Behavioural-variant frontotemporal dementia: diagnosis, clinical staging, and management.
ABSTRACT Patients with behavioural-variant frontotemporal dementia (bvFTD) present with insidious changes in personality and interpersonal conduct that indicate progressive disintegration of the neural circuits involved in social cognition, emotion regulation, motivation, and decision making. The underlying pathological changes are heterogeneous and are characterised by various intraneuronal inclusions. Biomarkers to detect these histopathological changes in life are becoming increasingly important with the development of disease-modifying drugs. Gene mutations have been found that collectively account for around 10-20% of cases. Recently, criteria proposed for bvFTD define three levels of diagnostic certainty: possible, probable, and definite. Detailed history taking from family members to elicit behavioural features underpins the diagnostic process, with support from neuropsychological testing designed to detect impairment in decision making, emotion processing, and social cognition. Brain imaging is important for increasing the level of diagnostic certainty. A recently developed staging instrument shows much promise for monitoring patients and evaluating therapies, which at present are aimed at symptom amelioration. Carer education and support remain of paramount importance.
- SourceAvailable from: Agustin Ibanez[Show abstract] [Hide abstract]
ABSTRACT: La cognición social es dependiente de la información sutil e implícita presente en el contexto durante interacciones sociales. Presentamos y describimos un modelo anátomo-funcional, denominado SCNM (del inglés Social Context Network Model), que pretende explicar cómo se procesa el contexto en situaciones sociales. Además, muestra cómo diferentes alteraciones de sus redes subyacen a los déficits en cognición social de pacientes con demencia frontotemporal, lesiones fronto-insulares, enfermedades del neurodesarrollo y otros cuadros neuropsiquiátricos. Se presentan estudios precursores basados en el SCNM y se los contrapone al enfoque descontextualizado de abordajes clásicos en cognición social. El SCNM es un modelo teórico que provee un conjunto de hipótesis que permiten examinar y comprender mejor los procesos subyacentes a los déficits en cognición social. A nivel clínico, propone el desarrollo de herramientas más ecológicas que las tradicionales, que permitirían una mejor detección y caracterización de distintas enfermedades neurológicas y psiquiátricas, como así también la implementación de ambientes en rehabilitación que imiten mejor las situaciones de la vida cotidiana.Revista de Psicología Social 01/2013; 28(3):299-315. · 0.50 Impact Factor
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ABSTRACT: Neurodegenerative diseases, such as frontotemporal dementia (FTD), are often associated with behavioral deficits, but the underlying anatomical and molecular causes remain poorly understood. Here we show that forebrain-specific expression of FTD-associated mutant CHMP2B in mice causes several age-dependent neurodegenerative phenotypes, including social behavioral impairments. The social deficits were accompanied by a change in AMPA receptor (AMPAR) composition, leading to an imbalance between Ca(2+)-permeable and Ca(2+)-impermeable AMPARs. Expression of most AMPAR subunits was regulated by the brain-enriched microRNA miR-124, whose abundance was markedly decreased in the superficial layers of the cerebral cortex of mice expressing the mutant CHMP2B. We found similar changes in miR-124 and AMPAR levels in the frontal cortex and induced pluripotent stem cell-derived neurons from subjects with behavioral variant FTD. Moreover, ectopic miR-124 expression in the medial prefrontal cortex of mutant mice decreased AMPAR levels and partially rescued behavioral deficits. Knockdown of the AMPAR subunit Gria2 also alleviated social impairments. Our results identify a previously undescribed mechanism involving miR-124 and AMPARs in regulating social behavior in FTD and suggest a potential therapeutic avenue.Nature Medicine 11/2014; · 28.05 Impact Factor
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ABSTRACT: This paper presents a critical account of research into the non-motor symptoms associated with amyotrophic lateral sclerosis (ALS). Although research examining the cognitive and behavioural features of ALS has been extensively report -ed, social communication and emotion recognition changes have not been comprehensively explored. Furthermore, the current research and diagnostic criteria for diagnosing such changes, which have served as a useful conceptual model, do not provide a means of assessing the subtle cognitive changes reported in non-demented ALS patients. In addition, the impact and challenges of providing care for a person with a diagnosis of ALS who is also experiencing changes in cog-nition and behaviour have been explored only tangentially in the literature, and require immediate attention. We argue that the establishment of criteria to detect mild cognitive impair-ment may serve as a useful model to provide effective clinical interventions for both patients and caregivers at the earliest possible moment.Acta Neuropsychologica 12/2011; 9(4):321-334.
