739818

research-article2017
TPP0010.1177/2045125317739818Therapeutic Advances in PsychopharmacologyJ. Young et al.

Therapeutic Advances in Psychopharmacology Review

Frontotemporal dementia: latest evidence

Ther Adv Psychopharmacol

2018, Vol. 8(1) 33­–48

and clinical implications DOI: 10.1177/

https://doi.org/10.1177/2045125317739818
https://doi.org/10.1177/2045125317739818
2045125317739818

© The Author(s), 2017.

Reprints and permissions:
Juan Joseph Young, Mallika Lavakumar, Deena Tampi, Silpa Balachandran http://www.sagepub.co.uk/
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and Rajesh R. Tampi

Abstract
Background: Frontotemporal dementia (FTD) describes a cluster of neurocognitive syndromes
that present with impairment of executive functioning, changes in behavior, and a decrease
in language proficiency. FTD is the second most common form of dementia in those younger
than 65 years and is expected to increase in prevalence as the population ages. This goal
in our review is to describe advances in the understanding of neurobiological pathology,
classification, assessment, and treatment of FTD syndromes.
Methods: PubMed was searched to obtain reviews and studies that pertain to advancements in
genetics, neurobiology, neuroimaging, classification, and treatment of FTD syndromes. Articles
were chosen with a predilection to more recent preclinical/clinical trials and systematic reviews.
Results: Recent reviews and trials indicate a significant advancement in the understanding
of molecular and neurobiological clinical correlates to variants of FTD. Genetic and
histopathologic markers have only recently been discovered in the past decade. Current
therapeutic modalities are limited, with most studies reporting improvement in symptoms
with nonpharmacological interventions. However, a small number of studies have reported
improvement of behavioral symptoms with selective serotonin reuptake inhibitor (SSRI)
treatment. Stimulants may help with disinhibition, apathy, and risk-taking behavior.
Memantine and cholinesterase inhibitors have not demonstrated efficacy in ameliorating
FTD symptoms. Antipsychotics have been used to treat agitation and psychosis, but safety
concerns and side effect profiles limit utilization in the general FTD population. Nevertheless,
recent breakthroughs in the understanding of FTD pathology have led to developments in
pharmacological interventions that focus on producing treatments with autoimmune, genetic,
and molecular targets.
Conclusion: FTD is an underdiagnosed group of neurological syndromes comprising multiple
variants with distinct neurobiological profiles and presentations. Recent advances suggest
there is an array of potential novel therapeutic targets, although data concerning their
effectiveness are still preliminary or preclinical. Further studies are required to develop Correspondence to:
pharmacological interventions, as there are currently no US Food and Drug administration Rajesh R. Tampi
MetroHealth Medical
approved treatments to manage FTD syndromes. Center, Case Western
Reserve University
School of Medicine,
2500 MetroHealth Drive,
Keywords:  classification, frontotemporal dementia, frontotemporal lobar degeneration, Cleveland, OH 44109, USA
genetics, neurobiology, treatment rajesh.tampi@gmail.com
Juan Joseph Young
Mallika Lavakumar
Received: 21 February 2017; revised manuscript accepted: 26 September 2017. Silpa Balachandran
Department of Psychiatry,
MetroHealth Medical
Center, Cleveland, OH,
USA Case Western
Reserve University,
Introduction executive functioning, behavior, and language. It Cleveland, OH, USA
Frontotemporal dementia (FTD) is a term used is considered the third most common form of Deena Tampi
to describe a group of neurocognitive disorders dementia following Alzheimer’s disease (AD) and Mercy Regional Medical
Center, 3700 Kolbe Rd,
that encompass progressive dysfunction in dementia with Lewy bodies.1 As per its namesake, Lorain, OH 44053, USA.

