52(2):187-94.
doi:10.1111/j.1532-5415.2004.52054.x.
74. Cintra, MTG, Rezende, NA; Torres, HOG. Advanced Dementia in a sample
of Brazilian elderly: Sociodemographic and morbidity analysis. Rev Assoc
Med Bras. 2016;62(8):735-41. doi:10.1590/1806-9282.62.08.735.
75. Doraiswamy PM, Leon J, Cummings J, Marin D, Neumann P. Prevalence
and Impact of Medical Comorbity in Alzheimer’s Disease. J Gerontol A Biol
Sci Med Sci. 2002;57(3):173-7. doi:10.1093/gerona/57.3.m173.
76. Downs M, Small N, Froggatt K. Person-centred Care for People with
Severe Dementia. In: Burns A, Winblad B (orgs). Severe Dementia.
New York: Wiley; 2007: 1-260.
77. Fiske J, Griffiths J, Jamieson R, Manger D. Guidelines for oral health care
for long-stay patients and residents. Gerodontology. 2008;17(1):55-64.
doi:10.1111/j.1741-2358.2000.00055.x.
78. Fulton AT, Rhodes-Kropf J, Corcoran AM, Chau D, Castillo EH. Palliative
Care for Patitents With Dementia in Long-Term Care. Clin Geriatr Med.
2011;27(2):153-70. doi:10.1016/j.cger.2011.01.002.
79. Gauthier S, Patterson C, Chertkow H, Gordon M, Herrmann N, Rockood
K, Rosa-Neto K, Soucy JP. 4th Canadian Consensus Conference
on the Diagnosis and Treatment of Dementia. Can J Neurol Sci.
2012;39(6Suppl5):1-8. doi:10.1017/s0317167100015183.
80. Herrera E, Caramelli P, Silveira ASB, Nitrini R. Epidemiologic survey of
Dementia in a community-dwelling Brazilian population. Alzheimer Dis Assoc
Disord. 2002; 16(2):103-8. doi:10.1097/00002093-200204000-00007.
81. Herrman N, Gauthier S Diagnosis and treatment of dementia: 6.
Management of severe Alzheimer disease. Can Med Am J.
2008;179(12):1279-87. doi:10.1503/cmaj.070804.
82. Hill JW, Futterman R, Duttagupta S, Mastey V, Lloyd JR, Fillit H. Alzheimer’s
disease and related dementias increase costs of comorbidities in managed
Medicare. Neurology. 2002;58(1):62-70. doi:10.1212/WNL.58.1.62.
83. Horgas AL, Elliott A, Marsiske M. Pain Assessment in Persons with
Dementia: Relationship between Self-report and Behavioral Observation.
J Am Geriatr Soc. 2009;57(1):126-32. doi:10.1111/j.1532-5415.2008.02071.x.
Dement Neuropsychol 2022 September;16(3 Suppl. 1):96-115
84. Husebo B, Ballard C, Sandvik R, Nilsen OB, Aarsland D. Efficacy of treating
pain to reduce behavioural disturbances in residents of nursing homes
with dementia: cluster randomised clinical trial. Br Med J, 2011;343:1-11.
doi:10.1136/bmj.d4065.
85. Hyland K, Fiske J, Matthews N. Nutritional and dental health management
in Parkinson’s disease. J Community Nurs. 2000;14(1):28-32.
86. James PA, Oparil S, Carter BL, William CC, Handler J, Lackland DT, et al.
Evidence-Based Guideline for the Management of High Blood Pressure in
Adults – Report From the Panel Members Appointed to the Eighth Joint
National Committee (JNC 8). JAMA. 2014;311(5):507-20. doi:10.1001/
jama.2013.284427.
87. Lee DS, Austin PC, Rouleau JL, Liu PP, Naimark D, Tu JV. Predicting
Mortality Among Hospitalized Patients for Heart Failure – derivation and
variation of a clinical model. JAMA. 2003;290(19):2581-87. doi:10.1001/
jama.290.19.2581.