www.thelancet.com/neurology Vol 10 February 2011
Lancet Neurol 2011; 10: 162–72
December 13, 2010
Australia, Randwick, NSW,
Australia (O Piguet PhD,
M Hornberger PhD,
E Mioshi PhD,
Prof J R Hodges FMedSci)
Prof John Hodges, Neuroscience
Research Australia, Barker St,
Randwick, NSW 2031, Australia
Behavioural-variant frontotemporal dementia: diagnosis,
clinical staging, and management
Olivier Piguet, Michael Hornberger, Eneida Mioshi, John R Hodges
Patients with behavioural-variant frontotemporal dementia (bvFTD) present with insidious changes in personality
and interpersonal conduct that indicate progressive disintegration of the neural circuits involved in social cognition,
emotion regulation, motivation, and decision making. The underlying pathological changes are heterogeneous and
are characterised by various intraneuronal inclusions. Biomarkers to detect these histopathological changes in life are
becoming increasingly important with the development of disease-modifying drugs. Gene mutations have been
found that collectively account for around 10–20% of cases. Recently, criteria proposed for bvFTD defi ne three levels
of diagnostic certainty: possible, probable, and defi nite. Detailed history taking from family members to elicit
behavioural features underpins the diagnostic process, with support from neuropsychological testing designed to
detect impairment in decision making, emotion processing, and social cognition. Brain imaging is important for
increasing the level of diagnostic certainty. A recently developed staging instrument shows much promise for
monitoring patients and evaluating therapies, which at present are aimed at symptom amelioration. Carer education
and support remain of paramount importance.
Frontotemporal dementia (FTD) is the clinical diagnostic
term now preferred to describe patients with a range of
progressive dementia syndromes associated with focal
atrophy of the orbitomesial frontal and anterior temporal
lobes.1 Epidemiological studies suggest that FTD is the
second most common cause of young-onset dementia
after Alzheimer’s disease (AD).2,3 Two independent
studies from the UK revealed a prevalence of around 15
cases per 100 000 population aged 45–64 years (95% CI
8–27 per 100 000).2 Although thought to be a rare cause
of dementia after age 65 years, FTD might be more
common than assumed because older adults rarely
undergo the types of investigation needed to establish a
confi dent diagnosis in vivo and are not generally followed
Unlike AD, both the clinical profi le and the underlying
pathological changes are heterogeneous in FTD. Two
broad presentations are
deterioration in social function and personality, known
as behavioural-variant FTD (bvFTD), and insidious
decline in language skills, known as primary progressive
aphasia, which can, in turn, be subdivided according the
predominant pattern of language breakdown into
progressive non-fl uent aphasia and semantic dementia.4–6
The syndrome of FTD overlaps with motor neuron
disease (MND) both clinically and pathologically, and
with some of the extrapyramidal motor disorders. Around
10% of patients with FTD develop clinical and
neurophysiological evidence of MND,7,8 and, similarly,
patients with MND show behavioural and/or language
changes that, in some instances, are severe enough to
qualify for a diagnosis of FTD.9 Of the extrapyramidal
disorders, corticobasal degeneration and progressive
supranuclear palsy show substantial overlap with FTD
and share the fi nding of abnormal tau pathology.10
This is a broad and rapidly evolving fi eld; therefore, in
this Review, we have focused on the clinical aspects of
bvFTD because there have been recent authoritative
reviews of the aphasic syndromes.4,6 Our aim is to place
advances in the diagnosis, staging, and management of
bvFTD within the context of recent pathological and
genetic discoveries. The assessment of any patient with
suspected bvFTD should involve behavioural and
neuropsychiatric tests, assessment of everyday abilities,
cognitive testing, and neuroimaging. Various blood and
CSF biomarkers are under development, but are not yet
available for routine clinical application. Genetic testing
is advised for those at high risk of a gene mutation
(fi gure 1).11
The subtypes of underlying pathological changes in
patients with FTD are classifi ed on the basis of the
pattern of protein accumulation, and are referred to
collectively as frontotemporal lobar degeneration
(FTLD).12 At post mortem, cases share, by defi nition, the
fi nding of bilateral frontotemporal atrophy with
neuronal loss, microvacuolation, and a variable degree
of astrocytic gliosis. The progression of this atrophy has
been examined by mapping the pattern in patients with
diff erent disease duration.13 Initially, mesial and orbital
frontal regions bear the brunt of the atrophy, followed
by the temporal pole, hippocampal formation,
dorsolateral frontal cortex, and the basal ganglia. This
pattern of progression of atrophy has been shown to
relate to the volume of cortical and subcortical regions,
and to the underlying neuron loss.14,15 Furthermore, it
forms the basis of a useful and quick MRI rating scale
The use of immunohistochemical staining has
revolutionised the fi eld of research in FTD. Inclusions of
the microtubule-binding protein tau are present in