journals.sagepub.com/home/tpp 33
Therapeutic Advances in Psychopharmacology 8(1)
it is a cluster of syndromes that result from degen-
eration of the frontal and temporal lobes, and is
subdivided into two categories that are unique in
respect to their predominating presentations;
namely, the behavioral subtype that accounts for
about half of FTD cases, and the language sub-
type.2 The language subtype is further subdivided
into nonfluent and semantic variants of primary
progressive aphasia (PPA), which are character-
ized by diverging localizations and underlying
cerebral dysfunction.2,3 The semantic and nonflu-
ent variants of PPA are both characterized by
prominent language impairment, but also differ
in neurological localization, severity of specific
symptoms, and the overall course of their presen-
tations. Illustrative of this, the semantic variant
exhibits bilateral anterior temporal lobe atrophy
and is associated with dysfunction of emotional
processing, compulsions, and decline in language
skills. In contrast, the nonfluent variant com-
monly presents with greater left hemisphere atro-
phy, and is associated with speech problems
earlier while behavioral disturbances develop later
in the disease course.3 As the population of geri-
atric patients grow and neurocognitive disorders
become more prevalent, there will be an increased
need for physicians with an expert understanding
of the diverse clinical findings that define the het-
erogeneous FTD subtypes. This review will focus
on the most recent findings concerning FTD
neurobiology, current classification and assess-
ment systems, and the most up-to-date expert
consensus on the treatment of this unique collec-
tion of syndromes.
Epidemiology
According to the World Health Organization
(WHO), there are an estimated 47.5 million peo-
ple who have dementia with another 7.7 million
new cases every year.4 Although AD is the most
common form of dementia, contributing to 60–
70% of cases, mixed types exist, and the overlap
between different forms of dementia is sizeable.
FTD is the second most common cause of
dementia in patients aged < 65 years,5 with a fur-
ther 25% of dementia cases in patients older than
65 years also attributed to FTD disorders.6
However, determining the total population with
underlying FTD pathology is difficult due to the
low disease frequency in a relatively large at-risk
population. Additionally, studies estimating inci-
dence and prevalence rates of FTD are limited
by the inherent difficulty identifying FTD disor-
ders.6,7 In the USA, Knopman and Roberts7
34 journals.sagepub.com/home/tpp
estimated that the prevalence of FTD between
the ages of 45–65 years ranged from 15 to 22 per
100,000 people, with incidence estimates rang-
ing from 2.7 to 4.1 per 100,000 members in the
same age range. Overall, they estimated approxi-
mately 20,000 to 30,000 cases of FTD in the
USA alone. Yet, these numbers may actually be
underestimating the occurrence of FTD syn-
dromes. This is especially evident, as older cases
of FTD begin to echo symptoms of AD further
confounding the delineation between the neuro-
cognitive disorders.6 Further emphasizing the
limitations of FTD epidemiologic studies,
Lambert and colleagues8 conducted a systematic
review with the goal of estimating prevalence
rates of early-onset dementia. They found a sig-
nificant disparity between studies estimating the
prevalence of early-onset FTD with estimates
ranging from 1.0 to 15.4 per 100,000 members
of the population. Adding to this, it appears that
the data presented was principally collected from
populations studied in the UK, mainland Europe,
and Japan, suggesting that the information gath-
ered may not be generalizable to the world-wide
population as a whole. For this reason, standard-
ization of study designs will likely aid in more
precisely defining FTD epidemiology globally, a
focus that future studies should pursue in the
future.
Classification and assessment systems
Researchers have developed multiple methodol-
ogies to classify FTD disorders using biological
and molecular signatures. However, diagnosis is
still obtained clinically due to the absence of
definitive biomarkers. The international consen-
sus criteria for the behavioral variant of FTD
(bvFTD) was published by the International
Behavioral Variant FTD Criteria Consortium9
to develop a sensitive standard for early screen-
ing and management of bvFTD. To be diag-
nosed, a patient must show progressive
deterioration of behavior or cognition by obser-
vation or history provided by a reliable caretaker
or informant in order to be diagnosed. Possible
bvFTD is diagnosed if three or more of the fol-
lowing are present: (a) early behavioral disinhi-
bition described as socially inappropriate
behavior, loss of manners/decorum, impulsivity
and rash actions; (b) early apathy or inertia; (c)
early loss of empathy or sympathy, including
diminished response to other people’s need
or sympathies, and diminished social interest;
(d) early perseverative or compulsive/ritualistic

