From FUS to Fibs: What's New in Frontotemporal ... - IOS Press

Journal of Alzheimer’s Disease 21 (2010) 349–360 349 

DOI 10.3233/JAD-2010-091513 

IOS Press 

Review 

From FUS to Fibs: What’s New in 

Frontotemporal Dementia? 

James R. Burrell a,b and John R. Hodges a,∗ 

a Prince of Wales Medical Research Institute, University of New South Wales, Sydney, Australia 

b Prince of Wales Clinical School, University of New South Wales, Sydney, Australia 

Accepted 1 February 2010 

Abstract. Frontotemporal dementia (FTD) is an important cause of non-Alzheimer’s dementia and is the second most common 

cause of young onset dementia. FTD presents with progressive changes in behavior and personality (behavioral variant FTD) 

or language deficits (also known as primary progressive aphasia), although both commonly coexist. Patients with progressive 

aphasia are subclassified according to the pattern of language deficits into those with progressive non-fluent aphasia (PNFA) 

and semantic dementia (SD). FTD is pathologically heterogeneous, both macroscopically and on a molecular level, with tau 

positive, TDP-43 positive, and FUS positive intraneuronal inclusions recognized on immunohistochemical analysis. TDP-43 

positive inclusions are also a feature of amyotrophic lateral sclerosis pathology, corroborating the observation of overlapping 

clinical features between the two conditions and reaffirming the FTD-ALS disease spectrum. Most FTD cases are sporadic, but an 

important minority is inherited in an autosomal dominant fashion, most commonly due to MAPT or progranulin gene mutations. 

Familial clusters of FTD and amyotrophic lateral sclerosis are also recognized but poorly understood. This paper reviews the 

clinical phenotypes, assessment and treatment of FTD in light of recent pathological and genetic discoveries. 

Keywords: Behavioral variant FTD, frontotemporal dementia, FTD-ALS, progressive non-fluent aphasia, semantic dementia, tau, 

TDP-43 

INTRODUCTION 

The recent demonstration of TAR-DNA binding protein 

43 (TDP-43) as the constituent of ubiquintated 

intraneuronal inclusions in frontotemporal dementia 

(FTD) and amyotrophic lateral sclerosis (ALS) has 

stimulated a surge of clinical, pathological, and genetic 

research into these overlapping entities. FTD is the second 

most common cause of young onset dementia after 

Alzheimer’s disease [1,2], and three distinct clinical 

phenotypes of FTD are recognized, each with variable 

degrees of progressive behavior and language distur- 

∗ Correspondence to: Prof. John R. Hodges, Prince of Wales 

Medical Research Institute, Cnr Barker St and Easy St, Randwick, 

Sydney, NSW 2031, Australia. Tel.: +61 2 9399 1132; Fax: +61 2 

9399 1005; E-mail: j.hodges@powmri.edu.au. 

ISSN 1387-2877/10/$27.50 © 2010 – IOS Press and the authors. All rights reserved 

bance. A proportion of patients with FTD also develop 

clinical and neurophysiological evidence of motor 

neuron dysfunction and many satisfy the El Escorial 

criteria for the diagnosis of ALS [3]. The pathology 

of FTD is heterogeneous with variable degrees of focal 

frontal and temporal atrophy [4]. Three intraneuronal 

inclusions types have been characterized immunohistochemically 

as tau, TDP-43 or fused in sarcoma (FUS) 

positive [5–8]. TDP-43 positive inclusions are the most 

common type in FTD and are also identified in the 

majority of ALS cases [9,10]. 

Until recently, FTD was considered a rare cause of 

dementia and clinical distinction from AD was considered 

very difficult [11,12]. Over time, the defining 

clinical features of FTD have been elucidated and 

three clinical phenotypes are recognized (see Fig. 1). 