approximately 40% of cases (FTLD-tau).16 Tau-positive
cases include the subset of patients with mutations in the
microtubule-associated protein tau (MAPT) gene. Further
www.thelancet.com/neurology Vol 10 February 2011 163
subclassifi cation is based on morphological criteria and
the predominance of either tau with three microtubule-
binding repeats (3R tau) or four microtubule-binding
repeats (4R tau).12 Most of the remaining cases are tau
negative and ubiquitin positive, and have inclusions
comprising the 43 kDa TAR DNA-binding protein (TDP-43;
FTLD-TDP), but a minority (around 5–10%) are negative
for both tau and TDP-43 proteins.17 Recently, inclusions of
the RNA-binding protein fused in sarcoma (FUS) have
been found in many of these cases (FTLD-FUS).16,18 The
search for FUS pathology was initiated after FUS gene
mutations were identifi ed in cases of familial MND.19,20
Both TDP-43 and FUS are RNA-processing proteins,
although the mechanisms leading to TDP-43 and FUS
accumulation and resulting neurodegeneration have not
yet been elucidated. A small proportion of cases have
either no inclusions or show ubiquitin-positive inclusions
that are TDP-43 and FUS negative, suggesting that
additional protein abnormalities will be found in FTLD.16
A major topic of investigation has been to establish the
association between clinical phenotypes and molecular
pathology. Unlike the progressive aphasic syndromes,
which are generally associated more with one histological
form of FTLD than another (progressive non-fl uent
aphasia with FTLD-tau, semantic dementia with
FTLD-TDP), in bvFTD any of the histological variants
can be found with an approximately 50:50 split between
FTLD-tau and FTLD-TDP,21–23 and a small proportion of
FTLD-FUS cases.24 With the advent of potential disease-
modifying therapies, ascertainment of a pathological
diagnosis in vivo will be increasingly important. As yet,
no reliable method for detecting these pathological
changes in life exists. CSF biomarkers seem to be the
most promising in distinguishing FTLD from AD: the
ratio of tau to amyloid β1–42 has been found to be lower in
FTLD than in AD.25 Increased concentrations of
CSF TDP-43 have also been reported in patients with
MND and FTD, but without pathological confi rmation of
the diagnosis. In addition, the substantial overlap
between cases and controls limits the applicability of the
assay in clinical practice.26
concentrations are exceptionally low in patients with
mutations in the granulin gene (GRN),27–29 and this assay
seems to be a sensitive and specifi c method of screening
for such cases,30 with suggestions that plasma TDP-43
concentrations could be related to brain pathology.31
Neuroimaging markers are discussed below.
Up to 40% of patients with FTD have a family history
of dementia,3 but the high community prevalence of
non-FTD dementia means that many of the elderly family
members included in such estimates almost certainly
have other causes of dementia. Patients with an autosomal
dominant pattern (aff ected fi rst-degree relatives across
two generations) account for only 10% of cases.11 The
strength of family history is highly predictive, in that
mutations can now be shown in most patients with two
or more fi rst-degree relatives with a dementia syndrome
compatible with FTD.11 Overall, patients with mutations
in MAPT and GRN each account for 5–11% of total FTD
cases.11 Mutations in the gene that encodes TDP-43,
TARDBP, and in FUS, recognised as a cause of familial
amyotrophic lateral sclerosis (ALS), have also been
identifi ed in a small number of cases of FTD-ALS,32–35 but
seem to be rare in uncomplicated FTD.11 Rare genetic
mutations causing FTD include those in the genes
encoding valosin-containing protein (VCP) and charged
multivesicular body protein 2B (CHMP2B; also known
as chromatin-modifying protein 2B). Mutations in VCP
cause FTD in association with inclusion body myopathy
and Paget’s disease of bone,36 whereas the CHMP2B gene
mutation is mostly confi ned to a large Danish cohort
with FTD.37,38 Familial clusters of FTD and MND have
been reported. A linkage study of FTD-MND clusters
has indicated a common locus in the region of
chromosome 9p13.2–21.3,39 but the causative gene has
not yet been identifi ed.
From a practical perspective, a detailed family history
should be taken for all patients with suspected FTD,
bearing in mind the overlap between MND and FTD,
that a diagnosis of FTD or Pick’s disease was rarely
made in the past, and the phenotypic variability within
families with gene mutations: one member might
present with bvFTD, whereas others have a progressive
aphasic syndrome or corticobasal syndrome. On the
basis of a comprehensive analysis of the frequency of
gene mutations according to strength of family history
and clinical syndrome in a large clinical cohort,31 we
recommend that patients with one or more fi rst-degree
relatives with a disease on the FTD spectrum should be
screened for MAPT and GRN gene mutations after
appropriate counselling in a clinical genetics setting.
Figure 1: Possible investigations after the diagnosis of suspected bvFTD
based on clinical assessment
*Presence of neurodegenerative disease and at least three of six behavioural or
cognitive core diagnostic criteria are required for diagnosis of the disease.