88. Lyketsos CG, Colenda CC, Beck C, Blank K, Doraiswamy MP,
Kalunian DA, et al. Position Statement of the American Association
for Geriatric Psychiatry Regarding Principles of Care for Patients With
Dementia Resulting From Alzheimer Disease. Am J Geriatr Psychiatry.
2006;14(7):561-73. doi:10.1097/01.JGP.0000221334.65330.55.
89. McWillimas L, Farrell C, Grande G, Keady J, Swarbrick C, Yorke J.
A systematic review of the prevalence of comorbid cancer and dementia
and its implication for cancer-related care. Aging Ment Health.
2017;22(10):1254-71. doi:10.1080/13607863.2017.1348476.
90. Manchery N, Subbiah GK, Nagappan N, Premnath P. Are oral health
education for carers effective in the oral hygiene management of elderly
with dementia? A systematic review. Dent Res J. 2020;17(1):1-9.
91. Mitchell SL. Advanced Dementia. N Engl J Med. 2015;372:2533-40.
doi:10.1056/NEJMcp1412652.
92. Morrison RS, Siu AL. A comparison of pain and its treatment in advanced
dementia and cognitively intact patients with hip fracture. J Pain Symptom
Manag. 2000;19(4):240-8. doi:10.1016/S0885-3924(00)00113-5.
93. Reisberg B, Wegiel J, Franssen E, Kadiyala S, Auer S, Souren L,et al.
Clinical Features of Severe Dementia: Staging. In: Burns A, Winblad B
(orgs). Severe Dementia. Hoboken: John Wiley & Sons Ltd, 2006: 1-260.
94. Schubert CC, Bustani M, Callahan CM, Perkins AJ, Carney CP,
Fox C, et al. Comorbidity Profile of Dementia Patients in Primary Care:
Are They Sicker? J Am Geriatr Soc. 2006;54(1):104-9. doi:10.1111/
j.1532-5415.2005.00543.x.
95. Sloan, FA, Trogdon JG, Curtis LH, Schulman KA. The Effect of Dementia
on Outcomes and Process of Care for Medicare Beneficiaries Admitted
with Acute Myocardial Infarction. J Am Geriatr Soc. 2004;52(2):173-81.
doi:10.1111/j.1532-5415.2004.52052.x.
96. Surr C, Griffiths AW, Kelley R, Ashley L, Cowdell F, Henry A, et al.
Navigating cancer treatment and care when living with comorbid dementia:
an ethnographic study. Support Care Cancer. 2021;29:2571-79.
doi:10.1007/s00520-020-05735-z.
97. Terpenning MS, Taylor GW, Lopatin DE, Kerr CK, Dominguez BL,
Loesche WJ. Aspiration pneumonia: dental and oral risk factors in an older
veteran population. J Am Geriatr Soc. 2001;49(5):557-89. doi:10.1046/
j.1532-5415.2001.49113.x.
98. Fiske J, Frenkel H, Griffiths J, Jones V; British Society of Gerodontology;
British Society for Disability and Oral Health. Guidelines for the
development of local standards of oral health care for people with
dementia. Gerodontology. 2006;23 Suppl 1:3-32. doi:10.1111/
j.1741-2358.2006.00140.x.
99. van Dijk PTM, Dippell DWJ, Meulen JHP, Habbema JDF. Comorbidity and
Its Effects on Mortality in Nursing Home Patients with Dementia. J Nerv
Ment Dis. 1996;184(3):180-7. doi:10.1097/00005053-199603000-00007.
100. Volicer L, McKee A, Hewitt S. Dementia. Neurol Clin. 2001;19(4):867-85.
doi:10.1016/S0733-8619(05)70051-7.
101. Warden V, Hurley AC, Volicer L. Development and Psychometric Evaluation
of the Pain Assessment in Advanced Dementia (PAINAD). Scale J Am Med
Dir Assoc. 2003;4:9-15. doi:10.1097/01.JAM.0000043422.31640.F7.