behavior (i.e. simple repetitive movements,
complex, compulsive, or ritualistic behavior, ste-
reotypy of speech); (e) hyperorality and dietary
changes, including altered food preferences,
binge eating, increased consumption of alcohol
and cigarettes, oral exploration or consumption
of inedible objects; (f) neuropsychological pro-
file demonstrates deficits in executive function-
ing and relative sparing of episodic memory and
visuospatial functioning. Probable bvFTD diag-
nosis would need to meet criteria for possible
bvFTD, but also includes imaging suggestive of
frontal or anterior atrophy on magnetic reso-
nance imaging (MRI) or computed tomography
(CT). Alternatively, positron emission tomogra-
phy (PET) or single-photon emission computed
tomography (SPECT) imaging demonstrating
hypoperfusion or hypometabolism in the frontal
or anterior temporal regions could be used to
diagnose probable bvFTD. Definitive bvFTD
with definite FTD pathology is diagnosed when
a patient meets criteria for possible bvFTD and
has one or both of the following: histopathologi-
cal evidence of FTD or if there is evidence of a
known pathogenic mutation. bvFTD is excluded
if a patient’s presentation is better accounted for
by other nondegenerative nervous system or
medical disorders, a psychiatric diagnosis, or
biomarkers are strongly indicative of other neu-
rocognitive disorders or neurodegenerative pro-
cesses such as AD.9
Gorno-Tempini and colleagues developed a com-
mon framework for the classification of PPA sub-
types to provide consistency in clinical diagnosis
and standardize PPA assessments for future clini-
cal studies.10 According to this framework, PPA is
diagnosed when a patient exhibits prominent dif-
ficulty with language wherein the deficits are the
principal cause of impairment of daily activities,
with aphasia being the most prominent deficit at
symptom onset and during the initial phase of the
disease. PPA diagnosis is excluded if the present-
ing symptoms are more consistent with other
neurocognitive disorders, medical conditions,
neurodegenerative processes, or a psychiatric
diagnosis. PPA is also excluded if there are prom-
inent initial episodic memory, visual memory,
visuospatial impairments, and initial behavioral
disturbance. Patients may be diagnosed with the
semantic variant of PPA (svPPA) if they exhibit
impaired confrontation naming (i.e. difficulty
naming or recognizing objects or drawings) and
impaired single-word comprehension, and have
at least three of the following: (a) impaired object
journals.sagepub.com/home/tpp 35
J Young, M Lavakumar et al.
knowledge; (b) surface dyslexia (i.e. inability to
recognize words as a whole) or dysgraphia; (c)
spared repetition; (d) spared speech production.
For an imaging-supported diagnosis, there must
either be predominant anterior temporal lobe
atrophy or predominant anterior temporal hypop-
erfusion/hypometabolism on SPECT or PET.
For a definite pathology diagnosis, there must be
histopathologic evidence or the presence of a
known pathogenic mutation.
The nonfluent variant of PPA (nfvPPA) diagno-
sis requires at least one of two core features
(agrammatism in language production or effort-
ful, halting speech not consistent with apraxia of
speech), and two out of three of the following
features: (a) impaired comprehension of complex
sentences; (b) spared single-word comprehen-
sion; (c) spared object knowledge. Imaging-
supported nfvPPA variant diagnosis is obtained
when there is imaging that demonstrates pre-
dominant left posterior-fronto-insular atrophy
on MRI or predominantly left posterior fronto-
insular hypoperfusion or hypometabolism on
SPECT or PET. Alternatively, nfvPPA with defi-
nite pathology diagnosis is present when there is
histopathologic evidence or the presence of a
known pathogenic mutation.
Like other PPA subtypes, individuals with the
logopenic variant of PPA exhibit language impair-
ment but with more specific difficulties in con-
frontation naming and syntax. These individuals
are more likely to have speech interrupted with
filling sounds, frequent pauses, phonological
errors, and impaired sentence repetition.11 The
diagnosis of logopenic variant PPA requires the
following core features to be present: impaired
single-word retrieval in spontaneous speech and
naming, and impaired repetition of sentences and
phrases. Additionally, three of four of the follow-
ing features must also be present for a diagnosis:
(a) speech (phonologic) errors in spontaneous
speech and naming; (b) spared single-word com-
prehension and object knowledge; (c) spared
motor speech; (d) absence of frank agrammatism.
As with other PPA-variant diagnoses, imaging-
supported diagnosis is made with corresponding
abnormalities in imaging. In the logopenic vari-
ant, MRI, SPECT, or PET scans must demon-
strate predominant left posterior perisylvian or
parietal atrophy/hypoperfusion/hypometabolism.
Definite histopathologic evidence or the presence
of a known pathogenic mutation would allow for
