NDT Oct 2023 Final

APPROACH TO EVALUATION
AND MANAGEMENT OF
DEMENTIA
PRESENTER: LIM KIM SAN
SUPERVISOR: DR ALVIN TAN
KAHOOT!
4911414
CONTENT
• Alzheimer’s Disease
• Vascular Dementia
• Dementia with Lewy Bodies
• Frontotemporal Lobe Dementia
Source: https://www.singhealth.com.sg/news/defining-med/Young-Onset-Dementia
ALZHEIMER’S DISEASE (AD)
ALZHEIMER’S DISEASE - PATHOGENESIS
1. Acetylcholine hypothesis
2. Aβ oligomer hypothesis
3. Tau hypothesis
ALZHEIMER’S DISEASE
- PATHOGENESIS
1. Acetylcholine hypothesis: Loss of
cholinergic neurons and
neurotransmission causes AD 1
2. Aβ oligomer hypothesis: Fibril-free
synthetic preparations of AβOs are
potent CNS neurotoxins that caused
selective nerve cell death 2,3
3. Tau hypothesis: Abnormal
phosphorylation of tau proteins is in Figure 1. The nucleus basalis of Meynert and its innervations
the background of AD progress 4 Source: Echeverry, Marcela & Guerrero, Sonia & Silva, Joao & Almeida, Maria &
Carrettiero, Daniel. (2018). Differences and Implications of Animal Models for the Study
of Alzheimer's Disease. 10.2174/9781681087153118020004.
1
Francis, P.T.; Palmer, A.M.; Snape, M.; Wilcock, G.K. The cholinergic hypothesis of Alzheimer’s disease: A review of progress. J. Neurol. Neurosurg. Psychiatry 1999, 66, 137–147.
2
Lambert, M.P.; Barlow, A.K.; Chromy, B.A.; Edwards, C.; Freed, R.; Liosatos, M.; Morgan, T.E.; Rozovsky, I.; Trommer, B.; Viola, K.L.; et al. Diffusible, nonfibrillar ligands derived from A 1-42 are potent central nervous system neurotoxins. Proc. Natl.
Acad. Sci. 1998, 95, 6448–6453.
3 Hardy, J.; Allsop, D. Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol. Sci. 1991, 12, 383–388.
4 Grundke-Iqbal, I.; Iqbal, K.; Tung, Y.C.; Quinlan, M.; Wisniewski, H.M.; Binder, L.I. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc. Natl. Acad. Sci. 1986, 83, 4913–4917.
- PATHOGENESIS
phosphorylation of tau proteins is in
the background of AD progress 4 Figure 2. Structural assemblies of Aβ peptides. AβO: Aβ oligomer.
Source: The β-secretase BACE1 in Alzheimer’s disease. Biol Psychiatry.
2021;89:745–56
1
2
Acad. Sci. 1998, 95, 6448–6453.
- PATHOGENESIS
the background of AD progress 4 Figure 3. Pathophysiological effects of Aβ oligomers.
Source: Oligomerization and conformational change turn monomeric β-amyloid and tau proteins toxic: Their
role in alzheimer’s pathogenesis. Molecules, 25(7), 1659. https://doi.org/10.3390/molecules25071659
1
2
Acad. Sci. 1998, 95, 6448–6453.
- PATHOGENESIS
Figure 4. Tau protein - In pathological condition
the background of AD progress 4 Source: Pathogenic Tau Protein Species: Promising Therapeutic Targets for Ocular
Neurodegenerative Diseases. Journal of Ophthalmic & Vision Research. 14. 491-505.
10.18502/jovr.v14i4.5459.
1
2
Acad. Sci. 1998, 95, 6448–6453.
Figure 5. Tau and B-amyloid aggregation and neurotoxicity
Source: Panza, Francesco & Lozupone, Madia & Seripa, Davide & Imbimbo,
Bruno. (2019). Amyloid-β Immunotherapy for Alzheimer's Disease – Is It Now A
Long Short? Annals of Neurology. 85. 303-315. 10.1002/ana.25410.
Acetylcholine Optimise acetylcholine

levels in the brain
Hypothesis neuronal circuit
Remove
Aβ oligomer Prove presence of Aβ
amyloid
oligomers in cerebral
hypothesis parenchyma
plagues/
oligomers
Tau Prove presence of Remove

phosphorylated tau in neurofibrillary
hypothesis cerebral parenchyma tangles
DIAGNOSTIC CRITERIA – NIA-AA 2018
A T N
Aggregated Aβ or associated Aggregated tau (neurofibrillary Neurodegeneration or
pathologic state tangles) or associated neuronal injury
pathologic state
• CSF Aβ42, or Aβ42/Aβ40 ratio • CSF phosphorylated tau (P- • Anatomic MRI
• Amyloid PET tau) • FDG PET
• Tau PET • CSF total tau (T-tau)
Table 1. AT(N) biomarker grouping

Source: Jack, C. R., Bennett, D. A., Blennow, K., Carrillo, M. C., Feldman, H. H.,
Frisoni, G. B., ... & Dubois, B. (2016). A/T/N: An unbiased descriptive classification
scheme for Alzheimer disease biomarkers. Neurology, 87(5), 539-547.
NIA-AA
DIAGNOSTIC
CRITERIA 2023
– DISCUSSED AT
AAIC 2023
Source: https://aaic.alz.org/downloads2023/NIA-AA-Revised-Clinical-Criteria-Figures-and-Tables-AAIC-2023.pdf
NIA-AA
DIAGNOSTIC
CRITERIA 2023
– DISCUSSED AT
AAIC 2023
Source: https://aaic.alz.org/downloads2023/NIA-AA-Revised-Clinical-Criteria-Figures-and-Tables-AAIC-2023.pdf
GOALS OF INVESTIGATIONS
1. Prove presence of Aβ oligomers or hyperphosphorylated tau:

• Brain biopsy
• Lumbar puncture with cerebrospinal (CSF) sampling
• PET scan
• Serum blood tests
2. Show evidence of neurodegeneration or neuronal injury
3. Assess for other concomitant pathologies
Source: The NINCDS-ADRDA Work Group criteria for the clinical diagnosis of probable
Alzheimer's disease, 1988
QUESTION 1
Figure 6. Hallmark pathology of Alzheimer's disease.

Source: Kumfor, Fiona & Halliday, Glenda & Piguet, Olivier. (2017). Clinical Aspects of
Alzheimer’s Disease. 10.1007/978-3-319-57193-5_2.
HISTOLOGY
Figure 7. Tau pathology in relation to other pathological features in Figure 8. Neurofibrillary tangle maturity level and neuritic morphologies in the CA1
Alzheimer's disease subsector of the hippocampus.
Source: Saint-Aubert, Laure & Lemoine, Laetitia & Chiotis, Konstantinos Source: Moloney, C. M., Lowe, V. J., & Murray, M. E. (2021). Visualization of
& Leuzy, Antoine & Rodriguez-Vieitez, Elena & Nordberg, Agneta. neurofibrillary tangle maturity in alzheimer’s disease: A clinicopathologic perspective
(2017). Tau PET imaging: present and future directions. Molecular for Biomarker Research. Alzheimer’s & Dementia, 17(9), 1554–1574.
Neurodegeneration. 12. 10.1186/s13024-017-0162-3. https://doi.org/10.1002/alz.12321
BIOMARKERS
• Cognitively unimpaired individuals with abnormal amyloid biomarkers

(evidence of Aβ deposition) have more rapid progression of atrophy,
hypometabolism, and clinical/cognitive decline 1,2
• The first biomarkers to become abnormal in carriers of deterministic AD
mutations are those of Aβ 3
1 Villemagne, V. L., Pike, K. E., Chételat, G., Ellis, K. A., Mulligan, R. S., Bourgeat, P., ... & Rowe, C. C. (2011). Longitudinal assessment of Aβ and cognition in aging and Alzheimer disease. Annals of neurology, 69(1), 181-192.
2 A.C. van Harten, L.L. Smits, C.E. Teunissen, P.J. Visser, T. Koene, M.A.Blankenstein, et al. Preclinical AD predicts decline in memory and executive functions in subjective complaints. Neurology, 81 (2013), pp. 1409-1416
3
R.J. Bateman, C. Xiong, T.L. Benzinger, A.M. Fagan, A. Goate, N.C. Fox, et al. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med, 367 (2012), pp. 795-804
CSF VS IMAGING
• CSF biomarkers
• Measures concentrations of proteins in CSF from the lumbar sac
• Reflect the rates of both production and clearance at a given point in time 1
• Ie Provides information about rate of amyloid plaque formation
• Imaging measures
• Represent the magnitude of the neuropathologic load or damage accumulated over time
• There may be disconcordance in both 2
• Eg. P-tau seems to plateau later in the disease 3 while the tau PET signal continues to
increase4
1
K. Blennow, H. Hampel. CSF markers for incipient Alzheimer's disease. Lancet Neurol, 2 (2003), pp. 605-613
2
S.J. Vos, B.A. Gordon, Y. Su, P.J. Visser, D.M. Holtzman, J.C. Morris, et al. NIA-AA staging of preclinical Alzheimer disease: discordance and concordance of CSF and imaging biomarkers. Neurobiol Aging, 44 (2016), pp. 1-8
3 A.M. Fagan, C. Xiong, M.S. Jasielec, R.J. Bateman, A.M. Goate, T.L.Benzinger, et al. Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer's disease. Sci Transl Med, 6 (2014), p. 226ra30
4 N. Mattsson, M. Scholl, O. Strandberg, R. Smith, S. Palmqvist, P.S. Insel, et al. 18F-AV-1451 and CSF T-tau and P-tau as biomarkers in Alzheimer's disease. EMBO Mol Med, 9 (2017), pp. 1212-1223
CSF
• CSF Aβ42, or Aβ42/Aβ40 ratio

• CSF Total tau (T-tau)
• CSF Phosphorylated tau (P-tau)
CSF AMYLOID: AΒ42 VS AΒ42/AΒ40 RATIO
• Aβn = Amyloid beta with n amino acids
• CSF Aβ40 is a reflection of total CSF amyloid levels
• Aβ42 is the predominant component in parenchymal plaques 1
• A decrease in CSF Aβ42 is characteristic of AD

• There is significant inter-subject variability in Aβ42 levels and definition of cut-
off for AD pathology is problematic 2
1 Gravina, S. A., Ho, L., Eckman, C. B., Long, K. E., Otvos, L., Jr, Younkin, L. H., Suzuki, N., & Younkin, S. G. (1995). Amyloid beta protein (A beta) in Alzheimer's disease brain. Biochemical and immunocytochemical analysis with antibodies specific for forms
ending at A beta 40 or A beta 42(43). The Journal of biological chemistry, 270(13), 7013–7016. https://doi.org/10.1074/jbc.270.13.7013
2
Hansson O., Lehmann S., Otto M., Zetterberg H., Lewczuk P. Advantages and disadvantages of the use of the CSF Amyloid beta (Abeta) 42/40 ratio in the diagnosis of Alzheimer’s Disease. Alzheimer’s Res. Ther. 2019;11:34. doi: 10.1186/s13195-019-0485-0
CSF AMYLOID: AΒ42 VS AΒ42/AΒ40 RATIO
• CSF Aβ42/40 ratio
• Reduced biases linked to pre-analytical or analytical factors 1
• Improved diagnostic performance especially in discordant cases 2
• Better concordance with PET amyloid imaging, compared to Aβ42 alone 3
• Aβ42 is usually present at a concentration ~10% that of Aβ40 4
1 Nutu M., Zetterberg H., Londos E., Minthon L., Nagga K., Blennow K., et al. (2013). Evaluation of the cerebrospinal fluid amyloid-beta1-42/amyloid-beta1-40 ratio measured by alpha-LISA to distinguish Alzheimer’s disease from other dementia
disorders. Dement. Geriatr. Cogn. Disord. 36 99–110. 10.1159/000353442
2
Dumurgier J., Schraen S., Gabelle A., Vercruysse O., Bombois S., Laplanche J. L., et al. (2015). Cerebrospinal fluid amyloid-beta 42/40 ratio in clinical setting of memory centers: a multicentric study. Alzheimers Res. Ther. 7:30.
3
Janelidze S., Zetterberg H., Mattsson N., Palmqvist S., Vanderstichele H., Lindberg O., et al. (2016). CSF Abeta42/Abeta40 and Abeta42/Abeta38 ratios: better diagnostic markers of Alzheimer disease. Ann. Clin. Transl. Neurol.3 154–165. 10.1002/acn3.274
4
Bitan, G., Kirkitadze, M. D., Lomakin, A., Vollers, S. S., Benedek, G. B., & Teplow, D. B. (2003). Amyloid beta -protein (Abeta) assembly: Abeta 40 and Abeta 42 oligomerize through distinct pathways. Proceedings of the National Academy of Sciences of the
United States of America, 100(1), 330–335. https://doi.org/10.1073/pnas.222681699
CSF TAU: T-TAU VS P-TAU
• T-tau is less specific than P-tau for AD