102. Wolf-Klein GP, Silverstone F, Brod MS, Levy A, Foley CJ, Termotto V, Breuer
J. Are Alzheimer Patients Healthier? J Am Geriatr Soc. 1988;36(3):219-24.
doi:10.1111/j.1532-5415.1988.tb01804.x.
103. Xue QI. The Frailty Syndrome: Definition and Natural History. Clin Geriatr
Med. 2011;27(1):1-15. doi:10.1016/j.cger.2010.08.009.
104. Zhu CW, Consentino S, Ornstein KA, Gu Y, Andrews H, Stern Y. Interactive
Effect of Dementia Severity and Comorbidities on Medical Expenditures.
J Alzheimers Dis. 2017;57(1):301-15. doi:10.3233/JAD-161077.
105. White H, Pieper C, Schmader K. The association of weight change
in Alzheimer’s disease with severity of disease and mortality:
A longitudinal analysis. J Americ Geriatr Soc. 1998;46(10):1223-7.
doi:10.1111/j.1532-5415.1998.tb04537.x.
Brucki SMD, et al.   Management in severe dementia.   113
 Dement Neuropsychol 2022 September;16(3 Suppl. 1):96-115
106. Hanson LC, Ersek M, Lin FC, Carey TS. Outcomes of feeding problems
in advanced dementia in a nursing home population. J Am Geriatr Soc.
2013;61(10):1692–7. doi:10.1111/jgs.12448.
107. Rubenstein LZ, Harker JO, Salvà A, Guigoz Y, Vellas B. Screening
for undernutrition in geriatric practice: Developing the short-form
mini-nutritional assessment (MNA-SF). J Geront Series A Biolog Sci
Med Sci. 2001;56(6):M366-72. doi:10.1093/gerona/56.6.m366.
108. Stratton RJ, Hackston A, Longmore D, Dixon R, Price S, Stroud M, et al.
Malnutrition in hospital outpatients and inpatients: Prevalence, concurrent
validity and ease of use of the “malnutrition universal screening tool”
(‘MUST’) for adults. British J Nut. 2004;92(5):799–808. doi:10.1079/
bjn20041258.
109. Volkert D, Chourdakis M, Faxen-Irving G, Frühwald T, Landi F,
Suominen, et al. ESPEN guidelines on nutrition in dementia. Clin Nutr.
2015;34(6):1052–73. doi:10.1016/j.clnu.2015.09.004.
110. Herke M, Fink A, Langer G, Wustmann T, Watzke S, Hanff AM, et al.
Environmental and behavioural modifications for improving food and
fluid intake in people with dementia. Cochrane Database Syst Rev.
2018;7(7):CD011542. doi:10.1002/14651858.CD011542.pub2.
111. Liu W, Cheon J, Thomas SA. Interventions on mealtime difficulties in
older adults with dementia: A systematic review. Int J Nurs Studies.
2014;51(1):14–27. doi:10.1016/j.ijnurstu.2012.12.021.
112. Abdelhamid A, Bunn D, Copley M, Cowap V, Dickinson A, Gray L, et al.
Effectiveness of interventions to directly support food and drink intake
in people with dementia: Systematic review and meta-analysis. BMC
Geriatrics. 2016;16(1):26. doi:10.1186/s12877-016-0196-3.
113. Prince M, Albanese E, Guerchet M, Prina M. Nutrition and dementia:
A review of available research. Chertsey: Compass group, 2014.
114. Espinosa-Val MC, Martín-Martínez A, Graupera M, Arias O,
Elvira A, Cabré M, et al. Prevalence, Risk Factors, and Complications
of Oropharyngeal Dysphagia in Older Patients with Dementia. Nutrients.
2020;12(3):1-15. doi:10.3390/nu12030863.
115. Özsürekci C, Arslan SS, Demir N, Çalı kan H, engül Ayçiçek G, Kılınç HE,
et al. Timing of Dysphagia Screening in Alzheimer’s Dementia. J Parenter
Enteral Nutr. 2020;44(3):516–24. doi:10.1002/jpen.1664.
