Behavioural-variant frontotemporal dementia: diagnosis, clinical ...

Review 

Lancet Neurol 2011; 10: 162–72 

Published Online 

December 13, 2010 

DOI:10.1016/S1474- 

4422(10)70299-4 

Neuroscience Research 

Australia, Randwick, NSW, 

Australia (O Piguet PhD, 

M Hornberger PhD, 

E Mioshi PhD, 

Prof J R Hodges FMedSci) 

Correspondence to: 

Prof John Hodges, Neuroscience 

Research Australia, Barker St, 

Randwick, NSW 2031, Australia 

j.hodges@neura.edu.au 

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. 

Introduction 

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 

to autopsy. 

Unlike AD, both the clinical profi le and the underlying 

pathological changes are heterogeneous in FTD. Two 

broad presentations are recognised: progressive 

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 

Pathology 

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 

described below. 

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 

162 www.thelancet.com/neurology Vol 10 February 2011

Possible phenocopy 

Possible bvFTD based on clinical, behavioural, 

cognitive, and ADL assessments* 

MRI 

Abnormal 

PET Probable bvFTD 

Normal 

Normal 

Abnormal 

Strong family history 

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 

daily living. 

subclassifi cation is based on morphological criteria and 

the predominance of either tau with three microtubulebinding 

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 diseasemodifying 

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 β 1–42 has been found to be lower in 

FTLD than in AD. 25 Increased concentrations of 

Yes 

Genetic screening 

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 Serum progranulin 

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. 

Genetics 

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. 

Review 

www.thelancet.com/neurology Vol 10 February 2011 163

Review 

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 

often older. 11 

Behavioural features 

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 

typify bvFTD. 

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, hyperreligiosity, 

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, 

including feeding. 50 

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 

bulbar MND. 7 

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 

not universal. 58 

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 

underlying pathology. 

bvFTD phenocopy syndrome: implications for 

diagnostic criteria 

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 


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 neuroimaging 

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 

Neuropsychology 

Cognition 

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 and visuospatial/ 

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 

cases. 68,69 

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 

Review 

Neurodegenerative disease 

Must be present for any FTD clinical syndrome 

Shows progressive deterioration of behaviour and/or cognition by observation or history 

Possible bvFTD 

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 

Probable bvFTD 

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 

Additional features 

A Presence of motor neuron fi ndings suggestive of motor neuron disease 

B Motor symptoms and signs similar to corticobasal degeneration and progressive 

supranuclear palsy 

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. 


Review 

Mild Moderate Severe 

Dorsolateral prefrontal and 

medial prefrontal cortices 

Orbitofrontal cortex 

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 

frontotemporal dementia. 

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 

interpersonal relationships. 

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 

bvFTD. 

Neuroimaging 

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 


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 

MRI changes. 61,89 

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 [ 99m Tc]hexamethylpropyleneamine 

oxime single-photon emission 

computed tomography (SPECT) or [ 18 F]-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-βdetecting 

[ 11 C]-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. 

Functional abilities 

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 

survival 

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 dementia rating 

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” 

on CDR. 

Review 


Review 

For the Mental Capacity Act 

see http://www.publicguardian. 

gov.uk 

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 

neuropathological subtype on survival remains 

contentious. 116,119 

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 nonpharmacological 

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 neuropsychiatric 

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 

Behaviour Activities of daily living 

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 

challenging behaviours. 

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, 

Basic Instrumental 

Mild Lack of aff ection No changes Diffi culties in managing correspondence 

Diffi culties in planning of fi nances 

Moderate Confused in unusual places 

Agitated, restless 

“Sweet tooth” 

Uncooperative 

Confused with the date 

Eats the same foods 

Impulsive 

Inability to choose clothes adequate to the 

occasion 

Severe .. Lack of appropriate manners at mealtimes 

Lack of initiation to eat if not served 

Very severe .. Cannot stay at home alone 

Not using cutlery adequately 

Does not go to toilet in time (urine) 

Profound .. Bedridden .. 

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 

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 

.. 


Search strategy and selection criteria 

References for this Review were identifi ed through searches 

of PubMed from 2000, until November, 2010, with the terms 

“frontotemporal dementia”, “frontotemporal lobar 

degeneration”, “behavioural-variant frontotemporal 

dementia”, and “frontal-variant frontotemporal dementia”. 

Articles were also identifi ed through searches of the authors’ 

own fi les. Only papers published in English were reviewed. 

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, combined with clinical 

investigations, neuro psychological testing, and 

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 diseasemodifying 

agents are developed. 

Contributors 

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. 

Acknowledgments 

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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Behavioural-variant frontotemporal dementia: diagnosis, clinical ...

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