• T-tau is also increased in traumatic brain injury, stroke 1 and Creutzfeldt-
Jakob disease 2
• The only disorder that consistently shows an increase in CSF P-tau is AD 3
1
C. Hesse, L. Rosengren, N. Andreasen, P. Davidsson, H. Vanderstichele, E. Vanmechelen, et al. Transient increase in total tau but not phospho-tau in human cerebrospinal fluid after acute stroke. Neurosci Lett, 297 (2001), pp. 187-190
2
T. Skillback, C. Rosen, F. Asztely, N. Mattsson, K. Blennow, H. Zetterberg, Diagnostic performance of cerebrospinal fluid total tau and phosphorylated tau in Creutzfeldt-Jakob disease: results from the Swedish Mortality Registry, JAMA
Neurol, 71 (2014), pp. 476-483
3 B. Olsson, R. Lautner, U. Andreasson, A. Ohrfelt, E. Portelius, M. Bjerke, et al. CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis, Lancet Neurol, 15 (2016), pp. 673-684
IMAGING
AMYLOID PET
• Uses ligand Florbetapir
• 70%–90% of patients meeting the
clinical criteria for AD have positive
amyloid PET results 1
• Prevalence of amyloid positivity
decreases with age in patients
with probable AD 2 Figure 9. Comparison of Amyloid PET images for cognitively normal individuals
vs individuals with Alzheimer’s disease
Source: https://jnm.snmjournals.org/content/jnumed/63/Supplement_1/13S/
F1.large.jpg?width=800&height=600&carousel=1
1 Rabinovici, G. D., Gatsonis, C., Apgar, C., Chaudhary, K., Gareen, I., Hanna, L., ... & Carrillo, M. C. (2019). Association of amyloid positron emission tomography with subsequent change in clinical management among medicare beneficiaries with
mild cognitive impairment or dementia. Jama, 321(13), 1286-1294
2 Ossenkoppele, R., Jansen, W. J., Rabinovici, G. D., Knol, D. L., van der Flier, W. M., van Berckel, B. N., Scheltens, P., Visser, P. J., Amyloid PET Study Group, Verfaillie, S. C., Zwan, M. D., Adriaanse, S. M., Lammertsma, A. A., Barkhof, F., Jagust, W.
J., Miller, B. L., Rosen, H. J., Landau, S. M., Villemagne, V. L., Rowe, C. C., … Brooks, D. J. (2015). Prevalence of amyloid PET positivity in dementia syndromes: a meta-analysis. JAMA, 313(19), 1939–1949. https://doi.org/10.1001/jama.2015.4669
AMYLOID PET
• Caveats:
• Amyloid PET ligands do not
bind to soluble Aβ oligomers
• Positive in cerebral amyloid
angiopathy (CAA)
Figure 9. Comparison of Amyloid PET images for cognitively normal individuals

vs individuals with Alzheimer’s disease
Source: https://jnm.snmjournals.org/content/jnumed/63/Supplement_1/13S/
F1.large.jpg?width=800&height=600&carousel=1
TAU PET
• Uses ligand flortaucipir
• Specific binding to paired
helical filaments tangles 1
• Binds weakly to sole 4R or
3R tau deposits in primary
tauopathies 2
• Does not bind to amyloid
plaques, α-synuclein and
other biomarkers 3
Figure 10. Tau PET images for patients with AD, CBD, PSP and Control
Source: http://biofinder.se/wp-content/uploads/2013/12/Figur-till-BioFINDER.jpg
1 Ikonomovic M, Abrahamson E, Kofler J, Paljug W, Debnath ML, Price J, et al. Neuropathology and biochemical correlations of [F-18]AV-1451 and [C-11]PiB PET imaging in a subject with Alzheimer's disease. In: Johnson KA, Jagust WJ, Klunk WE,
Mathis CA, eds. 11th Human Amyloid Imaging. Miami, Florida: 2017. p. 157.
2
M. Marquie, M.D. Normandin, C.R. Vanderburg, I.M. Costantino, E.A.Bien, L.G. Rycyna, et al. Validating novel tau positron emission tomography tracer [F-18]-AV-1451 (T807) on postmortem brain tissue. Ann Neurol, 78 (2015), pp. 787-800
3
M.R. Brier, B. Gordon, K. Friedrichsen, J. McCarthy, A. Stern, J.Christensen, et al. Tau and Aβ imaging, CSF measures, and cognition in Alzheimer’s disease. Sci Transl Med, 8 (2016), p. 338ra66
FDG PET
• FDG = Fluorodeoxyglucose
• PET scan shows increased
uptake in areas high in
metabolic activity
• Reduced uptake indicates
both cumulative loss of the
neuropil and functional
impairment of neurons 1 Figure 11. Comparison of FDG-PET images between normal control and mild AD
Source: Wu, Liyong & Rosa, Pedro & Gauthier, Serge. (2011). Use of Biomarkers in Clinical Trials of
Alzheimer Disease From Concept to Application. Molecular diagnosis & therapy.
1
S.J. Vos, B.A. Gordon, Y. Su, P.J. Visser, D.M. Holtzman, J.C. Morris, et al. NIA-AA staging of preclinical Alzheimer disease: discordance and concordance of CSF and imaging biomarkers Neurobiol Aging, 44 (2016), pp. 1-8
MRI BRAIN – STRUCTURAL ASSESSMENT
• Assess atrophy
• First manifest in the medial temporal lobe 1
• Other structures within the limbic lobe such as the posterior cingulate are
also affected early on
• Even in mildly affected individuals (e.g., mean MMSE of ∼24/30) entorhinal
volumes are already reduced by ∼20–30% and hippocampal volumes by ∼15–
25% 2,3
• Rates of hippocampal atrophy in mild AD are ∼3–5% per year 4
1
Scahill RI, Schott JM, Stevens JM, Rossor MN, Fox NC 2002. Mapping the evolution of regional atrophy in Alzheimer’s disease: Unbiased analysis of fluid-registered serial MRI. Proc Natl Acad Sci99: 4703–4707
2 Chan D, Fox NC, Scahill RI, Crum WR, Whitwell JL, Leschziner G, Rossor AM, Stevens JM, Cipolotti L, Rossor MN 2001. Patterns of temporal lobe atrophy in semantic dementia and Alzheimer’s disease. Ann Neurol 49: 433–442
3 Dickerson BC, Goncharova I, Sullivan MP, Forchetti C, Wilson RS, Bennett DA, Beckett LA, deToledo-Morrell L 2001. MRI-derived entorhinal and hippocampal atrophy in incipient and very mild Alzheimer’s disease. Neurobiol Aging 22: 747–754
4 Barnes J, Bartlett JW, van de Pol LA, Loy CT, Scahill RI, Frost C, Thompson P, Fox NC 2009. A meta-analysis of hippocampal atrophy rates in Alzheimer’s disease. Neurobiol Aging 30: 1711–1723
MEDIAL TEMPORAL ATROPHY GRADING (MTA)
• Visual score
• Performed on MRI using coronal T1
weighted images in a plane parallel to the
brainstem axis at the level of the anterior
pons
• Latest average score cut-offs 1:
• <65 years: ≥1 is abnormal
• 65-74 years: ≥1.5 is abnormal
• 75-84 years: ≥2 is abnormal
• >85 years: ≥2 is abnormal
Figure 12. MTA grading
• Also validated for assessment on CT brain Source: Radiopedia
1Jules J. Claus, Salka S. Staekenborg, Dana C. Holl, Jelmen J. Roorda, Jacqueline Schuur, Pieter Koster, Caroline E. M. Tielkes, Philip Scheltens. Practical use of visual medial temporal lobe atrophy cut-off scores in Alzheimer’s disease: Validation in
a large memory clinic population. (2017) European Radiology. 27 (8): 3147
ENTORHINAL CORTEX ATROPHY (ERICA) SCORE
• Calculated on thin coronal
imaging at right angles to the
long axis of the hippocampus and
assessed at the level of the
mammillary bodies
Figure 13. ERICA grading

Source: Roberge, X., Brisson, M., & Laforce, R. (2023). Specificity of Entorhinal
Atrophy MRI Scale in Predicting Alzheimer’s Disease Conversion. Canadian Journal of
Neurological Sciences, 50(1), 112-114. doi:10.1017/cjn.2021.253
ENTORHINAL CORTEX ATROPHY (ERICA) SCORE
• Scores
• 0 - Normal volume of the entorhinal
cortex and parahippocampal gyrus
• 1 - Mild atrophy + Widening of
the collateral sulcus
• 2 - Moderate atrophy + Elevation of the
entorhinal cortex away from the
adjacent cerebellar tentorium
• 3 - Marked atrophy + Wide cleft
between the entorhinal cortex and the
adjacent cerebellar tentorium
• Cut off score in predicting AD (compared to
subjective cognitive decline): 2 or greater
(83% sensitivity and 98% specificity) 1 Figure 13. ERICA grading
Source: Roberge, X., Brisson, M., & Laforce, R. (2023). Specificity of Entorhinal
Atrophy MRI Scale in Predicting Alzheimer’s Disease Conversion. Canadian Journal of
Neurological Sciences, 50(1), 112-114. doi:10.1017/cjn.2021.253
1 Enkirch S, Traschütz A, Müller A et al. The ERICA Score: An MR Imaging–based Visual Scoring System for the Assessment of Entorhinal Cortex Atrophy in Alzheimer Disease. Radiology. 2018;288(1):226-333. doi:10.1148/radiol.2018171888
MRI BRAIN
• Assess for possible underlying vascular damage

• Present as signal alterations on certain sequences such as white matter
hyperintensities on T2-weighted series
MRI BRAIN
• Functional MRI (fMRI)
• Measures changes in blood oxygen level–dependent (BOLD) MR signal 1
• In patients with clinically diagnosed AD, fMRI shows decreased hippocampal activity during the encoding of new
information 2,3
• Both task-related and resting fMRI techniques have the potential to detect early brain dysfunction related to AD, and
to monitor therapeutic response over relatively short time periods 4
• MRI with diffusion tensor imaging
• Allows for the interrogation of the microstructural integrity of white matter.
• Various structural MRI studies revealed variable degrees of WM abnormalities such as demyelination and gliosis 5
• MRI with arterial spin labelling
• Measures of cerebral blood flow - hypoperfusion to posterior cingulate, precuneus, inferior parietal, and lateral
prefrontal cortices 6
1 Kwong KK, Belliveau JW, Chesler DA, Goldberg IE, Weisskoff RM, Poncelet BP, Kennedy DN, Hoppel BE, Cohen MS, Turner R, et al. 1992. Dynamic magnetic resonance imaging of human brain activity during primary sensory stimulation. Proc Natl Acad Sci 89: 5675–5679
2 Hamalainen A, Pihlajamaki M, Tanila H, Hanninen T, Niskanen E, Tervo S, Karjalainen PA, Vanninen RL, Soininen H 2007. Increased fMRI responses during encoding in mild cognitive impairment. Neurobiol Aging 28: 1889–1903
3 Golby A, Silverberg G, Race E, Gabrieli S, O’Shea J, Knierim K, Stebbins G, Gabrieli J 2005. Memory encoding in Alzheimer’s disease: An fMRI study of explicit and implicit memory. Brain 128: 773–787
4 Kukolja J, Thiel CM, Fink GR 2009. Cholinergic stimulation enhances neural activity associated with encoding but reduces neural activity associated with retrieval in humans. J Neurosci29: 8119–8128
5 Kim KW, MacFall J, Payne M (2008) Classification of white matter lesions on magnetic resonance imaging in elderly persons. Biol Psychiatry, 64, 273–280.
6 Alsop DC, Dai W, Grossman M, Detre JA. Arterial spin labeling blood flow MRI: its role in the early characterization of Alzheimer's disease. J Alzheimers Dis. 2010;20:871–880
Amyloid PET Tau PET
QUESTION 2
• A 75-year-old woman with amnestic
multidomain dementia.
• What is the biomarker profile and

Tau PET MRI Brain
category (Based on NIA-AA 2018
diagnostic criteria?)
Amyloid PET Tau PET
QUESTION 2
• Abnormal amyloid PET
with Pittsburgh compound B (top
left)
• Tau PET with flortaucipir (top right
and bottom left) Tau PET MRI Brain
• Atrophy on MRI (bottom right).
• Biomarker profile A+T+(N)+.

• Biomarker category: Alzheimer’s
Dementia
Amyloid PET
QUESTION 3
• A cognitively unimpaired 67-year-old
man. Tau PET
• What is the biomarker profile and

category (Based on NIA-AA 2018
diagnostic criteria?)
MRI Brain
Amyloid PET
QUESTION 3
• Abnormal amyloid PET
• No uptake on tau PET Tau PET
• No atrophy on MRI
• Biomarker profile A+T−(N)−.