116. Alagiakrishnan K, Bhanji RA, Kurian M. Evaluation and management of
oropharyngeal dysphagia in different types of dementia: A systematic
review. Archives Gerontology Geriatrics. 2013;56(1):1–9. doi:10.1016/
j.archger.2012.04.011.
117. Boccardi, V., Ruggiero, C., Patriti, A., Marano, L. Diagnostic Assessment
and Management of Dysphagia in Patients with Alzheimer’s Disease.
J Alzheimers Dis. 2016;50(4):947–55. doi:10.3233/JAD-150931.
118. Egan A, Andrews C, Lowit A. Dysphagia and mealtime difficulties
in dementia: Speech and language therapists’ practices and perspectives.
Int J Lang Commun Disord. 2020;55(5):777–92. doi:10.1111/
1460-6984.12563.
119. Flynn E, Smith CH, Walsh CD, Walshe M. Modifying the consistency of food
and fluids for swallowing difficulties in dementia. Cochrane Database System
Rev. 2018;9(9):CD011077. doi:10.1002/14651858.CD011077.pub2.
120. Robbins J, Gensler G, Hind J, Logemann JA, Lindblad AS, Brandt D,
et al. Comparison of 2 interventions for liquid aspiration on pneumonia
incidence: A randomized trial. Ann Intern Med. 2008;148(7):509-18.
doi:10.7326/0003-4819-148-7-200804010-00007.
121. Saconato, M., Chiari, B. M., Lederman, H. M., Gonçalves, M. I. R.
Effectiveness of Chin-tuck Maneuver to Facilitate Swallowing in
Neurologic Dysphagia. Int Arch Otorhinolaryngol. 2016;20(1):13–7.
doi:10.1055/s-0035-1564721.
122. Ijaopo EO, Ijaopo RO. Tube feeding in individuals with advanced
dementia: a review of its burdens and perceived benefits. J Aging Res.
2019:7272067. doi:10.1155/2019/7272067.
123. Orlandoni P, Jukic Peladic N, Cherubini A. Enteral nutrition in advanced
dementia: An unresolved dilemma in clinical practice. Eur Geriatr Med.
2020;11(2):191–4. doi:10.1007/s41999-020-00292-4.
124. Murphy LM, Lipman TO. Percutaneous endoscopic gastrostomy
does not prolong survival in patients with dementia. Arch Intern Med.
2003;163(11):1351–3. doi:10.1001/archinte.163.11.1351.
125. Ribeiro Salomon, AL, Novaes MR. Outcomes of enteral nutrition for
patients with advanced dementia: A systematic review. J Nutr Health
Aging. 2015;19(2):169–77. doi:10.1007/s12603-014-0517-1.
126. Sanders, DS, Carter MJ, D’Silva J, James G, Bolton RP, Bardhan KD.
Survival analysis in percutaneous endoscopic gastrostomy feeding:
A worse outcome in patients with dementia. Am J Gastroenterol.
2000;95(6):1472-5. doi:10.1111/j.1572-0241.2000.02079.x.
114   Management in severe dementia.   Brucki SMD, et al.
127. Pasman HRW, Onwuteaka-Philipsen BD, Kriegsman DMW, Ooms ME,
Ribbe MW, van der Wal G. Discomfort in nursing home patients with severe
dementia in whom artificial nutrition and hydration is forgone. Arch Intern
Med. 2005;165(15):1729-35. doi:10.1001/archinte.165.15.1729.
128. Givens JL, Selby K, Goldfeld KS, Mitchell SL. Hospital transfers of
nursing home residents with advanced dementia. J Am Geriatr Soc.
2012;60(5):905-9. doi:10.1111/j.1532-5415.2012.03919.x.
129. Cintra MTG, Rezende NA, Torres HO, Cintra MTG, Rezende NA, Torres OG.
Advanced dementia in a sample of Brazilian elderly: Sociodemographic
and morbidity analysis. Rev Assoc Méd Bras. 2016;62(8):735-41.
doi:10.1590/1806-9282.62.08.735.