bvFTD=behavioural-variant frontotemporal dementia. ADL=activities of
Strong family history
Possible bvFTD based on clinical, behavioural,
cognitive, and ADL assessments*
www.thelancet.com/neurology Vol 10 February 2011
Those with an informative family history that reveals no
aff ected relatives can be confi dently reassured and need
not undergo gene screening.11 Of note, the age of onset
in patients with MAPT mutations is almost always
below 65 years, whereas those with GRN mutations are
Insidious changes in personality, interpersonal conduct,
and emotional modulation characterise bvFTD and
indicate progressive disintegration of the neural circuits
involved in social cognition, emotion regulation,
motivation, and decision making.40–43 Onset is typically
diffi cult to pinpoint. Since insight is limited, or absent, it
is vital that close family members are interviewed alone,
and sensitively, to elicit the nature of the early symptoms
and their progression. Assessment and diagnosis have
been greatly assisted by the development of carer-based
questionnaires designed to document the range of
symptoms found in the dementia, including the
Neuropsychiatric Inventory,44 Cambridge Behavioural
Inventory,45 and Frontal Behavioural Inventory.46 All of
the features found in bvFTD can occur in other
dementias, but their predominance and early emergence
Apathy is very common and manifests as inertia,
reduced motivation, lack of interest in previous hobbies,
and progressive social isolation. Disinhibition often
coexists with apathy, and produces impulsive actions
leading to overspending, tactless or sexually inappropriate
remarks, and a range of socially embarrassing behaviour.
New-onset pathological gambling or, more rarely, hyper-
religiosity, can be the presenting feature.47,48 Repetitive or
stereotypic behaviours might be apparent with
perseveration and a tendency to repeat phrases, stories,
or jokes. Some carers describe excessive hoarding, which
results in a state of squalor. Patients often lack empathy
and an inappropriately subdued grief reaction is a
common early symptom. Mental rigidity is common and
patients can have diffi culty adapting to new situations or
routines. A blunting of aff ect and reduction in range of
emotional expression is frequent and some patients show
elevation of mood resembling hypomania. Changes in
eating behaviour, with impaired satiety, change in
preferences towards sweet food, and dysregulation of
food intake are common and seen across cultures.49
These alterations in eating have recently been found to
be related to pathological changes in the hypothalamus,
which is crucial for coordinating metabolic needs,
Psychotic symptoms such as delusions, paranoid
ideation, and hallucinations are relatively rare in FTD,
except in patients with combined MND and in patients
with young-onset FTLD-FUS in whom such features are
present in up to 50%.7,51,52 Clinically, these patients seem
to present with fl orid behavioural symptoms. In addition,
their age of onset is often exceptionally young (≤40 years),24
and a positive family history seems rare in keeping with
the absence of FUS gene mutations in this group.24,52
Patients destined to develop clinical MND who have
FTLD-TDP also have a high rate of psychotic features
and progress rapidly even before the onset of typically
Of the features listed above, social disinhibition,
euphoria, stereotypical and aberrant motor behaviour,
and changes in eating preference most clearly
discriminate bvFTD from AD.45,53 Variability in the
symptom profi les reported across studies might have
arisen from the aggregation of patients at diff erent stages
of the disease. Increased behavioural changes have been
associated with disease severity.54 Agitation, disinhibition,
and irritability also seem to be more frequent in the later
stages,55 whereas restlessness and hyperorality are
present throughout the disease.56 Another important
variable is age of disease onset, with apathy being more
prominent in late-onset bvFTD,57 although this fi nding is
In summary, behavioural assessment is at the core of
assessment in patients with potential bvFTD and seems
to be more sensitive in distinguishing bvFTD from AD
than standard cognitive testing. Despite a substantial
increase in our knowledge of the behavioural changes in
bvFTD, which are at the root of so much carer distress
(see below), much remains uncertain concerning their
specifi city, neural basis, and their relation to the
bvFTD phenocopy syndrome: implications for
The diagnosis of bvFTD is by no means an easy task in
the early stages, and many of the symptoms overlap with
those seen in psychiatric disorders and other dementias.51
It is also increasingly apparent that a subset of patients
who present with the clinical features of bvFTD do not
progress to frank incapacitating dementia.59 Such patients
are almost always men and they either remain stable over
many years or improve.60,61 The symptom profi le as
reported by family members is identical, except that
activities of daily living (ADL) are less disrupted.60,62
Several features distinguish these non-progressor or
phenocopy cases from those with true FTD, notably
normal or marginal impairment on neuropsychological
tests of executive function, preserved memory and social
cognition, a lack of overt atrophy on MRI, and normal
metabolic (PET) brain imaging.59–61,63 The aetiology of the
phenocopy syndrome is a matter of debate. A proportion
of patients seem to have a developmental personality
disorder on the Asperger’s spectrum with decompensation
due to altered life circumstances (Hodges J, unpublished).
Some might have a chronic low-grade mood disorder, but
others remain a mystery.