• Biomarker category: Alzheimer’s
MRI Brain
pathologic change
SERUM/ PLASMA TESTS
Pathology Plasma Biomarkers
Amyloid Plasma Aβ42/Aβ40 1,2
Tau Plasma p-tau181, plasma p-tau231, plasma p-
tau181/Aβ42, and plasma p-tau231/Aβ42 3
Neurodegeneration Plasma neurofilament light (NfL)
• Amyloid and tau plasma biomarkers significantly correlated

with traditional biomarkers (ie, amyloid-PET, tau-PET, CSF
Aβ42 and CSF p-tau181),
1 Lewczuk, P., Matzen, A., Blennow, K., Parnetti, L., Molinuevo, J. L., Eusebi, P., Kornhuber, J., Morris, J. C., & Fagan, A. M. (2017). Cerebrospinal Fluid Aβ42/40 Corresponds Better than Aβ42 to
Amyloid PET in Alzheimer's Disease. Journal of Alzheimer's disease : JAD, 55(2), 813–822. https://doi.org/10.3233/JAD-160722
2 Li, Y., Schindler, S. E., Bollinger, J. G., Ovod, V., Mawuenyega, K. G., Weiner, M. W., Shaw, L. M., Masters, C. L., Fowler, C. J., Trojanowski, J. Q., Korecka, M., Martins, R. N., Janelidze, S., Hansson, O.,
& Bateman, R. J. (2022). Validation of Plasma Amyloid-β 42/40 for Detecting Alzheimer Disease Amyloid Plaques. Neurology, 98(7), e688–e699. https://doi.org/10.1212/WNL.0000000000013211
3 Park, J. C., Han, S. H., Yi, D., Byun, M. S., Lee, J. H., Jang, S., Ko, K., Jeon, S. Y., Lee, Y. S., Kim, Y. K., Lee, D. Y., & Mook-Jung, I. (2019). Plasma tau/amyloid-β1-42 ratio predicts brain tau deposition
and neurodegeneration in Alzheimer's disease. Brain : a journal of neurology, 142(3), 771–786. https://doi.org/10.1093/brain/awy347
• PrecivityAD: Plasma Aβ42/40 Ratio only
• Estimated around USD 1250
• PrecivityAD2: Plasma Aβ42/40 Ratio and p-tau217/np-tau217 ratio
• Combined into a proprietary statistical algorithm to calculate the Amyloid Probability Score
2 (APS2), a numerical value ranging from 0–100 à Positive (has high likelihood) or Negative
(has low likelihood) for the presence of brain amyloid plaques by amyloid PET scan
Figure 14. Hypothetical model of dynamic biomarkers of the AD that is expanded to explicate the preclinical phase
Source: 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;7:280–292.
GENETIC SCREENING
Early-onset AD Late-onset AD
• 1% of all AD cases • The apolipoprotein E (APOE) ε4 allele is
the first and most significant LOAD risk
• Autosomal Dominant inheritance
gene identified 2,3
• Examples
• Homozygosity increases the risk of
• APP gene (Chromosome 21) developing AD
• Presenilin 1 and 2 (PSEN1 and PSEN2) genes • Associated with higher cerebral Aβ
• Causes Aβ protein misfolding, aggregation, and deposition in individuals across the full
accumulation of brain parenchymal Aβ plaques1 clinical continuum of AD 4
1
Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2002;297:353–6.
2 Poirier J, Davignon J, Bouthillier D, Kogan S, Bertrand P, Gauthier S. Apolipoprotein E polymorphism and Alzheimer’s disease. Lancet. 1993;342:697–9.
3 Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261:921–3.
4 Sunderland T, Mirza N, Putnam KT, Linker G, Bhupali D, Durham R, et al. Cerebrospinal fluid beta-amyloid1-42 and tau in control subjects at risk for Alzheimer’s disease: the effect of APOE epsilon4 allele. Biol Psychiatry. 2004;56:670–6.
MANAGEMENT
NON-PHARMACOLOGICAL
SUPPLEMENTS
PHARMACOLOGICAL
NON-PHARMACOLOGICAL
• Cognitive Stimulation
• Eg. Arithmetic problems, puzzles
• Improves cognitive function, quality of life and well-being immediately when compared to those
receiving cognitive enhancers 1,2
• Reality orientation training
• Eg large calendars, door signs, orientation charts
• Correlated with cognitive and behavioural benefits 3
• Diet
• Mediterranean diet: Possible positive impact on memory and cognitive abilities
1
Woods B, Aguirre E, Spector AE, Orrell M. Cognitive stimulation to improve cognitive functioning in people with dementia. Cochrane Database of Systematic Rev. 2012;2
2
Olazaran J, Reisberg B, Clare L, et al. Non-pharmacological therapies in Alzheimer’s disease: A systematic review of efficacy. Demen Geriatr Cogn Disord. 2010;30:161–178.
3
Spector A, Orrell M, Davies S, Woods B. Reality Orientation for dementia: a review of the evidence of effectiveness from randomized controlled trails. Gerontologist. 2000;40(2):206–212
NON-PHARMACOLOGICAL
• Physical, emotional and social stimulation
• Dementia Day Care
• The estimated cost ranges between $1,260 and $1,575 per month before subsidy,
assuming daily attendance on weekdays and excluding transport services (AIC
website)
• Exercise programs
• Dementia Singapore Memories Cafe: Sing-a-long, drum circle
NON-PHARMACOLOGICAL
• Emotion-oriented intervention
• Validation therapy
• Administered by caregiver
• Focused on validating the personhood and emotions of a person with dementia
• Shown to relieve stress 1, promote contentment and decrease behavioral
disturbances 2
1 Mitchell G, Agnelli J. Non-pharmacological approaches to alleviate distress in dementia care. Nurs Stand. 2015;13:38–44.
2 Hitch S. Cognitive therapy as a tool for the caring elderly confused person. J Clin Nurs. 1994;3:49–55.
MANAGEMENT – NON-
PHARMACOLOGICAL
• Emotion-oriented intervention
• Reminiscence therapy 1,2
• Using photos, music, keepsakes
• Improves mood and mental
performance
• Mixed results for cognitive benefit
1
Huang HC, Chen TJ, Chen PY, et al. Reminiscence therapy improves cognitive functions and reduces depressive symptoms in
elderly people with dementia: A meta-analysis of randomized controlled trials. J Am Med Dir Assoc. 2015;16(12):1087–1094
2
Woods RT, Bruce E, Edwards RT, et al. REMCARE: Reminiscence groups for people with dementia and their family
caregivers-effectiveness and cost-effectiveness pragmatic multicentre randomised trial. Health Technol
Assess. 2012;16:1e116.
NON-PHARMACOLOGICAL
• Caregiver Training Programme/Support

• Post-diagnostic support
• Dementia counselling
• Dementia Singapore
• Dementia Helpline: 6377 0700
• COMIT and CREST
• Caregiver support groups
• Eldersit Service: For caregiver respite
NON-PHARMACOLOGICAL
• Long Term Care Plan

• Advanced Care Planning
• Preferred Place of Care
• Lasting Power of Attorney
SUPPLEMENT – SOUVENAID
• Dietary supplement with a
patented composition (Fortasyn
Connect™)
• In prodromal AD, and in mild and
mild-to-moderate AD, Souvenaid
results in little or no difference in
global or specific cognitive
functions 1
• Cost: About $5 per bottle
Figure 15. Souvenaid Supplement
Source: https://www.nutricia.com.sg/en/category/about-souvenaid/
1
Burckhardt, M., Watzke, S., Wienke, A., Langer, G., & Fink, A. (2020). Souvenaid for alzheimer’s disease. Cochrane Database of Systematic Reviews, 2020(12). https://doi.org/10.1002/14651858.cd011679.pub2
SUPPLEMENT – GINGKO BILOBA EXTRACT EGB761
Meta-analysis of 9 trials comparing EGb761 to placebo 1
• Inclusion criteria: Minimum of 12 weeks duration of
treatment for patients with dementia (AD, Vascular dementia
or mixed dementia)
• Result: For the Alzheimer subgroup, the standardized change
scores (ADAS-cog or SKT) were greater for ginkgo than for
placebo
• SMD = -0.63 (95% CI -1.16; -0.10, z = 2.35, N = 6, p = 0.02)
• Conclusion: Ginkgo biloba appears more effective than
placebo
1
Weinmann, S., Roll, S., Schwarzbach, C. et al. Effects of Ginkgo biloba in dementia: systematic review and meta-analysis. BMC Geriatr 10, 14 (2010). https://doi.org/10.1186/1471-2318-10-14
Strategies for the use of Ginkgo

biloba extract, EGb 761®, in the
treatment and management of
mild cognitive impairment in Asia:
Expert consensus 1
• Suggestion: it is clinically
appropriate to incorporate EGb
761® as part of the multidomain
intervention for MCI.
1
Kandiah, N., Chan, Y. F., Chen, C., Dasig, D., Dominguez, J., Han, S. H., Jia, J., Kim, S., Limpawattana, P., Ng, L. L., Nguyen, D. T., Ong, P. A., Raya-Ampil, E., Saedon, N., Senanarong, V., Setiati, S., Singh, H., Suthisisang, C., Trang, T. M., Turana, Y., … Ihl, R.
(2021). Strategies for the use of Ginkgo biloba extract, EGb 761® , in the treatment and management of mild cognitive impairment in Asia: Expert consensus. CNS neuroscience & therapeutics, 27(2), 149–162. https://doi.org/10.1111/cns.13536
• Side Effects
• Headache, giddiness
• Constipation
• Drug-drug Interactions
In clinical interaction studies, EGb 761 either induced or inhibited
Drugs mainly metabolized by cytochrome P450 isoenzymes
Cytochrome P450 (3A4) Substrates affected include: Warfarin, NOAC, Midazolam, Fluoxetine,
Haloperidol
Drugs that provoke a

Take into account the presence of ethanol (450 mg/mL) in the solution
disulfiram-alcohol-like formulation of EGb 761 when using such medications
reaction and CNS depressants
1 Weinmann, S., Roll, S., Schwarzbach, C. et al. Effects of Ginkgo biloba in dementia: systematic review and meta-analysis. BMC Geriatr 10, 14 (2010). https://doi.org/10.1186/1471-2318-10-14
PHARMACOLOGICAL
• Acetylcholinesterase Inhibitors
• N-methyl-D-aspartate (NMDA) Receptor Antagonist
• Immunotherapy
ACETYLCHOLINESTERASE INHIBITORS
• Mechanism: Inhibits break down

of ACh à Increases level and
duration of neurotransmitter
action
• Examples: Donepezil, Rivastigmine
Figure 16. Mechanism of action of Acetylcholinesterase Inhibitors

Source: https://link.springer.com/chapter/10.1007/978-981-16-4558-7_8
• Side Effects:
• GIT - Nausea, diarrhea,
decreased appetite, dyspepsia,
hypersalivation
• CVM - Bradycardia, Hypotension
• Neuro - Giddiness, Headache
• Eye – Miosis à Can precipitate
acute angle closure glaucoma
• GU - Urinary frequency/
Incontinence
Figure 17. Cholinergic effects
Source: https://basicmedicalkey.com/cholinergic-agonists-and-antagonists/
Cochrane Systematic Review: Cholinesterase inhibitors for Alzheimer’s disease 1

• 10 randomized, double blind, placebo-controlled trials for donepezil, galantamine
or rivastigmine
• Results: Treatment with donepezil, galantamine or rivastigmine at the
recommended dose for people with mild, moderate or severe dementia due to
Alzheimer's disease produced improvements in cognitive function (on average
-2.37 point with p<0.00001, in the midrange of the 70pt ADAS-Cog Scale)
• Benefit also seen on measures of ADLs
1 Birks, J. S. (2006). Cholinesterase inhibitors for alzheimer’s disease. Cochrane Database of Systematic Reviews, 2016(3). https://doi.org/10.1002/14651858.cd005593
Cholinesterase inhibitors for patients with Alzheimer's disease: systematic

review of randomised clinical trials 1
• 22 double blinded, randomised controlled trials examining efficacy of donepezil,
rivastigmine, or galantamine was compared with placebo in patients with
Alzheimer's disease
• Follow-up ranged from six weeks to three years
• Results: Improvement ranging from 1.5 points to 3.9 points in favour of the
respective cholinesterase inhibitors (using 70pt ADAS-Cog subscale)
1
Kaduszkiewicz, H., Zimmermann, T., Beck-Bornholdt, H.-P., & van den Bussche, H. (2005). Cholinesterase inhibitors for patients with alzheimer’s disease: Systematic review of Randomised Clinical Trials. BMJ, 331(7512), 321–327.
https://doi.org/10.1136/bmj.331.7512.321
MEMANTINE
• N-methyl-D-aspartate
(NMDA) Receptor Antagonist
• Mechanism:
Low- to moderate-affinity,
uncompetitive NMDA
receptor antagonist
à Prevents over-activation of
glutamine receptors
à Reduces neurotoxicity
Figure 18. Mechanism of action of Memantine

Source: https://psychscenehub.com/psychinsights/memantine-psychopharmacology/
MEMANTINE
• Side Effects:
• Common
• CNS: Dizziness, Headache, Confusion
• GIT: Diarrhea, Constipation
• Less Common:
• Hallucination, aggressive behaviour
• Vomiting, abdominal pain
• Hypertension
MEMANTINE
Memantine Treatment in Patients With Moderate to Severe Alzheimer Disease