a definite pathology specifier.
Therapeutic Advances in Psychopharmacology 8(1)
Familial frontotemporal dementia caused
by frontotemporal dementia-associated
mutations
FTD is a highly heritable disorder despite varying
heritability among different clinical syndromes
and subtypes due to a range of gene mutations.12
Up to half of FTD cases with autosomal-dominant
inheritance report a family history of FTD.13
Familial FTD also accounts for approximately one
third to half of all FTD cases and presents more
commonly as bvFTD than other FTD sub-
types.6,14 Mutations in microtubule-associated
protein tau (MAPT),15–25 progranulin (PGRN),26–38
and chromosome 9 open reading frame 72
(C9orf72) expansion mutations32,39–50 have been
found to be the most common causes of familial
FTD.51,52 Although FTD presentations are rela-
tively homogenous early in the disease course,
different biological correlates and varying genetic
mutations ultimately result in diverging clinical
courses.53 MAPT-associated familial FTD typi-
cally presents younger than FTD associated with
other mutations, and presents as bvFTD with or
without Parkinsonian symptoms, as well as with
or without language decline. MAPT mutations
occur on average at a frequency of 6–11% of all
FTD subjects, is inherited in an autosomal-dom-
inant manner, has high penetrance, and may have
a shorter duration of illness relative to other muta-
tions.17,54,55 The most prominent behavioral fea-
tures with MAPT mutations include disinhibition,
stereotyped repetitive behaviors, and obsessions.
Notably, apathy is less common than in PGRN
and C9orf72 cases. Semantic impairment is more
common later during the disease course. Episodic
memory loss may occur and mimic early onset
AD.56 MAPT mutations have been implicated in
the formation of hyperphosphorylated tau in cor-
tical and subcortical grey and white matter sug-
gesting a neuroanatomical correlation in the
development of clinical symptoms.55
PGRN mutations present with more variable
clinical presentations, but most commonly pre-
sent as bvFTD and less commonly as a nfvPPA
presentation.57 Mutations occur at a frequency of
5–20% in the FTD population, are inherited in
an autosomal-dominant manner, and have rela-
tively low penetrance until the age of 70.17,58,59
Apathy and social withdrawal are prominent in
their presentation, and 10–30% of cases may pre-
sent with episodic memory impairment.60
Neuropsychiatric symptoms are common and
patients may report delusions, hallucinations, or
exhibit ritualistic behaviors. There is also a
36 journals.sagepub.com/home/tpp
predominance of early language involvement
compared with MAPT or C9orf72 mutations.
Extrapyramidal symptoms occur between 40%
and 60% of PGRN-associated FTD cases.57,60
Interestingly, PGRN mutations, though thought
to be pathogenic, do not appear to increase the
risk of developing FTLD.54
FTD patients with the C9orf72 expansion muta-
tion present more commonly as bvFTD, motor
neuron disease, or a combination of the two,
although clinical presentations tend to be hetero-
geneous early in the disease process.41,61 Apathy,
disinhibition, and loss of empathy are prominent
behavioral features in this type of familial FTD.62
Complex stereotyped behaviors are common, but
language decline is rarer compared with patients
with MAPT or PGRN mutations. Patients typi-
cally have profound disruption of executive func-
tioning, may have reduced spontaneous speech,
echolalia, perseveration, impaired visual and ver-
bal episodic memory, apraxia, anomia, and dys-
calculia.63 C9orf72 expansion mutations exhibit
an autosomal-dominant pattern of inheritance, is
implicated in disease anticipation that affect suc-
cessive generations,44 and is considered the most
common cause of ALS-FTD (amyotrophic lateral
sclerosis associated with frontotemporal dysfunc-
tion).42,43,49 However, the minimum repeat length
required to indicate increased risk of disease is
unknown.47 These expansion mutations are
highly associated with transactive response DNA-
binding protein (TDP-43) pathology, and the
presence of neuronal cytoplasmic and intranu-
clear inclusions that are immunoreactive to ubiq-
uitin proteasome system markers. A confounding
factor to consider when diagnosing this subtype is
the possibility of AD-like biomarkers present in
the cerebrospinal fluid.60 Psychiatric presenta-
tions, including delusions, auditory/visual/tactile
hallucinations, somatoform symptoms, agitation,
and anxiety may be observed. Parkinson-like
symptoms are common and may present as gait
disturbance, tremor, akinesis, and rigidity. Most
patients do not respond to levodopa when
administered.60,62
Two other studied pathognomonic mutations
found in a minority of cases include mutations in
vasolin-containing protein (VCP) and transactive
DNA-binding protein (TARDBP).64 VCP muta-
tions have been implicated in ubiquitin–proteas-
ome pathway dysfunction, disruption of TDP-43
localization, and inducing neuronal apoptosis.65
Individuals with VCP mutations historically