The phenocopy syndrome has major implications for
the current clinical diagnostic criteria for FTD,5 which
require a profi le of symptoms compatible with the
www.thelancet.com/neurology Vol 10 February 2011 165
diagnosis without imaging or other confi rmatory test
results. These criteria also present diffi culties in their
application due to under-specifi cation of some features
and were derived by clinical consensus prior to the
publication of quantitative studies comparing cohorts
with pathologically verifi ed diagnoses. Recently proposed
criteria developed by an international FTD research
group (panel)64 build on recent work with operationalised
defi nitions that have three levels of diagnostic certainty:
possible, probable, and defi nite bvFTD. Patients qualify
for possible bvFTD on the basis of three core behavioural
or cognitive features (including social disinhibition,
apathy, loss of empathy, stereotypic behaviours or
alterations in eating pattern, and neuropsychological
defi cits indicative of frontal executive dysfunction). A
probable diagnosis requires the same clinical features
with evidence of progression and unequivocal neuro-
imaging abnormalities. The term “defi nite” is reserved
for those with neuropathology or a pathogenic gene
mutation. These new criteria (panel) are currently
undergoing validation against neuropathological changes
by an international consortium of researchers.64
Early in the disease process, patients with bvFTD can
perform relatively well on formal neuropsychological
tests despite the presence of signifi cant personality and
behavioural changes.65 The mini mental state examination
is insensitive, but the Addenbrooke’s cognitive
examination seems to detect at least 90% of cases at
presentation.66 The prototypical cognitive profi le is one of
relatively preserved language
constructive abilities. Whether patients with bvFTD show
executive dysfunctions remains contentious,67,68 and has
been complicated by the inclusion of phenocopy cases.
However, such defi cits constitute a central diagnostic
feature of the newly proposed clinical diagnostic criteria.64
Recent evidence suggests that the combination of specifi c
tests (eg, digit span backward task, Hayling test of
response inhibition, and the short version of the executive
and social cognition battery) might help diff erentiate
these cases, because results are typically abnormal in
patients with true bvFTD and normal in phenocopy
The presence of severe defi cits of episodic memory has
been used as an exclusion criterion for a clinical diagnosis
of bvFTD,5 although a proportion (10–15%) of patients
with pathologically confi rmed FTLD present with severe
amnesia.21,70 A recent report has indicated that defi cits in
episodic memory are more common than previously
reported.71 Carefully selected patients with bvFTD (ie,
after excluding phenocopy cases) had similar memory
impairments as seen in AD on tests of episodic memory,
even after accounting for disease severity.71 The criterion
of relative sparing of episodic memory compared with
executive functions proposed in the recent international
consensus criteria for bvFTD might need to be revisited
in the light of current research.62
The evidence reviewed thus far indicates that no specifi c
cognitive profi le seems to be associated with bvFTD early
in the disease, although careful cognitive assessment will
reveal defi cits, generally in the domains of executive
function and episodic memory. With disease progression,
the atrophy evolves to involve the anterior temporal
regions, and the pattern of defi cits becomes less distinct
from other FTD subtypes, notably semantic dementia.10
Panel: International consensus criteria for bvFTD
Must be present for any FTD clinical syndrome
Shows progressive deterioration of behaviour and/or cognition by observation or history
Three of the features (A–F) must be present; symptoms should occur repeatedly, not just
as a single instance:
A Early (3 years) behavioural disinhibition
B Early (3 years) apathy or inertia
C Early (3 years) loss of sympathy or empathy
D Early (3 years) perseverative, stereotyped, or compulsive/ritualistic behaviour
E Hyperorality and dietary changes
F Neuropsychological profi le: executive function defi cits with relative sparing of
memory and visuospatial functions
All the following criteria must be present to meet diagnosis:
A Meets criteria for possible bvFTD
B Signifi cant functional decline
C Imaging results consistent with bvFTD (frontal and/or anterior temporal atrophy on
CT or MRI or frontal hypoperfusion or hypometabolism on SPECT or PET)
Defi nite bvFTD
Criteria A and either B or C must be present to meet diagnosis:
A Meets criteria for possible or probable bvFTD
B Histopathological evidence of FTLD on biopsy at post mortem
C Presence of a known pathogenic mutation
Exclusion criteria for bvFTD
Criteria A and B must both be answered negatively; criterion C can be positive for possible
bvFTD but must be negative for probable bvFTD:
A Pattern of defi cits is better accounted for by other non-degenerative nervous system
or medical disorders
B Behavioural disturbance is better accounted for by a psychiatric diagnosis
C Biomarkers strongly indicative of Alzheimer’s disease or other neurodegenerative process
A Presence of motor neuron fi ndings suggestive of motor neuron disease
B Motor symptoms and signs similar to corticobasal degeneration and progressive
C Impaired word and object knowledge
D Motor speech defi cits
E Substantial grammatical defi cits
Criteria from Rascovsky et al.64 bvFTD=behavioural-variant frontotemporal dementia. FTD=frontotemporal
dementia. SPECT=single-photon emission computed tomography. FTLD=frontotemporal lobar degeneration.