Already Receiving Donepezil 1
• Randomized, double-blind, placebo-controlled clinical trial of 404 patients
with moderate to severe AD and MMSE scores of 5 to 14
• Primary Outcome: Change from baseline on the Severe Impairment
Battery (SIB), and on a modified 19-item AD Cooperative Study–Activities
of Daily Living Inventory (ADCS-ADL19)
1Tariot PN, Farlow MR, Grossberg GT, et al. Memantine Treatment in Patients With Moderate to Severe Alzheimer Disease Already Receiving Donepezil: A Randomized Controlled
Trial. JAMA. 2004;291(3):317–324. doi:10.1001/jama.291.3.317
MEMANTINE
• Results:
• Change in total mean scores favored memantine vs placebo
treatment for SIB, 0.9 (0.67) vs –2.5 (0.69), respectively (P<.001), and
ADCS-ADL19 (possible score range, 0-54), –2.0 (0.50) vs –3.4 (0.51),
respectively (P = .03)
• Less treatment discontinuation due to side effects for memantine vs
placebo: 15 (7.4%) vs 25 (12.4%), respectively.
1Tariot PN, Farlow MR, Grossberg GT, et al. Memantine Treatment in Patients With Moderate to Severe Alzheimer Disease Already Receiving Donepezil: A Randomized Controlled
Trial. JAMA. 2004;291(3):317–324. doi:10.1001/jama.291.3.317
Acetylcholine Optimise acetylcholine

levels in the brain
Hypothesis neuronal circuit
Remove
Aβ oligomer Prove presence of Aβ
amyloid
oligomers in cerebral
hypothesis parenchyma
plagues/
oligomers
Tau Prove presence of Remove

phosphorylated tau in neurofibrillary
hypothesis cerebral parenchyma tangles
IMMUNOTHERAPY
Figure 19. Mechanisms of action of different anti-amyloid antibodies in relation to stages of Aβ aggregation
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10457266/bin/13311_2023_1405_Fig3_HTML.jpg
Table 3. Negative phase 3 anti-amyloid immunotherapy trials in symptomatic AD
Source: Yadollahikhales, G., & Rojas, J. C. (2023). Anti-Amyloid Immunotherapies for Alzheimer's Disease: A 2023 Clinical Update.
Table 4. Clinical trial information for mAb treatments against AD and their findings
Source: Valiukas, Z., Ephraim, R., Tangalakis, K., Davidson, M., Apostolopoulos, V., & Feehan, J. (2022). Immunotherapies for Alzheimer’s Disease—A Review. .
IMMUNOTHERAPY
Figure 19. Mechanisms of action of different anti-amyloid antibodies in relation to stages of Aβ aggregation
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10457266/bin/13311_2023_1405_Fig3_HTML.jpg
DONANEMAB
IgG1 monoclonal Ab directed against insoluble, modified, N-terminal truncated form of β-
amyloid present only in brain amyloid plaques
à Aids plaque removal through microglial-mediated phagocytosis
Figure 20. Donanemab mechanism of action

Source: https://thebraindocs.com/wp-content/uploads/2023/05/Aducanumab-Alzheimers-Drug-1024x579.webp
DONANEMAB IN EARLY SYMPTOMATIC ALZHEIMER DISEASE
THE TRAILBLAZER-ALZ 2 RANDOMIZED CLINICAL TRIAL
• Randomized, double-blind, placebo-controlled, 18-month phase 3 trial
• Participants: 1736 participants with MCI/ mild dementia with amyloid and low/medium or
high tau pathology based on positron emission tomography imaging
• Enrolled from 277 medical research centres/hospitals in 8 countries
THE TRAILBLAZER-ALZ 2 RANDOMIZED CLINICAL
TRIAL
- METHODS
THE TRAILBLAZER-ALZ 2 RANDOMIZED CLINICAL TRIAL 1
THE TRAILBLAZER-ALZ 2 RANDOMIZED CLINICAL TRIAL 1
ADVERSE EVENTS
AE=adverse event; ARIA-E=amyloid-related imaging abnormalities-edema/effusions; ARIA-H=amyloid-related imaging abnormalities-

hemorrhage/hemosiderin deposition; IRR=infusion-related reaction; N, n=number of participants
AMYLOID-RELATED IMAGING ABNORMALITIES (ARIA)
• 2 types:
• Edema and effusion (ARIA-E)
• Microhaemorrhages and superficial siderosis (ARIA-H)
• Often asymptomatic and self-resolving
• Higher incidence in patients who are Apolipoprotein E ε4 allele carriers
AMYLOID-RELATED IMAGING ABNORMALITIES (ARIA)
• Pathogenesis
Binding of monoclonal antibodies to accumulated Aβ in the cerebral parenchyma
and vasculature with amyloid clearance
à Loss of vessel wall integrity
à Leak of proteinaceous fluid (i.e., ARIA-E) and heme products (i.e., ARIA-H) 1,2
1 Sperling RA, Jack CR Jr, Black SE, et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer's Association Research Roundtable
Workgroup. Alzheimers Dement 2011; 7:367–385
2 Barakos J, Purcell D, Suhy J, et al. Detection and management of amyloid-related imaging abnormalities in patients with Alzheimer's disease treated with anti-amyloid beta therapy. J Prev Alzheimers Dis 2022;
9:211–220
LECANEMAB
• Humanized IgG1 monoclonal

antibody that binds to soluble
Aβ aggregates (oligomers and
protofibrils) 1
• Given intravenously 10mg/kg
body weight every 2 weeks
• Costs about US$26,500 (S$35,200)
a year in the US
Figure _. How Lecanemab works

Source: https://www.alzheimersresearchuk.org/wp-content/uploads/2022/12/how-lecanemab-works.jpg
1 Tucker
S, Möller C, Tegerstedt K, Lord A, Laudon H, Sjödahl J, et al. The murine version of BAN2401 (mAb158) selectively reduces amyloid-β protofibrils in brain and cerebrospinal fluid of tg-ArcSwe mice. J
Alzheimers Dis. 2015;43(2):575–588. doi: 10.3233/JAD-140741
LECANEMAB
• Swedish family affected by early-onset Alzheimer’s disease, found to be carriers of the 'Arctic'
mutation
• Arctic Mutation 1
• Decreased Abeta42 and Abeta40 levels in plasma.
• Beta amyloid formed protofibrils at a much higher rate and in larger quantities than wild-
type (wt) Abeta
• Suggests alternative pathogenic mechanism for AD involving rapid Abeta protofibril
formation leading to accelerated buildup of insoluble Abeta intra- and/or
extracellularly
1 Basun H, Bogdanovic N, Ingelsson M, Almkvist O, Naslund J, Axelman K, et al. Clinical and neuropathological features of the arctic APP gene mutation causing early-onset Alzheimer disease. Arch
Neurol. 2008;65(4):499–505. doi: 10.1001/archneur.65.4.499.
LECANEMAB – CLARITY AD TRIAL
• Clarity AD Trial 1
• 18-month, multicenter, double-blind, phase 3 trial
• Participants: 1795 participants, aged 50 to 90 years, with early Alzheimer’s disease (MCI
or mild dementia due to AD) with evidence of amyloid on PET or by CSF testing.
• Method: Participants were randomly assigned in a 1:1 ratio to receive intravenous
lecanemab (10 mg/kg body weight every 2 weeks) or placebo
• Primary end-point: Change from baseline at 18 months in the score on the Clinical
Dementia Rating–Sum of Boxes (CDR-SB; range
1van Dyck, C. H., Swanson, C. J., Aisen, P., Bateman, R. J., Chen, C., Gee, M., Kanekiyo, M., Li, D., Reyderman, L., Cohen, S., Froelich, L., Katayama, S., Sabbagh, M., Vellas, B., Watson, D., Dhadda, S., Irizarry, M.,
Kramer, L. D., & Iwatsubo, T. (2023, January 5). Lecanemab in Early Alzheimer’s Disease. New England Journal of Medicine, 388(1), 9–21. https://doi.org/10.1056/nejmoa2212948
LECANEMAB – CLARITY AD TRIAL
AHEAD TRIAL
- BY YLLSOM MEMORY, AGEING AND COGNITION CENTRE (MACC)
• Funded by the National Institutes of Health and Eisai, Inc.

• Aims to test whether intervening ahead of symptoms may prevent future memory loss and
dementia.
• The two AHEAD trials enrol participants with different levels of amyloid in the brain:
1. Participants with intermediate amyloid levels take part in the AHEAD A-3 trial—the first study aimed at
investigating this very early stage of brain change. Participants in the A-3 trial receive a lower dose of
lecanemab
2. Participants with elevated amyloid levels take part in the AHEAD A-45 preclinical Alzheimer’s disease
trial and will receive a higher dose of lecanemab, which has been shown to lower brain amyloid levels in
people with Alzheimer’s dementia.
Aducanumab (EMERGE trial) Donanemab (TRAILBLAZER-ALZ) Lecanemab (clarity AD)
Placebo Most effective dose Placebo Placebo
Most effective dose difference vs. placebo Most effective dose
difference vs. placebo difference vs. placebo
Change ± SE Change ± SE Change ± SE
Primary outcome
CDRsb − 0.39 (− 22%) 1.74 ± 0.11 iADRS 3.20 (25%) − 10.06 CDRsb − 0.45 (− 27%) 1.66
95% CI − 0.69, 0.09 95% CI 0.12, 6.27 95% CI − 0.67, 0.23
P value 0.012 P value 0.04 P value < 0.001
Secondary outcomes
MMSE 0.6 (− 18%) − 3.3 ± 0.2 MMSE 0.64 ADCOMS − 0.05 0.214
95% CI 0.0, 1.1 95% CI − 0.40, 1.67 95% CI − 0.074, − 0.027
P value 0.049 P value P value < 0.001
ADAS-Cog13 − 1.40 (− 27%) 5.16 ± 0.40 ADAS-Cog13 − 1.86 ADAS-Cog14 − 1.44 5.58
95% CI − 2.46, − 0.34 95% CI − 3.63, − 0.09 95% CI − 2.27, − 0.61
P value 0.010 P value P value < 0.001
PET amyloid (composite PET amyloid PET amyloid 3.64
− .278 (− 71%) 4% increase − 85.06 0.93 − 59.1
SUVR) (centiloids) (centiloids)
95% CI − 0.306, − 0.250 95% CI − 92.6, − 77.4 95% CI − 62.2, − 55.6
P value < 0.0001 P value P value < 0.01
Table 5. Clinical effect of 3rd generation anti-amyloid immunotherapies

Source: Data adapted from Yadollahikhales, G., & Rojas, J. C. (2023). Anti-Amyloid Immunotherapies for Alzheimer's Disease: A 2023 Clinical Update.
VACCINATIONS
Source: Valiukas, Z., Ephraim, R., Tangalakis, K., Davidson, M., Apostolopoulos, V., & Feehan, J.
(2022). Immunotherapies for Alzheimer’s Disease—A Review.
VACCINATIONS
Table 6. Research information for several active vaccine treatments against AD and their findings.
Source: Valiukas, Z., Ephraim, R., Tangalakis, K., Davidson, M., Apostolopoulos, V., & Feehan, J. (2022). Immunotherapies for Alzheimer’s Disease—A Review. .
VASCULAR DEMENTIA
Figure 21. Pathobiology of Neurovascular Dysfunction in Vascular Cognitive Impairment
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719789/figure/F4/
RISK FACTORS
Subtypes Risk Factors
Large Vessel Disease - Hypertension 1
- Carotid artery atherosclerosis
- Cardioembolic (usually AF)
- Coronary artery disease
Small Vessel Disease - Hypertension 1
- Diabetes Mellitus 2
- Hyperlipidemia 3
- Hyperhomocysteinemia
- Chronic kidney disease
- Obstructive sleep apnea
- Lifestyle: Smoking 3, alcohol abuse, obesity
1 Gorelick PB, Scuteri A, Black SE, et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke2011;42:2672–713.
2 Biessels GJ, Despa F. Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications. Nat Rev Endocrinol2018;14: 591–604
3
Dichgans M, Zietemann V. Prevention of vascular cognitive impairment. Stroke 2012;43: 3137–46
Figure 22. Different cerebrovascular pathologies as outcomes of clinically diagnosed VaD.
Source: Kalaria, R. N. (2018). The pathology and pathophysiology of vascular dementia. Neuropharmacology, 134, 226–239.
https://doi.org/10.1016/j.neuropharm.2017.12.030
SMALL VESSEL DISEASE
Arteriolar Changes Outcomes