present as the triad of autosomal-dominant
hereditary inclusion body myopathy with Paget’s
disease of the bone and frontotemporal dementia
(IBMPFD).66–69 FTD symptoms typically include
behavioral changes, executive dysfunction, and
aphasia.70 Consequently, a number of European
and Asian cases detailing progressive myopathy
with signs and symptoms consistent with FTD
have been associated with VCP mutations.71–77 Of
particular note is one study78 that investigated
how the location of VCP gene mutations in 27
families related to the progression and severity of
symptoms. Critically, the investigators found that
the onset of neurocognitive deterioration fore-
shadowed a rapid progression of the disease lead-
ing to an average life span of 6 years.
Alternatively, TARDBP was found to be a major
component of ubiquitin-positive and tau-negative
inclusions in patients that have been diagnosed
with both amyotrophic lateral sclerosis (ALS) and
FTD.79 TARDBP has also been implicated in
both behavioral and semantic FTD cases with co-
occurring motor neuron disease (MND).80
However, other studies have reported cases of
individuals with TARDBP mutations that have
developed FTD without the progression of ALS
or MND symptoms.81,82 Clinical presentations of
patients with TARDBP mutations are highly het-
erogeneous and may present with apathy, poor
executive functioning, poor language comprehen-
sion, or disinhibition.83 It has been suggested that
mutations of TARDBP have led to increased
translocation of TDP-43 causing dysregulation of
neuronal endoplasmic reticulum calcium signal-
ing resulting in an increase in B-cell lymphoma 2
(Bcl-2) mediated neuronal apoptosis.84
Neurobiology
FTD is classified into distinct, major subtypes
based on their respective protein-based inclusions
and underlying molecular pathologies. Namely,
they are separated into the tau-based frontotem-
poral lobar degeneration (FTLD)-tau subtype,
the FTLD-TDP subtype associated with TDP-
43, the FTLD-FET subtype that is associated
with the fused in sarcoma (FUS) proteinopathy
and other FET [i.e. FUS, EWSR1 (EWS RNA-
binding protein 1), TAF15 (TATA-box binding
protein associated factor 15)] family proteins, and
FTLD-ubiquitin–proteasome system (UPS).59,85
(See Table 1 for a summary of FTD tauopathies)
FTLD-tau accounts for approximately 40% of
all FTD cases, and is characterized by misfolded
journals.sagepub.com/home/tpp 37
J Young, M Lavakumar et al.
tau tangles similar to those found in AD.86 The
tauopathy present in this variant involves hyper-
phosphorylated tau protein that forms insoluble
filamentous inclusions, which adversely affect
axonal transport regulation, microtubule forma-
tion, and microtubule stabilization. These
changes lead to a decrease in microtubule binding
and an increase in tau aggregation, the latter of
which induces neurotoxicity and nerve cell dys-
function.87 Tau aggregates in FTLD-tau subtypes
vary in the degree of phosphorylation and the
amount of tau isoforms they contain. This has
prompted their subclassifications into predomi-
nantly 3R or 4R (e.g. corticobasal degeneration,
progressive supranuclear palsy, argyrophilic grain
disease, globular glial tauopathy) tau isoform dis-
orders.59,88 These subtypes of FTLD tauopathies
also have distinct anatomical and histopathologi-
cal correlates. In general, FTD is associated with
severe neuronal pathology, and spherical argyro-
philic neuronal cytoplasmic inclusions composed
primarily of 3R tau isoforms.64 Progressive supra-
nuclear palsy (PSP), a movement disorder that
presents with rigidity, bradykinesia, and ophthal-
moplegia, is characterized by significant degener-
ation of subcortical regions including the
subthalamic nucleus, midbrain, substantia nigra,
globus pallidus, and striatum. Postmortem exam-
inations of PSP patients demonstrate spherical
and flame-shaped neurofibrillary tangles, tufted
astrocytes, and inclusions composed predomi-
nantly of the 4R tau isoform.89 FTD tauopathies
may also exhibit the corticobasal syndrome,
which may present as rigidity, bradykinesia, dys-
tonia, apraxia, and alien limb phenomenon, is
characterized by substantia nigra depigmenta-
tion, globus pallidus atrophy, and asymmetric
and focal cortical atrophy. This syndrome
exhibits similar traits compared with PSP, but
develop more white matter involvement and has
unique ring-shaped collections called astrocytic
plaques caused by tau accumulation in
astrocytes.59,89
Alternatively, neuronal inclusions immunoreac-
tive to ubiquitin are characteristic of the FTLD-
TDP and FTLD-FET forms.85,90 In FTLD-TDP,
these neuronal inclusions are primarily composed
of TDP-43, which has been associated with mul-
tiple genetic markers thought to be pathogno-
monic of FTD. These include mutations of
PGRN, C9orf72, and VCP.86,91 In mice, accu-
mulation of the insoluble, phosphorylated cyto-
plasmic TDP-43 and loss of nuclear TDP-43 is
associated with brain atrophy, muscle
Therapeutic Advances in Psychopharmacology 8(1)
Table 1.  Frontotemporal dementia tauopathies.59
Tauopathies Presentation
Pick’s disease bvFTD or nfvPPA
Progressive Rigidity, ophthalmoplegia,
supranuclear palsy bradykinesia
Corticobasal Rigidity, bradykinesia, dystonia,
degeneration apraxia, alien limb phenomenon
FTD, frontotemporal dementia; bvFTD, behavioral variant FTD; nfvPPA, nonfluent variant primary progressive aphasia.
denervation, motor neuron loss, and progressive
motor impairments that are commonly observed
both in FTLD-TDP and ALS suggesting a com-
mon neuropathological pathway.92 FTLD-TDP
is further subdivided into Types A, B, C, and D
that differ in the constitution of pathological
inclusions and their distribution within the corti-
ces.93 Patients with FTLD-TDP Type A have
predominantly neuronal cytoplasmic inclusions
and dystrophic neurites with TDP-43 immunore-
active lesions in the second layer of the cortices.
FTLD-TDP type B features more neuronal cyto-
plasmic inclusions in the superficial and deeper
cortical layers. FTLD-TDP type C has a signifi-
cant amount of dystrophic neurites demonstrat-
ing a ‘corkscrew appearance’ through the cortical
layers. FTLD-TDP type D is associated with
multiple neuronal intranuclear inclusions and
dystrophic neurites with fewer neuronal cytoplas-
mic inclusions.85,93 Protein immunoreactivity to
members of the FET protein family, with FUS
being the more well-known FTD-associated pro-
teinopathy, is the last major subgroup of FTD
pathology, and is associated with co-aggregation
of FET proteins into ubiquitinated inclusions
found in severe cases of sporadic FTD.59,86 Of
note, FUS protein involvement in the pathology
of certain FTD subtypes is suggestive of a com-
mon neuropathologic mechanism and close rela-
tionship between the FTD disorders and ALS,
since FUS has been described as a common cause
of autosomal-dominant ALS.92,94 Interestingly,
FTD-associated proteinopathies including tau,
TDP-43, and FUS have demonstrated aggrega-
tion and seeding behavior in both in vivo and in
vitro models, suggesting FTD pathologies have
prion-like characteristics.86,87 Lastly, the FTLD-
UPS subtype is characterized by ubiquitin-immu-
noreactive inclusions that do not label for tau,
TDP-43, or FET proteins.12,95–97 This subtype is
commonly associated with a mutation in the
38 journals.sagepub.com/home/tpp
Histopathology Tau isoform
Pick bodies, argyrophilic neuronal 3R
cytoplasmic inclusions
Spherical and flame-shaped 4R
neurofibrillary tangles, tufted
astrocytes
White matter degeneration with –
ring-shaped astrocytic plaques
charged multivesicular body protein 2B
(CHMP2B) gene that leads to dysfunction in the
endosomal ESCRTIII complex that causes dis-
ruption of endosomal traffic.98–101 A decline in
levels of CHMP2B results in a decrease of hip-
pocampal dendritic branching and reduced excit-
atory synapse activity effectively diminishing
synaptic plasticity and causing neurodegenerative
deficits.102 This subtype typically presents with
changes in behavior and personality (i.e. disinhi-
bition, apathy, loss of emotion, dyscalculia, pro-
gressive aphasia that leads to mutism), as well
extrapyramidal motor symptoms as the disease
progresses.98 However, CHMP2B mutations are
relatively rare,103 and do not appear to increase
the risk of development of FTD.104
Neuroimaging
A recent review105 of neuroimaging studies have
detailed advances in quantifying brain atrophy in
FTD using volumetric MRI measurements and
by observing hypometabolism in specific regions
using [18F] fluorodeoxyglucose PET (18F-FDG
PET). Volumetric MRI studies they reviewed
focused mainly on cerebral loss of grey matter
with the goal of improving accurate diagnosis and
characterization of FTD variants. In these stud-
ies, MRI imaging demonstrated disruption of the
salience network, default mode network, left
hemisphere language and semantic networks, and
executive control networks that imply pathoana-
tomical relationships in FTD syndromes.
Notably, one study has demonstrated how base-
line salience network resting state activity may
predict behavioral changes in FTD.106 MRI stud-
ies of bvFTD patients in particular show losses in
the prefrontal cortex, anterior temporal regions,
insula, anterior cingulate, striatum, and thala-
mus, which differentiate bvFTD from AD with
relatively high sensitivity and specificity. A recent