130. Teno JM, Gozalo P, Mitchell SL, Kuo S, Fulton AT, Mor V. Feeding Tubes
and the Prevention or Healing of Pressure Ulcers. Arch Intern Med.
2012;172(9):697–701. doi:10.1001/archinternmed.2012.1200.
131. Teno JM, Mitchell SL, Kuo SK, Gozalo PL, Rhodes RL, Lima JC,
et al. Decision-making and outcomes of feeding tube insertion:
A five-state study. J Am Geriatr Soc. 2011;59(5):881–6. doi:10.1111/
j.1532-5415.2011.03385.x.
132. Goldberg LS, Altman KW. The role of gastrostomy tube placement in
advanced dementia with dysphagia: A critical review. Clin Interv Aging.
2014;9:1733-9. doi:10.2147/CIA.S53153.
133. Palecek EJ, Teno JM, Casarett DJ, Hanson LC, Rhodes RL, Mitchell SL.
Comfort Feeding Only: A Proposal to Bring Clarity to Decision-Making
Regarding Difficulty with Eating for Persons with Advanced Dementia. J Am
Geriatr Soc. 2010;58(3):580–4. doi:10.1111/j.1532-5415.2010.02740.x.
134. Azevedo LVDS, Calandri IL, Slachevsky A, Graviotto HG, Vieira MCS,
Andrade CB, et al. Impact of Social Isolation on People with Dementia
and Their Family Caregivers. J Alzheimers Dis. 2021;81(2):607-17.
doi:10.3233/JAD-201580.
135. Bamford C, Lee R, McLellan E, Poole M, Harrison-Dening K, Hughes J,
et al. What enables good end of life care for people with dementia?
A multi-method qualitative study with key stakeholders. BMC Geriatr.
2018;18(1):302. doi:10.1186/s12877-018-0983-0.
136. Borelli WV, Augustin MC, Oliveira PBF, Reggiani LC, Bandeira-de-Mello RG,
Schumacher-Schuh AF, et al. Neuropsychiatric Symptoms in Patients with
Dementia Associated with Increased Psychological Distress in Caregivers
During the COVID-19 Pandemic. J Alzheimers Dis. 2021;80(4):1705-12.
doi:10.3233/JAD-201513.
137. Cintra MT, Rezende NA, Torres HO. Advanced dementia in a sample of
Brazilian elderly: Sociodemographic and morbidity analysis. Rev Assoc
Méd Bras. 2016;62(8):735-41. doi:10.1590/1806-9282.62.08.735.
138. Citko J, Moss AH, Carley M, Tolle S. The National POLST Paradigm
Initiative. J Palliat Med. 2011;14(2):241-2. doi:10.1089/jpm.2010.9730.
139. Dezorzi LW, Raymundo MM, Goldim JR, Oliveira CAV. Spirituality in
the continuing education of healthcare professionals: An approach to
palliative care. Palliat Support Care. 2019;17(6):662-7. doi: 10.1017/
S1478951519000117.
140. Durgante H, Contreras ML, Backhouse T, Mavrodaris A, Ferreira MG,
Paulo DLV, et al. Challenges in dementia care: comparing key issues from
Brazil and the United Kingdom. Dement Neuropsychol, 2020;14(3):216-22.
doi:10.1590/1980-57642020dn14-030003.
141. Harzheim E, Gonçalves MR, Umpierre RN, Silva Siqueira AC, Katz N,
Agostinho MR, et al. Telehealth in Rio Grande do Sul, Brazil: Bridging the
Gaps. Telemed E-Health. 2016;22(11):938-44. doi:10.1089/tmj.2015.0210.
142. Hickman SE, Keevern E, Hammes BJ. Use of the physician orders for life-
sustaining treatment program in the clinical setting: a systematic review of
the literature. J Am Geriatr Soc. 2015;63(2):341-50. doi:10.1111/jgs.13248.