• Wall thickening by • Increased perivascular spacing
hyalinosis • Lacunar infarcts (predominantly
• Reduction or increment occurring in the white matter, basal
of the intima ganglia and thalamus) 1
• Severe arteriolosclerosis • Microinfarction
• Fibroid necrosis • Microbleeds
1 Deramecourt, V., Slade, J.Y., Oakley, A.E., Perry, R.H., Ince, P.G., Maurage, C.A., Kalaria, R.N., 2012. Staging and natural history of cerebrovascular pathology in dementia. Neurology 78, 1043e1050.
- White matter disease or subcortical
leukoencephalopathy with
incomplete infarction is a common
pathological change associated with
dementia 1
- Deep cerebral structures and white
matter are rendered most vulnerable
because the vessels are end arteries
almost devoid of anastomoses 2
Figure 23. Schematic of Penetrating Artery in Normal and SVD Subjects.
Source: Kalaria, R. N. (2018). The pathology and pathophysiology of vascular
dementia. Neuropharmacology, 134, 226–239.
https://doi.org/10.1016/j.neuropharm.2017.12.030
1 Deramecourt, V., Slade, J.Y., Oakley, A.E., Perry, R.H., Ince, P.G., Maurage, C.A., Kalaria, R.N., 2012. Staging and natural history of cerebrovascular pathology in dementia. Neurology 78, 1043e1050.
2 Kalaria, R. N., & Erkinjuntti, T. (2006). Small vessel disease and subcortical vascular dementia. Journal of clinical neurology (Seoul, Korea), 2(1), 1–11. https://doi.org/10.3988/jcn.2006.2.1.1
1. Periventricular lesions in white matter
2. Subcortical infarcts/ Lacunes
3. Cortical infarcts
4. Subcortical and cortical microinfarcts
5. Microhaemorrhages and microbleeds
6. CAA in leptomeningeal vessels
7. Superficial siderosis (various causes)
Figure 23. Different Cerebrovascular Pathologies associated with Dementia in

cerebral SVD.
Source: Kalaria, R.N., Kenny, R.A., Ballard, C.G., Perry, R., Ince, P., Polvikoski, T.,
2004. Towards defining the neuropathological substrates of vascular dementia. J.
Neurol. Sci. 226, 75e80.
CEREBRAL AMYLOID ANGIOPATHIES (CAA)
• Occurs most commonly in AD 1,2
• But can often be found in cerebrovascular disease
in the absence of AD pathology 3
• Independent substrate for cognitive impairment 4
• Features
• Severe amyloid deposition within walls of meningeal
and intracerebral vessels
• Affects mostly leptomeningeal and cortical vessels Figure 24. Micrograph of cerebral amyloid angiopathy using congo red stain
Source: https://encrypted-tbn0.gstatic.com/images?q=tbn:
• Lobar intracerebral haemorrhage ANd9GcSSkA4LWW6cF0pj8qrCnw7EtF3aIhq9r8dH8o8ibjSYdA&s
1 Charidimou, A., Gang, Q., Werring, D.J., 2012. Sporadic cerebral amyloid angiopathy revisited: recent insights into pathophysiology and clinical spectrum. J Neurol Neurosurg Psychiatry 83, 124e137.
2 Grinberg,L.T., Thal, D.R., 2010. Vascular pathology in the aged human brain. Acta Neuropathol. 119, 277e290.
3 Cohen, D.L., Hedera, P., Premkumar, D.R., Friedland, R.P., Kalaria, R.N., 1997. Amyloid- beta protein angiopathies masquerading as Alzheimer's disease? Ann. N. Y. Acad. Sci. 826, 390e395.
4 Arvanitakis, Z., Leurgans, S.E., Wang, Z., Wilson, R.S., Bennett, D.A., Schneider, J.A., 2011b. Cerebral amyloid angiopathy pathology and cognitive domains in older persons. Ann. Neurol. 69, 320e327.
Boston
Criteria
EVALUATION
HISTOLOGY
Figures 24. Pathological changes found in stroke involving large artery and small vessel diseases.
Source: Kalaria, R.N., Kenny, R.A., Ballard, C.G., Perry, R., Ince, P., Polvikoski, T., 2004. Towards defining the
neuropathological substrates of vascular dementia. J. Neurol. Sci. 226, 75e80.
IMAGING
• Leukoariosis
• Bright on MRI T2 weighted images
(Left)
• Dark on CT (Right)
• Usual locations = Subcortical and
periventricular areas around frontal
and occipital horns, and in the
centrum semiovale
Figure 26. MRI Brain images of T2 (Left) and FLAIR (Right) sequences
Source: Case courtesy of Frank Gaillard, Radiopaedia.org, rID: 10674
IMAGING
• Cerebral atrophy
• Superficial siderosis (Top right)
Figure 25. MRI Images showing superficial siderosis
• Lacunar infarcts (Bottom right) Source: https://www.ahajournals.org/cms/asset/bf7c3442-e5c2-41b4-9627-d4825efedf62/40ff1.jpg
• Most common locations:

putamen and the pallidum,
followed by the pons, thalamus,
caudate nucleus, internal
capsule, and corona radiata 1
Figure 26. CT Brain and MRI images showing lacunar infarcts

Source: Courtesy of Radiopedia
1
Caplan L. R. (2015). Lacunar infarction and small vessel disease: pathology and pathophysiology. Journal of stroke, 17(1), 2–6. https://doi.org/10.5853/jos.2015.17.1.2
IMAGING – FAZEKA SCALE
• Best scored on transverse FLAIR or T2-weighted

images.
Scale Finding
0 None or a single punctate WMH lesion
1 Multiple punctate lesions
2 Beginning confluency of lesions (bridging)
3 Large confluent lesions
• Severe white matter changes are independently

and strongly predictive of rapid global functional
decline 1 Figure 28. Fazeka Scale
Source: https://radiologyassistant.nl/assets/dementia-role-of-
mri/a50979771dcebf_fazekas2.jpg
1 Inzitari,
D., Pracucci, G., Poggesi, A., Carlucci, G., Barkhof, F., Chabriat, H., Erkinjuntti, T., Fazekas, F., Ferro, J. M., Hennerici, M., Langhorne, P., O'Brien, J., Scheltens, P., Visser, M. C., Wahlund, L. O., Waldemar, G., Wallin, A., Pantoni, L., & LADIS Study
Group (2009). Changes in white matter as determinant of global functional decline in older independent outpatients: three year follow-up of LADIS (leukoaraiosis and disability) study cohort. BMJ (Clinical research ed.), 339, b2477.
https://doi.org/10.1136/bmj.b2477
Imaging
– CAA
Figure 27. The distribution of sporadic small vessel disease in the brain and the topography of cerebral microbleeds
Source: https://www.frontiersin.org/articles/10.3389/fneur.2012.00133/full
Figure 28. Neuroimaging of Vascular Cognitive Impairment
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719789/bin/nihms-1047851-f0006.jpg
BIOMARKERS
• Many have been studied, including oxLDL,

miRNA, CSF MMP2 and MMP9, NTProBNP,
leptin, HDL-bound PON 1, Kallikrein 6. 1
• Evidences from the literature are
heterogeneous and mostly inconclusive
• Serum NfL has been considered a potential
circulating biomarker for both sporadic SVD
and CADASIL burden 2
1
Cipollini, V., Troili, F., & Giubilei, F. (2019). Emerging Biomarkers in Vascular Cognitive Impairment and Dementia: From Pathophysiological Pathways to Clinical Application. International journal of molecular sciences, 20(11), 2812.
https://doi.org/10.3390/ijms20112812
2 Duering M., Konieczny M.J., Tiedt S., Baykara E., Tuladhar A.M., Van Leijsen E., Lyrer P., Engelter S.T., Gesierich B., Achmüller M., et al. Serum Neurofilament Light Chain Levels Are Related to Small Vessel Disease Burden. J. Stroke. 2018;20:228–238.
doi: 10.5853/jos.2017.02565
MANAGEMENT
NON-PHARMACOLOGICAL
PHARMACOLOGICAL
NON-PHARMACOLOGICAL
• Smoking cessation 1
• Alcohol use cessation
• Exercise
• DAPA (Dementia and Physical Activity) trial 2
• FABS (Fitness for the Aging Brain Study) 3
• LIFE (Lifestyle Interventions and Independence for Elders) study 4
• Healthy, balanced diet/ Mediterranean diet 5
1
Choi D, Choi S, Park SM. Effect of smoking cessation on the risk of dementia: a longitudinal study. Ann Clin Transl Neurol 2018;5:1192–9.
2 Lamb SE, Sheehan B, Atherton N, et al. Dementia And Physical Activity (DAPA) trial of moderate to high intensity exercise training for people with dementia: randomised controlled trial. BMJ 2018;361:k1675.
3 Lautenschlager NT, Cox KL, Flicker L, et al. Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial. JAMA 2008;300:1027–37.
4 Sink KM, Espeland MA, Castro CM, et al. Effect of a 24-month physical activity intervention vs health education on cognitive outcomes in sedentary older adults: the LIFE Randomized Trial. JAMA 2015;314:781–90
5
Ngandu T, et al., A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet, 2015. 385(9984): p.
2255–63
NON-PHARMACOLOGICAL
A 2 year multidomain intervention of diet, exercise, cognitive training, and
vascular risk monitoring versus control to prevent cognitive decline in at-risk
elderly people (FINGER): A randomised controlled trial 1
• Participants: 1260 individuals aged 60–77 years recruited from previous national surveys
• Inclusion criteria: CAIDE (Cardiovascular Risk Factors, Aging and Dementia) Dementia Risk
Score of at least 6 points and cognition at mean level or slightly lower than expected for age.
• Method: Randomly assigned participants in a 1:1 ratio to a:
• 2 year multidomain intervention (diet, exercise, cognitive training, vascular risk monitoring)
• Control group (general health advice)
• Primary outcome: Change in cognition as measured through comprehensive neuropsychological
test battery (NTB) Z score
1
Ngandu T, et al., A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet, 2015. 385(9984):
p. 2255–63
NON-PHARMACOLOGICAL
• Findings:
• Estimated mean change in NTB
total Z score at 2 years was 0.20
(SE 0.02, SD 0.51) in the
intervention group and 0.16
(0.01, 0.51) in the control group
• Suggests that a multidomain
intervention could improve or
maintain cognitive functioning
in at-risk elderly people from
the general population.
BLOOD PRESSURE CONTROL
SPRINT (Systolic Blood Pressure PROGRESS (Perindopril Protection Against

Intervention Trial) MIND 1 Recurrent Stroke Study) 2
• Randomized controlled open-label trial • Randomized, double-blind, placebo-controlled
• Participants: Adults with increased risk for trial
cardiovascular disease but without diabetes • Participants: 6105 subjects from 172 centres
and stroke in Asia, Australasia, and Europe
• Compared Intensive BP lowering to • Compared perindopril-based blood pressure
<120mmHg with a target <140mmHg lowering regimen vs placebo
• Findings: Intensive BP lowering reduced the • Findings: Active treatment in patients with
risk of MCI or dementia + associated with cerebrovascular disease lowered the risk of
smaller increase in white matter cognitive decline by 19%
hyperintensities on brain MRI
1 Williamson JD, Pajewski NM, Auchus AP, et al., for the SPRINT MIND Investigators for the SPRINT Research Group. Effect of intensive vs standard blood pressure control on probable dementia: a randomized clinical trial. JAMA2019; 321:553–61
2 Tzourio C, Anderson C, Chapman N, et al. Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Arch Intern Med2003;163:1069–75
OTHER CARDIOVASCULAR RISK FACTORS
MANAGEMENT
Diabetes Hyperlipidemia Atrial Fibrillation
Heart Protection Study and