retrospective observational study also suggests
that there are specific anatomical phenotypes
based on the salience and semantic appraisal net-
works that may contribute in classifying the oth-
erwise heterogeneous bvFTD subgroups.107 The
svPPA exhibits more asymmetric temporal lobe
atrophy on imaging scans with primarily anterior
and inferior regional atrophy more commonly
seen in the left hemisphere. The earliest changes
observed are grey matter losses in the inferior
temporal and fusiform gyri, temporal pole, and
parahippocampal entorhinal cortex. Notably,
temporal pole atrophy could be seen on MRI
imaging despite a patient’s continued ability to
maintain activities of daily functioning. However,
the severity of functional decline does later cor-
relate with the extent of atrophy as it progresses to
orbitofrontal, inferior frontal, insular, and ante-
rior cingulate cortices anteriorly. While both vari-
ants of PPA share the trait of primarily left
hemisphere atrophy, the nfvPPA differs from
svPPA in distribution during the course of the
disease. In nfvPPA, atrophic losses may begin in
the inferior frontal gyrus (particularly in the pars
opercularis), dorsolateral prefrontal cortex, supe-
rior temporal gyrus, and insula. Over time, these
losses will include the prefrontal and temporal
lobe structures in the right hemisphere. Ipsilateral
anterior frontal, lateral temporal, and anterior
parietal lobes are also affected. Lastly, the logo-
penic PPA subtype has a more posterior profile
involving the left temporoparietal and posterior
cingulate atrophy in the early stages of disease
progression. In summary, bvFTD subtypes pre-
sent with frontal and temporal lobe pathology
that includes key tracts such as the corpus callo-
sum and cingulum, while PPA subtypes are more
focal and asymmetric presenting with white mat-
ter changes in specific networks associated with
language processing. Other pathologically defined
forms also exhibit specific atrophic patterns. PSP
is associated with midbrain atrophy, and TDP-43
proteinopathies present with a variation of sym-
metric and asymmetric atrophic findings accord-
ing to the underlying TDP type.
18F FDG-PET imaging studies also demonstrate
patterns of hypometabolism that correlate with
areas of atrophy, and are useful in differentiating
AD from FTD. In FTD, PET studies typically
demonstrate hypometabolism in the anterior
frontotemporal regions including the cingulate
gyri, uncus, insula, subcortical areas, basal gan-
glia, and medial thalamic regions. Hypometabolism
is limited to frontal, parietal, and temporal
journals.sagepub.com/home/tpp 39
J Young, M Lavakumar et al.
cortices during the early stages of the disease but
spreads outwards as the disorder progresses.
Orbitofrontal, dorsolateral, medial prefrontal cor-
tex, and anterior poles display hypometabolism in
bvFTD patients’ PET scans. Likewise, svPPA
patients exhibit more asymmetrical presentations
with exclusively left temporal lobe hypometabo-
lism, nfvPPA imaging shows hypometabolism in
the left frontal and superior temporal regions, and
logopenic variants demonstrate a left parietotem-
poral hypometabolism extending to anterior tem-
poral and frontal regions.105,108 However, it is
important to note that there is considerable indi-
vidual variability when using imaging to classify
FTD disorders as a consequence of heterogeneity
in genetic associations and the underlying patho-
logical causes that are yet to be fully understood.
Consequently, neurobiological and imaging
markers remain ancillary modalities in the diag-
nosis and classification of FTD subtypes in con-
trast to the gold standard of clinical evaluations.
Please see Table 2 for a summary of neuroimag-
ing findings commonly found in FTD variants.
Management and treatment
There is a lack of quality studies and reports con-
cerning the management of problematic behav-
iors in FTD with mainly sparse case reports and
case series detailing their effectiveness.
Nevertheless, nonpharmacological strategies are
considered the preferred intervention before
resorting to pharmacological therapies that may
exacerbate medical comorbidities that affect more
elderly patients. The main purpose of nonphar-
macological interventions is to prevent disruptive
behaviors, provide symptom relief, and lessen
caregiver distress. Environmental approaches aim
to decrease irritability, aggression, and anxiety
that arise from patients’ difficulty processing
information from the array of daily stimuli. These
interventions include reducing noise, limiting
stimulation, simplifying social parameters by lim-
iting interaction to small groups of people, and
facilitating the removal of complicated daily activ-
ities that may confuse, and therefore agitate,
patients. There should be special care in imple-
menting hearing aids, and optimizing sensory
stimulation to limit patient discomfort.
Introducing games or old hobbies may reduce
disinhibition and inappropriate behavior. Exercise
has been suggested to reduce behavioral symp-
toms as well. Confronting and challenging psy-
chotic symptoms may lead to more agitation, so
reassurance and distracting patients are
Therapeutic Advances in Psychopharmacology 8(1)