www.thelancet.com/neurology Vol 10 February 2011
The diffi culty in identifying profi les of cognitive defi cits
specifi c to bvFTD has led to an interest in aspects of social
cognition (theory of mind), emotion recognition and
complex problem solving, and the use of naturalistic tasks
(ie, tasks indicating cognitive and non-cognitive demands
more akin to daily activities). The orbitomesial frontal
cortices are crucial for performance in these domains,
and lesions within these brain regions have been shown
to negatively aff ect tests measuring these cognitive
constructs.72 The Iowa gambling task of complex decision
making requires individuals to inhibit responses that
result in short-term high fi nancial gains but long-term
losses in favour of responses resulting in small gains in
the short term and reduced long-term losses.73 This task
was found to diff erentiate between patients with bvFTD,
who consistently failed to inhibit the prepotent responses
favouring short-term gains leading to long-term loss, and
healthy controls. Interestingly, this defi cit is not related to
performance on other cognitive tasks.74
Emotion recognition and social cognition
A marked impairment in emotion detection and
recognition is evident early in the course of bvFTD,75,76
and seems to be most pronounced for negative emotions
(eg, fear, sadness, anger, and disgust).76,77 Disorders of
emotion detection and regulation are part of the clinical
diagnostic criteria for the disease (ie, early emotional
blunting, early decline in social interpersonal conduct).
However, such defi cits are not limited to this subtype of
FTD and are also present in semantic dementia.78
Diffi culties in detecting and understanding emotions are
observed with static (photos) or dynamic (fi lms) visual
stimuli, voices, or even music. Importantly, physiological
responses (eg, skin conductance) to some emotional
stimuli are preserved.79 Defi cits have also been observed
in detecting more complex emotions, such as
embarrassment.80 These defi cits might be amenable to
retraining to enhance their recognition and improve
Patients with bvFTD are also impaired on many aspects
of social cognition. For example, the often reported
feature of lack of empathy and coldness is confi rmed on
formal testing.81 Theory of mind is impaired in bvFTD,
as exemplifi ed by defective ability to infer intention and
mental states in others or to take someone else’s point of
view,74,75,82 and impaired detection of social faux pas,82
discrimination of sincere from sarcastic exchanges,63
and understanding of situations requiring moral
judgment.83 Whereas most of the tasks developed remain
in the research arena, well validated tests of emotion and
sarcasm detection exist,84,85 which will hopefully become
part of the standard cognitive assessment in suspected
By use of structural MRI, atrophy of the mesial frontal,
orbitofrontal, and anterior insula cortices can be reliably
observed on images acquired in the coronal plane
(fi gure 2).42,86,87 A combination of frontal and anterior
temporal cortical and basal ganglia atrophy might also be
seen at presentation in some patients.88 This atrophy can
be quickly and reliably estimated using relatively simple
visual rating scales developed specifi cally for FTD.89
However, an apparently normal MRI on visual inspection
does not completely exclude a diagnosis of bvFTD,
because the changes can be subtle in the early stages.
The development of automated quantitative methods,
including voxel-based morphometry and cortical
thickness mapping, has been important in revealing
selective atrophy of the anterior cingulate and frontal
insular cortices early in the course of bvFTD,42,90,91 which
is distinct from the pattern seen in other variants of FTD
and in AD.92 The anterior cingulate-frontal insular
complex contains a unique population of neurons, the
von Economo cells, which are thought to be crucial in the
development and maintenance of social cognition and
have been shown to be depleted in patients with bvFTD
at autopsy.43,93 More recently, sophisticated MRI methods
of exploring network connectivity have shown signifi cant
changes in connectivity among the regions most sensitive
to atrophy in bvFTD compared with healthy controls or
patients with other dementia syndromes.94,95
Patterns of grey matter atrophy might be predictive of
the underlying pathological process in bvFTD, with
bilateral dorsolateral prefrontal atrophy being suggestive
of Pick body inclusions (ie, Pick’s disease), and
Figure 2: Visual rating scale to estimate the severity of cortical atrophy in the dorsolateral, medial, and
orbitofrontal cortices in suspected cases of bvFTD
Modifi ed from Hornberger et al,87 by permission of Karger AG, Basel. bvFTD=behavioural-variant
Dorsolateral prefrontal and
medial prefrontal cortices
www.thelancet.com/neurology Vol 10 February 2011 167
asymmetric left and right temporal lobe atrophy being
associated with FTLD-TDP and FTLD-tau, respectively.96
Marked atrophy of the caudate nucleus might also be
predictive of FTLD-FUS.24,97 However, patterns of atrophy
seem to relate more closely to clinical features than to
specifi c pathological changes.98
Brain changes in bvFTD are not limited to the cortex.
Atrophy is also present in many subcortical brain regions,
including the amygdala, hippocampus, caudate, striatum,
putamen, thalamus, and hypothalamus,50,99 accompanied
by reduction in connectivity among subcortical structures.95
In addition, atrophy of the amygdala has been proven to be
an effi cient discriminator between bvFTD and AD.99
By contrast with the well documented cortical grey
matter changes, presence and severity of white matter
changes in bvFTD have only recently been investigated.100
Frontal lobe white matter volume reduction largely
parallels the atrophy in the adjacent grey matter in bvFTD,
with diff erent subtypes of FTD showing specifi c patterns
of white matter atrophy.101 Using diff usion tensor imaging,
an index of changes in the microstructural organisation of
white matter, a study has successfully diff erentiated
bvFTD from AD and other FTD subtypes.102 Patients with
bvFTD seem to show a selective reduction in some white
matter tracts (superior longitudinal fasciculus, uncinate
fasciculus, cingulum tracts, and genu and splenium of the
corpus callosum), particularly those within frontal lobe
(eg, genu of the corpus callosum) or those connecting
frontal and temporal brain regions (eg, uncinate
fasciculus).102 Whether these white matter changes are
reliable diagnostic markers for bvFTD remains unclear.