No evidence that Retrospective analysis of
PROSPER (PROspective Study
treatment of registry data from 440,106
of Pravastatin in the Elderly at
hyperglycemia and Swedish patients 3 :
Risk) trial 2 :
diabetes reduces the Statin treatment had no effect Oral anticoagulation at
risk of dementia or baseline lowered the risk of
on dementia incidence and
cognitive decline 1 incident dementia by 29%.
cognitive decline
1 Biessels GJ, Despa F. Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications. Nat Rev Endocrinol2018;14: 591–604.
2 Heart Protection Study Collaborative G. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7–22
3
Friberg L, Rosenqvist M. Less dementia with oral anticoagulation in atrial fibrillation. Eur Heart J 2018;39:453–60.
COGNITIVE ENHANCERS
• Acetylcholinesterase Inhibitors and
Memantine
• RCTs showed small benefits on cognition 1
• Trials were of 6-month duration with similar
vascular dementia criteria and outcome
measures.
• AHA and Canadian Stroke Best Practices
recommends: Cholinesterase inhibitors can be
considered for use in vascular cognitive
impairment (Intermediate grade evidence)
1Kavirajan H, Schneider LS. Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia: a meta-analysis of randomised controlled trials. Lancet Neurol2007;6:782–92
2Gorelick PB, Scuteri A, Black SE, et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke
Association. Stroke2011;42:2672–713.
FOOD FOR THOUGHT
How do acetylcholinesterase inhibitors and memantine

help in vascular dementia?
MANAGEMENT
• Naftidrofuryl – Uncertain benefit

• Serotonin 5-HT2 receptor antagonist
• Propentofylline – Uncertain benefit
• Phosphodiesterase inhibitor and adenosine reuptake inhibitor
DEMENTIA
WITH LEWY BODIES
PATHOGENESIS
• Alpha-synucleinopathy
• Pathologically characterized by Lewy
bodies and Lewy neurites in the
brainstem, limbic system, and cortical
areas 1,2
• Other changes include:
• Alzheimer’s disease pathology with β-
amyloid deposition
• Neurofibrillary tangles
Figure 32. Alpha-synuclein fibril aggregate formation from the monomeric form.
Source: https://a.static-abcam.com/CmsMedia/Media/postcardalphasynuclein1000x806px.jpg
1 McKeith I, Mintzer J, Aarsland D, Burn D, Chiu H, Cohen-Mansfield J, et al. Dementia with Lewy bodies. Lancet Neurol (2004) 3:19–28. 10.1016/S1474-4422(03)00619-7
2 Fujishiro H, Ferman TJ, Boeve BF, Smith GE, Graff-Radford NR, Uitti RJ, et al. Validation of the neuropathologic criteria of the third consortium for dementia with Lewy bodies for prospectively diagnosed cases. J Neuropathol Exp Neurol (2008) 67:649–56.
10.1097/NEN.0b013e31817d7a1d
Figure 33. Schematic overview including the main pathological
features of prodromal and classical α-synucleinopathies.
Source: https://www.frontiersin.org/articles/10.3389/
fneur.2021.737195/full
PATHOGENESIS
• α-synuclein oligomers
→ Synaptic damage
→ Abnormal neurotransmitter signalling 1 + Oxidative damage in frontal cortex and
neocortex 2
• Cognitive Dysfunction
• Contributed by cholinergic and dopaminergic denervation of neocortex 3
• May be due to associated Alzheimer’s disease pathology
• Amount of α-synuclein pathology may or may not be related to risk of dementia 4
1 Dalfó E, Albasanz JL, Martin M, Ferrer I.Abnormal metabotropic glutamate receptor expression and signaling in the cerebral cortex in diffuse Lewy body disease is associated with irregular alpha-synuclein/phospholipase C (PLCβ1) interactions. Brain
Pathol (2004) 14:388–98. 10.1111/j.1750-3639.2004.tb00082.x
2 Dalfó E, Ferrer I. Early α-synuclein lipoxidation in neocortex in Lewy body diseases. Neurobiol Aging (2008) 29:408–17. 10.1016/j.neurobiolaging.2006.10.022
3 Shimada H, Hirano S, Shinotoh H, Aotsuka A, Sato K, Tanaka N, et al. Mapping of brain acetylcholinesterase alterations in Lewy body disease by PET. Neurology (2009) 73:273–8. 10.1212/WNL.0b013e3181ab2b58
4 Parkkinen L, Kauppinen T, Pirttilä T, Autere JM, Alafuzoff I. α-Synuclein pathology does not predict extrapyramidal symptoms or dementia. Ann Neurol (2005) 57:82–91. 10.1002/ana.20321
EVALUATION
HISTOLOGY
Figure 39. Pathological findings of dementia with Lewy bodies on autopsy

Source: https://www.researchgate.net/publication/339619488/figure/fig1/AS:864630079504387@1583155283238/P
athological-findings-of-dementia-with-Lewy-bodies-on-autopsy-a-Left-Cingulate.jpg
IMAGING
• Radionuclide Imaging
• Single-photon emission computed tomography (SPECT)
• Positron emission tomography (PET)
• Structural MRI
• Functional MRI
• Others:
• Diffusion tensor imaging
• MIBG Myocardial Scintigraphy
RADIONUCLIDE IMAGING
- SPECT
• Uses 123FP-CIT ligand
• Utility
• Demonstrates alterations in the
dopamine transporter (DAT) à Reflects
changes in the nigrostriatal pathway
• Analyses cerebral perfusion and
metabolism
Figure 34. Comparison of FP-CIT scans between Alzheimer’s disease (AD) and
dementia with Lewy bodies (DLB).
Source: Neuroimaging characteristics of dementia with Lewy bodies. Alz Res
Therapy 6, 18 (2014). https://doi.org/10.1186/alzrt248
1 Lobotesis K, Fenwick JD, Phipps A, Ryman A, Swann A, Ballard C, McKeith IG, O'Brien JT: Occipital hypoperfusion on SPECT in dementia with Lewy bodies but not AD. Neurology. 2001, 56: 643-649. 10.1212/WNL.56.5.643.
RADIONUCLIDE IMAGING
- SPECT
Findings:
• Reduced binding in the striatum à DAT Loss
• Can be demonstrated before clinical
parkinsonism is apparent
• Decreased DAT levels associated with
visual hallucinations 1
• Hypometabolism in the occipital lobes 2
• Linked to visual hallucinations in DLB 3 Figure 35. Comparison of FP-CIT scans between Alzheimer’s disease (AD) and
dementia with Lewy bodies (DLB).
Source: Neuroimaging characteristics of dementia with Lewy bodies. Alz Res
Therapy 6, 18 (2014). https://doi.org/10.1186/alzrt248
1 Roselli F, Pisciotta NM, Perneczky R, Pennelli M, Aniello MS, De Caro MF, Ferrannini E, Tartaglione B, Defazio G, Rubini G, Livrea P: Severity of neuropsychiatric symptoms and dopamine transporter levels in dementia with Lewy bodies: a 123I-FP-CIT SPECT
study. Mov Disord. 2009, 24: 2097-2103. 10.1002/mds.22702.
2 Lobotesis K, Fenwick JD, Phipps A, Ryman A, Swann A, Ballard C, McKeith IG, O'Brien JT: Occipital hypoperfusion on SPECT in dementia with Lewy bodies but not AD. Neurology. 2001, 56: 643-649. 10.1212/WNL.56.5.643.
3 Perneczky R, Drzezga A, Boecker H, Forstl H, Kurz A, Haussermann P: Cerebral metabolic dysfunction in patients with dementia with Lewy bodies and visual hallucinations. Dement Geriatr Cogn Disord. 2008, 25: 531-538. 10.1159/000132084.
RADIONUCLIDE IMAGING - PET
Assesses amyloid Assesses cholinergic Assesses nigrostriatal

Assesses metabolism pathways projections
(Ligand: FDG) deposition
(Ligand: N-[11C]methyl (Ligand: 11C-
(Ligand: Florbetapir)
piperidin-4-yl acetate) dihydrotetrabenazine)
• Hypoperfusion in • Cortical amyloid load is • Widespread reductions • Reduced binding in

occipital cortex and and significantly raised in of acetylcholinesterase posterior and anterior
visual association >80% of DLB patients activity putamen and caudate
cortices 1 (rare in PDD) 2 • Particularly affecting nucleus 5
• Relative preservation of • Increased deposition the posterior regions
the posterior cingulate associated with more and thalamus 1,4
aggressive rate of
cognitive decline and
visuospatial
impairments 3
1 Klein JC, Eggers C, Kalbe E, Weisenbach S, Hohmann C, Vollmar S, Baudrexel S, Diederich NJ, Heiss WD, Hilker R: Neurotransmitter changes in dementia with Lewy bodies and Parkinson disease dementia in vivo. Neurology. 2010, 74: 885-892.
10.1212/WNL.0b013e3181d55f61.
2 Edison P, Rowe CC, Rinne JO, Ng S, Ahmed I, Kemppainen N, Villemagne VL, O'Keefe G, Någren K, Chaudhury KR, Masters CL, Brooks DJ: Amyloid load in Parkinson's disease dementia and Lewy body dementia measured with [11C]PIB positron emission
tomography. J Neurol Neurosurg Psychiatry. 2008, 79: 1331-1338. 10.1136/jnnp.2007.127878.
3 Rowe CC, Ng S, Ackermann U, Gong SJ, Pike K, Savage G, Cowie TF, Dickinson KL, Maruff P, Darby D, Smith C, Woodward M, Merory J, Tochon-Danguy H, O'Keefe G, Klunk WE, Mathis CA, Price JC, Masters CL, Villemagne VL: Imaging beta-amyloid burden in
aging and dementia. Neurology. 2007, 68: 1718-1725. 10.1212/01.wnl.0000261919.22630.ea.
4 Kotagal V, Müller MLTM, Kaufer DI, Koeppe RA, Bohnen NI: Thalamic cholinergic innervation is spared in Alzheimer disease compared to parkinsonian disorders. Neurosci Lett. 2012, 514: 169-172. 10.1016/j.neulet.2012.02.083.
5 Gilman S, Koeppe RA, Little R, An H, Junck L, Giordani B, Persad C, Heumann M, Wernette K: Striatal monoamine terminals in Lewy body dementia and Alzheimer's disease. Ann Neurol. 2004, 55: 774-780. 10.1002/ana.20088.
Source: https://radiopaedia.org/cases/cingulate-island-sign-1
RADIONUCLIDE IMAGING - PET
Assesses amyloid Assesses cholinergic Assesses nigrostriatal

Assesses metabolism pathways projections
(Ligand: FDG) deposition
(Ligand: N-[11C]methyl (Ligand: 11C-
(Ligand: Florbetapir)
piperidin-4-yl acetate) dihydrotetrabenazine)
• Hypoperfusion in • Cortical amyloid load is • Widespread reductions • Reduced binding in

occipital cortex and and significantly raised in of acetylcholinesterase posterior and anterior
visual association >80% of DLB patients activity putamen and caudate
cortices 1 (rare in PDD) 2 • Particularly affecting nucleus 5
• Relative preservation of • Increased deposition the posterior regions
the posterior cingulate associated with more and thalamus 1,4
aggressive rate of
cognitive decline and
visuospatial
impairments 3
1 Klein JC, Eggers C, Kalbe E, Weisenbach S, Hohmann C, Vollmar S, Baudrexel S, Diederich NJ, Heiss WD, Hilker R: Neurotransmitter changes in dementia with Lewy bodies and Parkinson disease dementia in vivo. Neurology. 2010, 74: 885-892.
10.1212/WNL.0b013e3181d55f61.
2 Edison P, Rowe CC, Rinne JO, Ng S, Ahmed I, Kemppainen N, Villemagne VL, O'Keefe G, Någren K, Chaudhury KR, Masters CL, Brooks DJ: Amyloid load in Parkinson's disease dementia and Lewy body dementia measured with [11C]PIB positron emission
tomography. J Neurol Neurosurg Psychiatry. 2008, 79: 1331-1338. 10.1136/jnnp.2007.127878.
3 Rowe CC, Ng S, Ackermann U, Gong SJ, Pike K, Savage G, Cowie TF, Dickinson KL, Maruff P, Darby D, Smith C, Woodward M, Merory J, Tochon-Danguy H, O'Keefe G, Klunk WE, Mathis CA, Price JC, Masters CL, Villemagne VL: Imaging beta-amyloid burden in
aging and dementia. Neurology. 2007, 68: 1718-1725. 10.1212/01.wnl.0000261919.22630.ea.
4 Kotagal V, Müller MLTM, Kaufer DI, Koeppe RA, Bohnen NI: Thalamic cholinergic innervation is spared in Alzheimer disease compared to parkinsonian disorders. Neurosci Lett. 2012, 514: 169-172. 10.1016/j.neulet.2012.02.083.
5 Gilman S, Koeppe RA, Little R, An H, Junck L, Giordani B, Persad C, Heumann M, Wernette K: Striatal monoamine terminals in Lewy body dementia and Alzheimer's disease. Ann Neurol. 2004, 55: 774-780. 10.1002/ana.20088.
STRUCTURAL MRI FUNCTIONAL MRI
• Less pronounced global atrophy • Different patterns of functional

compared to AD 1 connectivity between AD and DLB
• Relative preservation of the medial • Eg. decreased connectivity with
temporal lobe prefrontal and visual cortices in DLB
• Less severe hippocampal atrophy 2 compared to the AD group 3
1 Watson R, O’Brien JT: Differentiating dementia with Lewy bodies and Alzheimer’s disease using MRI. Neurodegener Dis Manag. 2012, 2: 411-420. 10.2217/nmt.12.41.
2 Chow N, Aarsland D, Honarpisheh H, Beyer MK, Somme JH, Elashoff D, Rongve A, Tysnes OB, Thompson PM, Apostolova LG: Comparing hippocampal atrophy in Alzheimer's dementia and dementia with lewy bodies. Dement Geriatr Cogn Disord.
2012, 34: 44-50. 10.1159/000339727.
3 Galvin JE, Price JL, Yan Z, Morris JC, Sheline YI: Resting bold fMRI differentiates dementia with Lewy bodies vs Alzheimer disease. Neurology. 2011, 76: 1797-1803. 10.1212/WNL.0b013e31821ccc83.
Figure 36. Coronal T1-weighted MRI images in Alzheimer disease (AD),
dementia with Lewy bodies (DLB), and normal controls (NC)
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496518/
MIBG MYOCARDIAL
SCINTIGRAPHY
• 123Iodine-MIBG myocardial scintigraphy
quantifies postganglionic sympathetic
cardiac innervation, which is reduced in
Lewy body disease 1,2
1 Nakajima K, Okuda K, Yoshimura M, et al. Multicenter cross-calibration of I-123 metaiodobenzylguanidine

heart-to-mediastinum ratios to overcome camera-collimator variations. Journal of nuclear cardiology :
Figure 37. 123Iodine-metaiodobenzylguanidine myocardial imaging in patients with
official publication of the American Society of Nuclear Cardiology 2014;21:970-978. dementia with Lewy bodies (DLB), and age-matched normal controls (NC)
2 Treglia G, Cason E, Giordano A. Diagnostic Performance of Myocardial Innervation Imaging Using MIBG Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496518/#R46
Scintigraphy in Differential Diagnosis between Dementia with Lewy Bodies and Other Dementias: A
Systematic Review and a Meta-Analysis. Journal of Neuroimaging 2012;22:111-117.
POLYSOMNOGRAPHY
• Demonstrates REM sleep without atonia 1