Table 2.  Frontotemporal dementia neuroimaging correlations.105

Variant MRI findings PET/SPECT findings

bvFTD Atrophy in prefrontal cortex, anterior temporal Decreased FA in uncinate fasciculus,
regions, anterior cingulate, the striatum, genu of corpus callosum and cingulum,
thalamus, the insula superior and inferior longitudinal
fasciculi, inferior fronto-occipital
fasciculus
nfvPPA Predominant left hemisphere cortical Decreased FA in left uncinate fasciculus,
loss; atrophy predominantly affecting pars inferior longitudinal fasciculus tracts,
opercularis in the inferior frontal gyrus corpus callosum, cingulum; notable
extending to prefrontal and temporal cortices, sparing of occipital white matter,
caudate and putamen atrophy bilaterally brainstem, cerebellum
svPPA Predominant left hemisphere cortical loss; Decreased FA in left superior longitudinal
grey matter loss predominantly in inferior fasciculus, corpus callosum, left
temporal and fusiform gyri, temporal pole, cingulum, left orbitofrontal, inferior
parahippocampal cortex, entorhinal cortex; frontal, anterior temporal, inferior
losses extend to anterior cingulate, orbitofrontal, parietal white matter regions
inferior frontal, and insular cortices
Logopenic Atrophy of left temporoparietal and posterior Notable white matter losses in left
PPA cingulate frontoparietal regions including left
superior longitudinal fasciculus and
arcuate fasciculus
FTD, frontotemporal dementia; bvFTD, behavioral variant FTD; FA, fractional anistotrophy; MRI, magnetic resonance
imaging; nfvPPA, nonfluent variant primary progressive aphasia; PET, positron emission tomography; PPA, primary
progressive aphasia; SPECT, single-photon emission computed tomography; svPPA, semantic variant primary
progressive aphasia.

considered to be more acceptable alternatives in
decreasing behavioral symptoms. Clinicians have
attempted to modify compulsions, apathy, and
lack of motivation using reward systems, although
there are limited data concerning this interven-
tion. Cognitive behavioral therapy is currently
being studied as a possible option to modulate
behavior, but studies are still preliminary.109,110
There are currently no US Food and Drug
Administration (FDA) approved pharmacologi-
cal therapies for FTD.111 There is limited evi-
dence that antidepressants such as selective
serotonin reuptake inhibitors (SSRIs) may be
useful for impulsivity, irritability, eating behavior,
and disinhibition.112 For example, one small, ran-
domized-controlled, open-label 14-month trial113
reported improvement of behavioral symptoms in
subjects with ages ranging from 64 to 68 years
after being prescribed paroxetine at dosages of up
to 20 mg/day. Notably, subjects tolerated parox-
etine well and exhibited improvement in
Neuropsychiatric Inventory (NPI) scoring.
However, a follow-up study114 using placebo con-
trols with a similarly small subject population
determined that paroxetine administration at
dosages up to 40 mg/day provided little objective
improvement and may have caused impairment
in several neuropsychological tests including vis-
ual discrimination tasks, errors in paired-associ-
ates learning task, and delayed pattern recognition
memory accuracy. Discrepancies between study
results were attributed to subjects responding
more favorably to lower doses of paroxetine sug-
gesting a higher rate of tolerability at 20 mg daily
compared with higher dosages. Additionally, par-
oxetine may be more effective when prescribed
earlier in the disease process, although it is diffi-
cult to determine without more in-depth and
higher-powered studies.
Citalopram is another SSRI that has been
recently shown to provide some improvement in
FTD patient behavior. Herrmann and colleagues
found improvement with a citalopram challenge
at 40 mg daily dosages that led to a decrease
in behavioral symptoms including irritability,
depression, apathy, and disinhibition, while also
improving overall NPI scores.115 More recently,
in a randomized double-blinded placebo-con-
trolled crossover study, bvFTD patients who
were prescribed 30 mg daily dosages of citalo-
pram demonstrated improved disinhibition
symptoms in addition to a partial restoration of