Patients with the phenocopy syndrome who present with
the clinical features of bvFTD show normal or marginal
Serial MRIs show signifi cant atrophy over time in
bvFTD. Annual rate of overall brain atrophy can reach 8%,
almost twice as severe as that documented in AD, although
some patients with bvFTD show atrophy rates similar to
those seen in healthy controls (0·3% per year), which
might be due to the inclusion of phenocopy cases.103
Functional neuroimaging techniques, such as [99mTc]-
hexamethylpropyleneamine oxime single-photon emission
computed tomography (SPECT) or [18F]-fl uorodeoxyglucose
(FDG)-PET are increasingly being used to help with the
diagnosis of bvFTD. Frontal hypoperfusion is present on
SPECT in bvFTD and diff ers from the pattern of
hypoperfusion observed in AD, which is predominant in
the temporoparietal and posterior cingulate cortices.104
Although SPECT seems to be more sensitive than
structural MRI in detecting early pathological changes in
bvFTD, quantifi cation and specifi city of these changes
have not been established. Hypometabolism on FDG-PET
is detected consistently and reliably in frontal brain regions
in patients with bvFTD compared with those with AD, who
show posterior cingulate hypometabolism early in the
disease process.105 These changes are detected before any
changes are visible on structural MRI, making FDG-PET
the most sensitive diagnostic tool currently available.
FDG-PET is also particularly useful in helping to identify
phenocopy cases as these will show preserved frontal
metabolism. However, in patients showing clear brain
atrophy on structural MRI, little additional diagnostic
benefi t is gained by doing a PET scan, because focal
atrophy is a positive predictive marker of FTD.
A novel PET technique, which uses the amyloid-β-
detecting [11C]-Pittsburgh compound B, has shown
promising results in discriminating AD and FTD
cases,106,107 particularly those presenting with language
defi cits rather than behavioural changes. Its use as a
routine test remains to be established, but its clinical
applicability is evident as therapeutic interventions are
being developed that are likely to be pathology specifi c.
In summary, neuroimaging investigations in the
diagnosis of bvFTD are powerful tools, which can reliably
diff erentiate bvFTD from other FTD subtypes and from
other dementia syndromes, and can corroborate clinical
diagnostics based on neuropsychiatric symptoms.
Disability in everyday life is more pronounced in bvFTD
than in AD or in the language variants of FTD,65,108,109 even
after controlling for length of symptoms or cognitive
performance.65,109 Compared with AD, a large proportion
of patients with bvFTD are impaired in ADL, and show
an early impairment in basic ADL at initial assessment.110
Marked changes in driving abilities occur and are
associated with the degree of behavioural change,111 which
has clear practical implications. A 12-month follow-up
study also identifi ed signifi cant changes in ADL, which
were associated with general cognitive decline.112 However,
these changes were not present in phenocopy cases.
Disease progression, functional staging, and
Most studies, to date, have used the clinical dementia
rating (CDR) scale to measure dementia severity.113 This
instrument, which was originally developed for AD, is
biased towards memory impairment and most likely
underestimates the level of dementia severity in bvFTD. A
version adapted for FTD includes language and behavioural
domains (FTLD-CDR),114 and the sum-of-boxes score seems
to be sensitive to change in most patients with FTD.
Recently, the frontotemporal
scale (FRS) was developed specifi cally for FTD.115 This
staging tool incorporates changes in behaviour and ADL
(table). On the FRS, patients with bvFTD tend to show
greater disease severity and a faster progression through
the clinical stages than patients with the language
variants of FTD, even after adjusting for length of
symptoms.115 Importantly, the FRS confi rmed that the
CDR tends to underestimate dementia severity in bvFTD,
with a great proportion of moderate and severe cases on
the FRS being rated as “questionable dementia” or “mild”
www.thelancet.com/neurology Vol 10 February 2011
Patients with bvFTD seem to progress faster than
patients with AD, with median survival (from fi rst
assessment) of about 3·0–4·5 years,110,116,117 although this
fi nding has not been universal.118 Factors determining
reduced survival are associated with MND or ALS and
language impairment at diagnosis.117 The eff ect of
on survival remains
Therapeutic intervention and caregiver stress
Currently, no disease-specifi c treatment interventions for
FTD exist. Consequently, treatment largely remains
supportive and involves a combination of non-
pharmacological and pharmacological measures aimed at
reducing the eff ect of distressing symptoms.120 The role of
pharmacological interventions in FTD remains uncertain,
and only small and often confl icting treatment trials have
been done so far; these studies have not considered the
eff ect on carer stress as a major outcome variable.