• Highly specific predictor of lewy-related
pathology
• PSG: REM sleep without atonia + History
of RBD + Dementia
= ≥90% likelihood of a-synucleinopathy 2
Figure 38. Polysomnography readings for normal control (top) and

patient with DLB (bottom)
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496518/#R46
1 McCarter SJ, St Louis EK, Duwell EJ, et al. Diagnostic thresholds for quantitative REM sleep phasic burst duration, phasic and tonic muscle activity, and REM atonia index in REM sleep behavior disorder with and without comorbid obstructive sleep
apnea. Sleep 2014;37:1649-1662.
2 Boeve BF, Silber MH, Ferman TJ, et al.. Clinicopathologic correlations in 172 cases of rapid eye movement sleep behavior disorder with or without a coexisting neurologic disorder. Sleep Med 2013;14:754–762
GENETIC AND FLUID BIOMARKERS
• Limited understanding regarding code genes involved

• Genetic markers associated with α-synuclein gene (SNCA) may be
associated with DLB syndrome 1
• CSF α-synuclein is not yet proven as a biomarker
Guella I, Evans DM, Szu-Tu C, et al.. Alpha-synuclein genetic variability: a biomarker for dementia in Parkinson disease. Ann Neurol2016;79:991–999.
Figure 38. Coronal T1-weighted MRI images in Alzheimer disease (AD),
dementia with Lewy bodies (DLB), and normal controls (NC)
Table 7. Summary findings in DLB compared to AD, PDD and Healthy Controls (HC)
MANAGEMENT
NON-PHARMACOLOGICAL
• Patient and caregiver education
• Exercise 1
• Cognitive training 2
• Caregiver training on management of agitation and psychosis3
• Sleep safety for REM sleep behaviour disorder:
• Lowered bed
• Sleeping apart from partners
• Bed rails with paddings
• Removing sharp objects in vicinity
1 Uc EY, Doerschug KC, Magnotta V, et al.. Phase I/II randomized trial of aerobic exercise in Parkinson disease in a community setting. Neurology 2014;83:413–425
2 Leung IH, Walton CC, Hallock H, Lewis SJ, Valenzuela M, Lampit A. Cognitive training in Parkinson disease: A systematic review and meta-analysis. Neurology 2015;85:1843-1851.
3 Huh TJ, Arean PA, Bornfeld H, Elite-Marcandonatou A. The effectiveness of an environmental and behavioral approach to treat behavior problems in a patient with dementia with Lewy bodies: a case study. Ann Longterm Care 2008;16:17-21.
PHARMACOLOGICAL
• Motor symptoms
• Cognition
• Neuropsychiatric symptoms
• Sleep-wakefulness disturbance
• Autonomic dysfunction
PHARMACOLOGICAL
• Motor symptoms
• Levodopa
• Initiation dose is lower in DLB than in Parkinson's disease, eg co-careldopa 12.5mg/50mg OM-TDS
• Adverse effects: Psychosis, postural hypotension, sedation, nausea, vomiting
• Efficacy: 1/3 improve, 1/3 experience psychotic symptoms (hallucinations or delusions ) 1
• Zonisamide
• Suphonamide antiepileptic medication; Given as an adjunctive therapy to levodopa 2
• Dosage 25-50mg once daily
• Adverse effects: Decreased appetite, loss of weight
1 Goldman JG, Goetz CG, Brandabur M, Sanfilippo M, Stebbins GT. Effects of dopaminergic medications on psychosis and motor function in dementia with Lewy bodies. Mov Disord 2008; 23: 2248–50.
2 Murata M, Odawara T, Hasegawa K, et al. Adjunct zonisamide to levodopa for dementia with Lewy bodies parkinsonism: a randomized double-blind phase 2 study. Neurology 2018; 90: e664–72.
PHARMACOLOGICAL
• Cognition
• Acetylcholinesterase inhibitors
• Donepezil and rivastigmine are EQUALLY EFFECTIVE in improving cognition for patients with
DLB and those with Parkinson’s disease dementia 1,2
• Rivastigmine may be associated with more adverse effects than donepezil 1,2
• Evidence of the efficacy of a third cholinesterase inhibitor, galantamine, in patients with Lewy
body dementia is sparse
• Memantine
• Evidence for efficacy mixed 1,2
1 Stinton C, McKeith I, Taylor JP, et al. Pharmacological management of Lewy body dementia: a systematic review and meta-analysis. Am J Psychiatry 2015; 172: 731–42.
2 Wang HF, Yu JT, Tang SW, et al. Efficacy and safety of cholinesterase inhibitors and memantine in cognitive impairment in Parkinson’s disease, Parkinson’s disease dementia, and dementia with Lewy bodies: systematic review with meta-analysis and
trial sequential analysis. J Neurol Neurosurg Psychiatry 2015; 86: 135–43.
PHARMACOLOGICAL
• Acetylcholinesterase inhibitors
• May have substantial reduction in apathy and improve visual hallucinations and delusions1
• Scores that aggregate apathy, delusions, depression, and hallucinations have indicated a benefit to patients
with dementia with Lewy bodies from donepezil, but not rivastigmine 2
• Antipsychotics
• Neuroleptic sensitivity
• Can consider low dose quetiapine, which may be relatively safer 3
• Antidepressants
• Studies non-conclusive and provide mixed results for selective serotonin-reuptake inhibitors and tricyclics 4
1 Maust D, Kim H, Seyfield L, et al. Antipsychotics, other psychotropics, and the risk of death in patients with dementia: number needed to harm. JAMA Psychiatry 2015;10.1001/jamapsychiatry.2014.3018.
2 Mori E, Ikeda M, Kosaka K. Donepezil for dementia with Lewy bodies: a randomized, placebo-controlled trial. Ann Neurol 2012; 72: 41–52
3 Ehrt U, Broich K, Larsen J, Ballard C, Aarsland D. Use of drugs with anticholinergic effect and impact on cognition in Parkinson's disease: a cohort study. Journal of Neurology, Neurosurgery and Psychiatry 2010;81:160-165.
4 Seppi K, Ray Chaudhuri K, Coelho M, et al. Update on treatments for nonmotor symptoms of Parkinson’s disease—an evidence-based medicine review. Mov Disord 2019; 34: 180–98
Table 8. Cholinesterase inhibitors and memantine for the treatment of cognitive and neuropsychiatric symptoms in
patients with Lewy body dementia
Source: Taylor, J. P., McKeith, I. G., Burn, D. J., Boeve, B. F., Weintraub, D., Bamford, C., Allan, L. M., Thomas, A. J., &
O'Brien, J. T. (2020). New evidence on the management of Lewy body dementia.
NEUROLEPTIC SENSITIVITY
• Neuroleptic medications have increased potential to exacerbate preexisting

parkinsonian symptoms secondary to pre-existing nigrostriatal dopaminergic
deficiencies 1
• Features
• Worsened tremor, rigidity, gait instability, cognition, and hallucinations, and psychosis
• Predisposed to neuroleptic malignant syndrome (characterized by muscle rigidity, fever,
and altered mental status) 2
• Cardiac risk factors: QTc prolongation, myocarditis, cardiomyopathy, torsades de pointes,
and sudden cardiac death 3
1 Aarsland D, Perry R, Larsen JP, et al. Neuroleptic sensitivity in Parkinson’s disease and parkinsonian dementias. J Clin Psychiatry. 2005;66(5):633–37.
2 Teng PR, Yeh CH, Lin CY, et al. Olanzapine-induced neuroleptic malignant syndrome in a patient with probable dementia with Lewy bodies. J Neuropsychiatry Clin Neurosci.
3 Stoner SC. Management of serious cardiac adverse effects of antipsychotic medications. Ment Health Clin. 2017;7(6):246–54
OTHER TREATMENT
• Electroconvulsive therapy
• May reduce depressive symptoms (4 RCTs with total of 22 patients) 1
• 2 RCTs did not show statistically significant improvement in cognition or hallucination 2,3
1 Connors MH, Quinto L, McKeith I, et al. Non-pharmacological interventions for Lewy body dementia: a systematic review. Psychol Med2018; 48: 1749–58.
2 Elder GJ, Ashcroft J, da Silva Morgan K, et al. Transcranial direct current stimulation in Parkinson’s disease dementia: a randomised double-blind crossover trial. Brain Stim 2017; 10: 1150–51.
3 Elder GJ, Colloby SJ, Firbank MJ, McKeith IG, Taylor JP. Consecutive sessions of transcranial direct current stimulation do not remediate visual hallucinations in Lewy body dementia: a randomised controlled trial. Alzheimers Res
Ther2019; 11: 9.
Caution On Use Of Anticholinergic Medications
à Can Cause Confusion And Psychosis 1
1 Ehrt U, Broich K, Larsen J, Ballard C, Aarsland D. Use of drugs with anticholinergic effect and impact on cognition in Parkinson's disease: a cohort study. Journal of Neurology, Neurosurgery and Psychiatry 2010;81:160-165.
PHARMACOLOGICAL
• Sleep-wakefulness disturbance
• Melatonin 1
• Cautious use of bedtime clonazepam: Can worsen cognition and gait impairment
• Non-benzodiazepines (eg Zopiclone, Zolpidem) have not been trialled in patients with
DLB
• Will need to weigh against negative effects on cognition, daytime sleepiness, and increase in
risk of falls and fractures 2
1 Aurora RN, Zak RS, Maganti RK, et al.. Best practice guide for the treatment of REM sleep behavior disorder (RBD). J Clin Sleep Med2010;6:85–95.
2 Asaly A, Kolenberg Geron L, Treves N, Matok I, Perlman A. Z-drugs and risk for falls and fractures in older adults—a systematic review and meta-analysis. Age Ageing 2018; 47: 201–08
PHARMACOLOGICAL
• Restless Leg Syndrome

• Dopaminergic medications: Ropinirole, Pramipexole, Rotigotine (not trialled in patients
with DLB) 1
• Gabapentin, Pregabalin may be as effective as doperminergic medications 1
• REM Sleep Behaviour Disorder
• Medication reconciliation: Antidepressants can worsen REM sleep haviour disorder 2
• Clonazepam, Melatonin 3
• Pramipexole (observational studies suggest potential effectiveness) 4
1 Iftikhar IH, Alghothani L, Trotti LM. Gabapentin enacarbil, pregabalin and rotigotine are equally effective in restless legs syndrome: a comparative meta-analysis. Eur J Neurol 2017; 24: 1446–56.
2 Gagnon J-F, Postuma RB, Montplaisir J. Update on the pharmacology of REM sleep behavior disorder. Neurology 2006; 67: 742–47.
3 Jung Y, St Louis EK. Treatment of REM sleep behavior disorder. Curr Treat Options Neurol 2016; 18: 50.
4 Schaeffer E, Berg D. Dopaminergic therapies for non-motor symptoms in Parkinson’s disease. CNS Drugs 2017; 31: 551–70.
PHARMACOLOGICAL
• Orthostatic Hypotension
• Non-pharmacological: Standing up slowly, increasing fluid and salt intake if able,
compression hosiery
• Fludrocortisone and midodrine are both suggested for treatment of orthostatic hypotension
in patients with PDD (NICE Guidelines)
• Alternative: Droxidopa (prodrug that converts to norepinephrine) is licensed to treat the same
condition in Japan and USA
• Urinary urgency
• No trials on patients with Lewy body dementia thus far
1 Aurora RN, Zak RS, Maganti RK, et al.. Best practice guide for the treatment of REM sleep behavior disorder (RBD). J Clin Sleep Med2010;6:85–95.
PHARMACOLOGICAL
• Delayed gastric emptying
• Gastric emptying in patients with DLB is slower than in those with PDD 1
• Slow gastric emptying correlates with severity of motor impairment 2
• Can be worsened with dopaminergic medications
• Lifestyle modifications: Avoid high fat foods, driving during meals, walking after meals
• Hyperhidrosis
• Associated with disease severity
• No treatment trials have been done
1 Doi H, Sakakibara R, Masuda M, et al. Gastrointestinal function in dementia with Lewy bodies: a comparison with Parkinson disease. Clin Auton Res 2019; published online Feb 11. DOI: 10.1007/s10286-019-00597-w.
2 Goetze O, Nikodem AB, Wiezcorek J, et al. Predictors of gastric emptying in Parkinson’s disease. Neurogastroenterol Motil 2006; 18: 369–75.
Lancet Scihub
FRONTOTEMPORAL
LOBE DEMENTIA (FTD)
INTRODUCTION
• Underlying frontotemporal lobar

degeneration (FTLD)
• Pathological aggregation of protein in the
frontal and temporal lobes with micro-
vacuolation, neuronal loss and astrocytic
gliosis 1
Figure 29. Types of FTD