40 journals.sagepub.com/home/tpp

serotonergic neurotransmission in dysfunctional
prefrontal cortical systems as measured by mag-
netoencephalography and
electroencephalography.116
Studies of sertraline efficacy in treating FTD
symptoms are limited to mainly observational
studies. One study comparing stereotypical
behavior in FTD and AD subjects suggested that
stereotypical movements in FTD could be
decreased with sertraline administration at a dos-
age range of 50–100 mg/day.117 A case study of a
53-year-old ALS-FTD patient indicated that ser-
traline treatment could also decrease inappropri-
ate sexual behavior in addition to decreasing
aggressive behavior which was helpful in mini-
mizing caregiver burden.118
Alternatively, treatment with trazodone at dos-
ages of at least 300 mg/day over 12 weeks has
been reported to be helpful in decreasing symp-
toms of problematic eating, agitation, irritability,
dysphoria, and depression, although adverse
events were more prominent in subjects being
prescribed the psychotropic. Typical emergent
side effects included fatigue, dizziness, and hypo-
tension, but the authors reported that these symp-
toms were mild in severity.119 At least one
open-label 12-week trial showed a treatment
response with fluvoxamine administration from a
dosage range of 50–150 mg/day (mean dose was
110 mg/day) improving stereotypic behavior, eat-
ing behavior, and roaming behavior.120
Stimulants have been proposed as alternative
treatments due to their mechanism of action in
elevating extracellular catecholamine concentra-
tions to improve cognitive functioning and lessen
frontostriatal and orbitofrontal dysfunction
reported to affect risk-taking behavior in FTD
patients.121–123 Exemplifying this, one study123
found that eight patients who were prescribed
methylphenidate at 40 mg daily dosages demon-
strated decreased risk-taking behavior with over-
all improvement in general behavior. Additionally,
a randomized double-blinded crossover trial
comparing dextroamphetamine and quetiapine
use in FTD patients found that dextroampheta-
mine administration decreased disinhibition and
apathy symptoms, while being more tolerable
than quetiapine, which caused sedation in their
subject population.124 Despite these studies sug-
gesting the safety and efficacy of stimulants in
treating specific symptoms common in the FTD
population, a clinician’s medical decision-making
journals.sagepub.com/home/tpp 41
J Young, M Lavakumar et al.
process should take into account the limited data
provided by these stimulant studies due to their
low power and questionable generalizability, as
well as possible side effects and tolerability issues
of stimulants in more elderly patients.
Memantine and cholinesterase inhibitors have
not demonstrated clinically significant efficacy in
treating FTD patients, and may also hasten cog-
nitive decline or worsen behavioral symp-
toms.125,126 This is likely due to a lack of consistent
evidence of a cholinergic deficit in FTD without
concomitant pathology of other major neurocog-
nitive disorders.127 However, at least one study
reported some efficacy in improving behavioral
symptoms with galantamine treatment in an
aphasic subgroup of FTD without a preponder-
ance of serious adverse events, although no effect
was found in overall treatment of the general
FTD subject population.128
Complaints of insomnia may be due to behavioral
dysfunction or neuronal degeneration causing
impairment of the sleep/wake cycle. However,
primary sleep disorders such as restless leg syn-
drome may also contribute to insomnia and can
be treated with alpha-2-delta calcium channel
ligands (e.g. gabapentin, pregabalin) or dopamin-
ergic agents. Agitation may be controlled by atyp-
ical antipsychotics such as risperidone, olanzapine,
quetiapine, and clozapine, but they are not FDA-
approved and could be detrimental in a demen-
tia-associated agitation due to increased risk of
mortality and unwanted side effects.111,129,130 Of
note, antipsychotics have been suggested to be
more helpful in treating psychotic symptoms in
patients with the C9orf72 subtype of FTD, but
once again, data is limited with increased risk of
extrapyramidal side effects and morbidity in
dementia patients preventing safe utilization of
these neuroleptics.131 Consequently, due to the
limited data and power of pharmacologic treat-
ment studies in FTD populations; nonpharmaco-
logical interventions and caregiver support are the
preferred management options.125
Due to the limited contemporary psychopharma-
cologic interventions available to physicians, sev-
eral novel approaches are being researched to
develop more effective treatments for FTD
symptoms. One such approach is the use of the
neuropeptide, oxytocin, to aid in mediating
behavior and improving apathy and empathy
in svPPA patients.132 Another study suggested
agomelatine, a melatonin receptor agonist, may
Therapeutic Advances in Psychopharmacology 8(1)
improve apathy in FTD patients.133 A preclinical
trial reported active immunization against tau
aggregates using anti-tau antibodies may improve
cognition through decreasing tauopathy.134 A
study investigating the effectiveness of inhibiting
tau aggregation in bvFTD patients using leuco-
methylthioninium was recently completed, but
detailed results are pending release and publica-
tion.135 Other targets for therapy include disrupt-
ing the downstream effects of PGRN and
C9orf72 mutations.111 For example, antisense
oligonucleotides are being used to target the
transcription elongation factor SUPT4H1/
SUPT5H to bi-directionally suppress C9orf72
RNA transcription.136 Other proposed methods
involve elevating PGRN levels through molecu-
lar manipulation of biological pathways using
suberoylanilide hydroxamic acid, androgen treat-
ment, and bafilomycin A1.135
Conclusion
The entirety of the FTD clinical syndrome is
now known to be composed of complex and het-
erogeneous variants that vary in presentation,
genetic alterations, and pathological processes.
Consequently, there is a need for physicians to
become well versed in the diagnostic criteria set
forth by consortiums and expert consensus in
order to properly assess and manage FTD
patients. According to recent epidemiologic
studies, FTD is likely to be underdiagnosed due
to the inherent difficulty accurately diagnosing
these disorders. These findings underline the
need to standardize and update current criteria
to increase diagnostic sensitivity, and allow for
better management of these variants at an earlier
stage of the disease course. There have been sev-
eral breakthroughs in genetic and neuroimaging
studies that have elucidated the pathophysiologi-
cal characteristics of these FTD subtypes in the
past decade. However, FTD pathology is still
relatively unknown and requires further investi-
gations to produce more effective diagnostic bio-
markers and therapies, especially as later course
presentations begin to mimic AD symptomatol-
ogy. Current management guidelines recom-
mend a focus on nonpharmacological
interventions, as these have been found to be the
most studied and effective practices at the dis-
posal of clinicians. Contemporary pharmacologi-
cal treatment options are still lacking due to a
deficit of comprehensive randomized controlled
trials to determine efficacy and safety, although
there is limited evidence of SSRI efficacy in
42 journals.sagepub.com/home/tpp
decreasing FTD-specific symptomatology and
difficult behavior. Additionally, the extensive list
of symptoms that are being targeted for interven-
tion typically necessitates a variety of therapies
for clinical improvement, which fundamentally
complicates treatment planning. However, this
renewed interest in FTD research gives hope for
future advancements that aim to increase diag-
nostic capabilities, and expand treatment options
through novel therapeutic targets.
Funding
This research received no specific grant from any
funding agency in the public, commercial, or not-
for-profit sectors.
Conflict of interest statement
Mallika Lavakumar received honorarium from
Oakstone and receives research funding from the
Health Research Services Administration.
Rajesh R Tampi receives honorarium from
Oakstone and royalties from Lippincott Williams
& Wilkins.
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