143. Marcucci FCI, Cabrera MAS, Perilla AB, Brun MM, Barros, EML,
Martins VM, Rosenberg JP, Yates P. Identification and characteristics of
patients with palliative care needs in Brazilian primary care. BMC Palliative
Care. 2016;15(1), 1-10. doi:10.1186/s12904-016-0125-4.
144. Nakamura AE, Opaleye D, Tani G, Ferri CP. Dementia underdiagnosis in
Brazil. Lancet, 2015;385(9966):418-9. doi:10.1016/S0140-6736(15)60153-2.
145. Nitrini R, Barbosa MT, Brucki SMD, Yassuda MS, Caramelli P. Current
trends and challenges on dementia management and research in Latin
America. J Global Health, 2020;10(1):1-10. doi:10.7189/jogh.10.010362.
146. Sampson EL, Candy B, Davis S, Gola AB, Harrington J, King M,et al.
Living and dying with advanced dementia: A prospective cohort study
of symptoms, service use and care at the end of life. Palliat Med,
2017;32(3):668-81. doi:10.1177/0269216317726443.
147. Schafirovits-Morillo L, Suemoto CK. Severe dementia: A review on diagnoses,
therapeutic management and ethical issues. Dement Neuropsychol,
2010;4(3):158-64. doi:10.1590/S1980-57642010DN40300003.

148. Viana BM, Bicalho MAC, Moraes EN, Romano-Silva MA. Twenty-four-year
demographic trends of a Brazilian long-term care institution for the
aged. J Am Med Dir Assoc. 2015;16(2):174.e1-6. doi:10.1016/
j.jamda.2014.11.012.
149. Wittmann-Vieira R, Goldim JR. Bioética e cuidados paliativos: tomada
de decisões e qualidade de vida. Acta Paul Enferm. 2012;25(3):334–9.
doi:10.1590/S0103-21002012000300003.
150. Low JA, Ho E. Managing ethical dilemmas in end-stage neurodegenerative
diseases. Geriatrics. 2017;2(1):1-7. doi:10.3390/geriatrics2010008.
151. Passmore MJ, Ho A, Gallagher R. Behavioral and psychological symptoms
in moderate to severe Alzheimer’s disease: a palliative care approach
emphasizing recognition of personhood and preservation of dignity.
J Alzheimers Dis. 2012;29(1):1-13. doi:10.3233/JAD-2012-111424.
152. Piers R, Albers G, Gilissen J, De Lepeleire J, Steyaert J, van Mechelen W,
et al. Advance care planning in dementia: recommendations for heal-
thcare professionals. BMC Palliat Care. 2018;17(1):88. doi:10.1186/
s12904-018-0332-2.
Dement Neuropsychol 2022 September;16(3 Suppl. 1):96-115
153. Cipriani G, Di Fiorino M. Euthanasia and other end of life in patients
suffering from dementia. Leg Med. 2019;40:54-9. doi:10.1016/
j.legalmed.2019.07.007.
154. Congedo M, Causarano R, Alberti F, Bonito V, Borghi L, Colombi L,
et al. Ethical issues in end of life treatments for patients with dementia.
Eur J Neurol. 2010;17:774-9. doi:10.1111/j.1468-1331.2010.02991.x.
155. Fontaneda AJD, Sainz MIL. Problemas éticos y legales en la demência
severa. El derecho a morir en paz. Rev Esp Ger Gerontol. 2009;44(2):43-
7. doi:10.1016/j.regg.2009.06.011.
156. Allen W. Medical ethics issues in dementia and end of life. Curr Psychiatry
Rep. 2020;22(6):31. doi:10.1007/s11920-020-01150-7.
157. Bello DVME, Schultz RR. Dementia and legal determination of capacity. Arq
Neuro-Psiquiatr. 2017;75(6):349-53. doi:10.1590/0004-282X20170061.
158. Toh HJ, Low JA, Lim ZY, Lim Y, Siddiqui S, Tan L. Jonsen’s four topics
approach as a framework for clinical ethics consultation. Asian Bioeth.
2018;10(1):37-51. doi:10.1007/s41649-018-0047-y.
Brucki SMD, et al.   Management in severe dementia.   115