Source: https://www.dementiaaide.com/blogs/tips-for-
dementia/fronto-temporal-dementia-guide
1 Brun A. Frontal lobe degeneration of non-Alzheimer type. I. Neuropathology. Arch Gerontol Geriatr. 1987;6:193–208
Fused in sarcoma
protein (FTLD-FUS) 3,4
• Accounts for around FTD PATHOLOGY
Frontotemporal lobar
10% of cases degeneration (FTLD)-tau 1,2
FTLD-FUS
10%
• Accounts for ~40% of FTD
cases
FTLD-tau • Three microtubule repeats (3-
43 kDA TAR DNA- 40%
R): Pick's disease
binding protein
• Four microtubule repeats (4-
(TDP-43; FTLD-TDP) 1,2
R): Progressive supranuclear
• Accounts for more TDP-43
palsy (PSP) and cortical basal
than half of FTD cases 50% degeneration (CBD)
• 4 subtypes of TDP-43 • Strongly associated with non-
pathology fluent variant PPA (nfvPPA)
• Associated with
semantic-variant PPA
(svPPA) 2
1 Mackenzie IR, Neumann M, Bigio EH, et al. Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol. 2010;119(1):1–4.
2 Snowden J, Neary D, Mann D. Frontotemporal lobar degeneration: clinical and pathological relationships. Acta Neuropathol. 2007;114(1):31–38.
3 Mackenzie IR, Foti D, Woulfe J, et al. Atypical frontotemporal lobar degeneration with ubiquitin-positive, TDP-43-negative neuronal inclusions. Brain. 2008;131(Pt 5):1282–1293.
4 Neumann M, Rademakers R, Roeber S, et al. A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain. 2009;132(Pt 11):2922–2931.
EVALUATION
HISTOLOGY
Figure 31. FTLD proteinopathies

Source: https://www.med.upenn.edu/digitalneuropathologylab/assets/user-
content/images/site-images/frontotemporal-lobar-degeneration-figure-1-website.png
IMAGING
- INTERNATIONAL CONSORTIUM PROPOSED NEW CRITERIA 2011 1
Behavioural-variant • CT/MRI: Frontal and/or Anterior temporal atrophy

• Single-photon emission computed tomography (SPECT) or
FTD PET: Frontal hypoperfusion or hypometabolism
• CT/MRI: Predominant anterior temporal lobe atrophy

Semantic-variant PPA • SPECT or PET: Predominant anterior temporal hypoperfusion
or hypometabolism
Non-fluent variant • CT/MRI: Predominant left posterior fronto-insular atrophy

• SPECT or PET: Predominant left posterior fronto-insular
PPA hypoperfusion or hypometabolism
1 Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011;134(Pt 9):2456–2477. Provides the new framework for the classification and diagnosis of
behavioral variant FTD (bvFTD)
IMAGING
QUESTION 4: WHAT IS THE DIAGNOSIS?
R L
Figure 30. T1-weighted structural MRI in patients with behavioral variant frontotemporal dementia, semantic
variant primary progressive aphasia and nonfluent variant primary progressive aphasia
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4824317/bin/nihms773421f1.jpg
BIOMARKERS
• Neuroinflammation à Serum TNF 1,2

• Only researched in rat models
1 Lee BS, Jun IG, Kim SH, et al. Intrathecal gabapentin increases interleukin-10 expression and inhibits pro-inflammatory cytokine in a rat model of neuropathic pain. J Korean Med Sci. 2013;28(2):308–314
2 Tang W, Lu Y, Tian QY, et al. The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice. Science. 2011;3324(6028):478–48
Definite diagnosis requires presence of the clinical syndrome
with genetic or pathological confirmation of FTLD.
GENETIC SCREENING
• Approximately 40% of FTD cases have a family history of dementia 1

• 10% of patients have autosomal dominant inheritance 2
• Most common genes responsible: MAPT, Proganulin (PGRN) and C9ORF72
• svPPA least likely to be familial 3
1 Rosso SM, Donker Kaat L, Baks T, et al. Frontotemporal dementia in the Netherlands: patient characteristics and prevalence estimates from a population-based study. Brain. 2003;126(Pt 9):2016–2022.
2 Rohrer JD, Guerreiro R, Vandrovcova J, et al. The heritability and genetics of frontotemporal lobar degeneration. Neurology. 2009;73(18):1451–1456.
3 Goldman JS, Farmer JM, Wood EM, et al. Comparison of family histories in FTLD subtypes and related tauopathies. Neurology. 2005;65(11):1817–1819.
MANAGEMENT
PHARMACOLOGICAL
• No disease-modifying treatment available
• In development: Progranulin replacement and Immunomodulation in svPPA
• Behavioral Management
• Anti-depressants: SSRI 1, Trazodone 2
• Anti-psychotics: Olanzapine 3, Risperidone 4, Aripiprazole 5
• Acetylcholinesterase inhibitors: Data limited, may worsen neuropsychiatric symptoms 6
• Note: Some patients presenting with features of FTD may have underlying Alzheimer’s
pathology!!
• Memantine: No evidence
1 Ikeda M, Shigenobu K, Fukuhara R, et al. Efficacy of fluvoxamine as a treatment for behavioral symptoms in frontotemporal lobar degeneration patients. Dement Geriatr Cogn Disord. 2004;17(3):117–121.
2 Lebert F, Stekke W, Hasenbroekx C, et al. Frontotemporal dementia: a randomised, controlled trial with trazodone. Dement Geriatr Cogn Disord. 2004;17(4):355–359.
3 Moretti R, Torre P, Antonello R, et al. Olanzapine as a treatment of neuropsychiatric disorders of Alzheimer's disease and other dementias: a 24-month follow-up of 68 patients. Am J Alzheimers Dis Other Demen. 2003;18(4):205–214.
4 Curtis RC, Resch DS. Case of pick's central lobar atrophy with apparent stabilization of cognitive decline after treatment with risperidone. J Clin Psychopharmacol. 2000;20(3):384–385
5 Fellgiebel A, Muller MJ, Hiemke C, et al. Clinical improvement in a case of frontotemporal dementia under aripiprazole treatment corresponds to partial recovery of disturbed frontal glucose metabolism. World J Biol Psychiatry. 2007;8(2):123–126.
6 Mendez MF, Shapira JS, Mcmurtray A, et al. Preliminary findings: behavioral worsening on donepezil in patients with frontotemporal dementia. Am J Geriatr Psychiatry. 2007;15(1):84–87
NON-PHARMACOLOGICAL
• Caregiver Education
• Identification of triggers for problematic behaviours
• Behavioural strategies
• Coping skills
• Mindfulness and positive appraisal 1
• Caregiver Support
• Caregivers of patients with FTD report higher levels of generalized
distress burden and report feeling less competent than caregivers
of AD patients 2
1 Dowling GA, Merrilees J, Mastick J, et al. Life enhancing activities for family caregivers of people with frontotemporal dementia. Alzheimer Dis Assoc Disord. 2013;28(2):175–181.
2 De Vugt ME, Riedijk SR, Aalten P, et al. Impact of behavioural problems on spousal caregivers: a comparison between Alzheimer's disease and frontotemporal dementia. Dement Geriatr Cogn Disord. 2006;22(1):35–41.
END OF LIFE CARE
- Hospice criteria for dementia include:
1. Dementia of sufficient severity
2. The first occurrence of medical complications (eg aspiration pneumonia, upper urinary
tract infection, worsening stage 3-4 decubiti, recurrent fever after course of antibiotics or
>10% weight loss over 6 months
- Dementia severity qualifies for hospice when the patient has passed Stage 7-C of
the FAST scale
• Seven studies met the inclusion criteria, five of which were set in the United
States and two in Israel.
• All but one study found that Functional Assessment Staging phase 7c, currently
widely used to assess hospice admission eligibility in the United States, was not a
reliable predictor of 6-month mortality.
• There is lack of prognosticator concordance across the literature
• Retrospective cohort study of data
from the Minimum Data Set (MDS)
• Population: Patients with advanced
dementia who were admitted to
New York nursing homes
• Method: Mortality risk index score
created to stratify residents into
different levels of risk for 6-month
mortality (12 variables)
• Estimates 6-month mortality with
greater accuracy than existing
prognostic guidelines.
FINANCIAL ASSISTANCE
SCHEMES
QUESTION 5: WHICH OF THE FOLLOWING IS NOT USED BY
MOH IN ITS SEVERE DISABILITY ASSESSMENT? (CHOOSE 2)
• Dressing
• Showering
• Transferring
• Ambulation
• Continence
• Cognitive Impairment
QUESTION 5: WHICH OF THE FOLLOWING IS NOT USED BY
MOH IN ITS SEVERE DISABILITY ASSESSMENT? (CHOOSE 2)
• Dressing
• Showering
• Transferring
• Ambulation
• Continence
• Dementia
Table 9. Levels of Disability
Source: https://www.sma.org.sg/UploadedImg/1641354483_2019OctAIC%20Says.pdf
Table_. Schemes for patients with varied levels of disability
Source: https://www.sma.org.sg/UploadedImg/
1641354483_2019OctAIC%20Says.pdf
NOT COVERED TODAY
• Management of BPSD
• Evaluation and Management of Parkinson Disease Dementia, Progressive Supranuclear Palsy,
Corticobasal Degeneration

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APPROACH TO EVALUATION

Acetylcholine Optimise acetylcholine

Tau Prove presence of Remove

Table 1. AT(N) biomarker grouping

1. Prove presence of Aβ oligomers or hyperphosphorylated tau:

Figure 6. Hallmark pathology of Alzheimer's disease.

• Cognitively unimpaired individuals with abnormal amyloid biomarkers

• CSF Aβ42, or Aβ42/Aβ40 ratio

• A decrease in CSF Aβ42 is characteristic of AD

• T-tau is less specific than P-tau for AD

Figure 9. Comparison of Amyloid PET images for cognitively normal individuals

Figure 13. ERICA grading

• Assess for possible underlying vascular damage

• What is the biomarker profile and

• Biomarker profile A+T+(N)+.

• What is the biomarker profile and

• Biomarker profile A+T−(N)−.

• Amyloid and tau plasma biomarkers significantly correlated

• Caregiver Training Programme/Support

• Long Term Care Plan

Strategies for the use of Ginkgo

Drugs that provoke a

• Mechanism: Inhibits break down

Figure 16. Mechanism of action of Acetylcholinesterase Inhibitors

Cochrane Systematic Review: Cholinesterase inhibitors for Alzheimer’s disease 1

Cholinesterase inhibitors for patients with Alzheimer's disease: systematic

Figure 18. Mechanism of action of Memantine

Memantine Treatment in Patients With Moderate to Severe Alzheimer Disease

Acetylcholine Optimise acetylcholine

Tau Prove presence of Remove

Figure 20. Donanemab mechanism of action

AE=adverse event; ARIA-E=amyloid-related imaging abnormalities-edema/effusions; ARIA-H=amyloid-related imaging abnormalities-

• Humanized IgG1 monoclonal

Figure _. How Lecanemab works

• Funded by the National Institutes of Health and Eisai, Inc.

Table 5. Clinical effect of 3rd generation anti-amyloid immunotherapies

Arteriolar Changes Outcomes

Figure 23. Different Cerebrovascular Pathologies associated with Dementia in

• Most common locations:

Figure 26. CT Brain and MRI images showing lacunar infarcts

• Best scored on transverse FLAIR or T2-weighted

• Severe white matter changes are independently

• Many have been studied, including oxLDL,

SPRINT (Systolic Blood Pressure PROGRESS (Perindopril Protection Against

Diabetes Hyperlipidemia Atrial Fibrillation

Heart Protection Study and

How do acetylcholinesterase inhibitors and memantine

• Naftidrofuryl – Uncertain benefit

Figure 39. Pathological findings of dementia with Lewy bodies on autopsy

Assesses amyloid Assesses cholinergic Assesses nigrostriatal

• Hypoperfusion in • Cortical amyloid load is • Widespread reductions • Reduced binding in

Assesses amyloid Assesses cholinergic Assesses nigrostriatal

• Hypoperfusion in • Cortical amyloid load is • Widespread reductions • Reduced binding in

• Less pronounced global atrophy • Different patterns of functional

1 Nakajima K, Okuda K, Yoshimura M, et al. Multicenter cross-calibration of I-123 metaiodobenzylguanidine

• Demonstrates REM sleep without atonia 1

Figure 38. Polysomnography readings for normal control (top) and

• Limited understanding regarding code genes involved

• Neuroleptic medications have increased potential to exacerbate preexisting

• Restless Leg Syndrome

• Underlying frontotemporal lobar

Figure 29. Types of FTD

Figure 31. FTLD proteinopathies