Selective serotonin reuptake inhibitors have been used to
treat disinhibition and challenging behaviours, but
evidence for their use remains contradictory.121,122 Atypical
antipsychotics such as olanzapine have been used for
patients with prominent agitation, aggressive behaviour,
or psychosis.123 Anticholinesterase inhibitors, the mainstay
of AD therapy, do not have an established role in the
treatment of FTD. One study reported improvement in
measures of behavioural disturbance and carer stress
with rivastigmine,124 although deterioration in neuro-
psychiatric symptoms without cognitive improve ment
was shown with donepezil.125 Several drugs under
development attempt to reduce aggregation of tau or
TDP-43 and hence slow the fundamental pathological
process in FTD.120,126
Caregiver intervention, which should be the most
eff ective treatment within the context of dementia, has
also not been trialled in FTD caregivers. A model for
behavioural management has been proposed, whereby a
focus on the antecedent–behaviour–consequence model
could be applied to diff erent patient situations with
recommendations for specifi c behaviours exhibited in
bvFTD,127 but research studies are needed to verify their
benefi ts. This would be timely, because caregivers of
patients with FTD present with high rates of burden and
stress. Recent studies have shown that caregiver burden
in FTD is much greater than in AD.128–130 Behavioural
changes rather than level of disability seem to be
correlated with caregiver distress and burden in bvFTD,129
although very few studies have been done. Evidence
indicates that caregiver health is a major contributor to
carer stress, with depression accounting for 58% of the
variance of stress scores in FTD caregivers.130 The key to
reducing caregiver stress seems to lie in increasing their
understanding of the symptoms and ways of dealing with
Driving and other aspects of capacity in bvFTD are
clearly of great practical importance, but have been
subject to little systematic research. A single study of
driving competence in bvFTD suggested signifi cant
problems, even at an early stage of the disease.111 On that
basis, a driving assessment would seem to be
recommended in all cases. In Australia, the UK, and
many other countries, an established code of practice
exists governing the issue of legal capacity associated
with the relevant Mental Capacity Act. Its application is
relatively straightforward in patients with advanced
bvFTD, but establishing a lack of capacity could be
complex in the early stages of the disease. Of note,
BehaviourActivities of daily living
Mild Lack of aff ection No changesDiffi culties in managing correspondence
Diffi culties in planning of fi nances
Changes in driving ability
Decline in standard of execution of household chores
Diffi culties dialling telephone
Lacks interest in fi nances
Cannot plan meals as well as before
Problems with shopping
Needs supervision when preparing a meal
Needs prompting to do household chores
Needs prompting to prepare meal
Needs prompting to take medications
Needs prompting to do leisure activities
Needs help with dosage of medications
Diffi culties managing cash
Moderate Confused in unusual places
Confused with the date
Eats the same foods
Inability to choose clothes adequate to the
Severe.. Lack of appropriate manners at mealtimes
Lack of initiation to eat if not served
Cannot stay at home alone
Not using cutlery adequately
Does not go to toilet in time (urine)
Very severe ..
Modifi ed from Mioshi et al,115 by permission of Wolters Kluwer Health. bvFTD=behavioural-variant frontotemporal dementia.
Table: Characteristics of each severity stage in the disease progression of bvFTD
For the Mental Capacity Act
www.thelancet.com/neurology Vol 10 February 2011 169
capacity is not a global phenomenon but is situation
specifi c. Moreover, unlike in AD, in which capacity can
be impaired by amnesia (which is easier to assess), in
bvFTD, the key cognitive variables are insight and
judgment, which are much harder to assess and quantify.
Finally, many useful publications and DVDs are available
for caregivers, which can be accessed through the
Frontotemporal Dementia Research Group website or
the Association for FTDs.
Conclusions and future directions
Knowledge of the clinical presentation of bvFTD and its
pathological processes has improved substantially over
the past 20 years. Clinicians have become more aware of
this disabling neurodegenerative condition, which aff ects
individuals who are often still in the workforce or have
young children. Careful medical history and information
from family members,
investigations, neuro psychological
investigations of social cognition, have increased case
identifi cation. Sensitivity has also improved with the use
of advanced structural and functional neuroimaging
techniques. However, the major challenge that remains is
to improve the prediction of the underlying neuropathology
in patients with bvFTD during life. Eff orts to identify
potential disease biomarkers for the disease are promising
but will require further investigations. This line of
research will become particularly relevant as disease-
modifying agents are developed.
All authors contributed equally to the conception, literature review, and
writing of this Review.
Confl icts of interest
The authors declare that they have no confl icts of interest.
This project was supported in part by a National Health and Medical
Research Council (NHMRC) of Australia project grant (#510106). OP is
supported by an NHMRC clinical career development award
fellowship (#510184). JRH is supported by an Australian Research
Council Federation fellowship (#FF0776229) and was previously
supported by the UK Medical Research Council.
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