The behavioral variant of FTD (bvFTD) is character-

350 J.R. Burrell and J.R. Hodges / From FUS to Fibs: What’s New in Frontotemporal Dementia? 

Fig. 1. Clinical Phenotypes of FTD. FTD is subclassified as behavioral variant (bvFTD) if behavior and personality changes predominate; Tau 

(green) and TDP-43 (blue) pathology are equally prevalent. Language variants include progressive non-fluent aphasia (PNFA), in which tau 

pathology is most prevalent and semantic dementia (SD), in which TDP-43 pathology is almost universal. 

Fig. 2. MRI appearances in FTD. T1 weighted, coronal MRI images reveal: A) bvFTD – dorsolateral and orbitomesial, bifrontal atrophy, with 

dilatation of anterior horns of lateral ventricles (left > right); B) PNFA – moderate temporal atrophy (left > right) with subtle enlargement of 

the sylvian fissure due to insula atrophy (single arrow); C) SD – anterior temporal atrophy, severe on the left (double arrow) and moderate on the 

right with associated orbitofrontal atrophy. 

ized by marked changes in behavior and personality, 

with relatively preserved language function. Alternatively, 

patients with semantic dementia (SD) and progressive 

non-fluent aphasia (PNFA) develop progressive 

language deficits, with more subtle personality and 

behavior changes. FTD is a progressive neurodegenerative 

disorder and the median survival from symptom 

onset is 6–8 years, but patients with FTD and ALS have 

an even worse prognosis [13,14]. 

This review cannot cover every facet of this rapidly 

evolving field, but rather attempts to place the recent 

pathological and genetic discoveries within the context 

of the clinical phenotypes of FTD and to outline an 

approach to clinical assessment and treatment. 

PATHOLOGY 

Focal frontal and temporal atrophy is identified in 

patients with FTD on autopsy [4], but the pattern of 

atrophy varies significantly among the clinical phenotypes. 

Bilateral mesial and orbitofrontal and temporal 

atrophy is the characteristic finding in patients with 

bvFTD. In SD, anterior and inferior temporal lobe atrophy 

is a universal feature, usually worse on the left 

than the right [15,16]. There may also be mild frontal 

atrophy. In PFNA, left-sided inferior frontal, insula, 

and perisylvian atrophy, is characteristic and is often 

severe [17].

J.R. Burrell and J.R. Hodges / From FUS to Fibs: What’s New in Frontotemporal Dementia? 351 

Microscopically, FTLD is characterized by microvacuolation 

and neuronal loss, with variable degrees 

of white matter myelin loss and astrocytic gliosis 

[4], and intraneuronal as well as intraglial inclusions. 

The use of immunohistochemical staining has 

revolutionized the field and allows further categorization 

of the molecular pathology. Tau positive inclusions 

are present in approximately 40% of FTLD cases 

and the remainder are tau negative but ubiquitin positive 

[18]. Tau positive cases can be characterized biochemically 

as either predominantly three microtubule 

binding repeats tau (3R tau) or four microtubule binding 

repeat (4R tau), with further subclassification based 

on established morphologic criteria [4,19]. TDP-43 

accounts for the majority of the ubiquitin positive cases 

and more than half of all FTD cases overall, but 

a minority FTD cases are both tau and TDP-43 negative 

[10]. Very recently, FUS positive inclusions have 

been demonstrated in these cases [6]. The search for 

FUS pathology was only initiated after FUS gene mutations 

were identified in cases of familial ALS, further 

emphasizing the links between FTD and MND [20– 

23]. Ubiquitin positive, TDP-43 negative inclusions 

have recently been demonstrated in patients with ALS 

due to mutations of FUS [24]. TDP-43 and FUS are 

RNA processing proteins, however, the link between 

these mutations and disease pathogenesis has not yet 

been elucidated [25]. 

The clinical phenotypes are associated with specific 

molecular pathologies to variable degrees. Tau positive 

and TDP-43 positive inclusions are equally prevalent in 

patients with bvFTD, whereas SD as well as FTD cases 

with coexistent ALS, are almost exclusively associated 

with TDP-43 pathology, although the distribution of 

inclusions differs between phenotypes [15,19,26,27]. 

In PNFA, tau positive inclusions are most commonly 

identified and can be further classified histopathologically 

as Pick’s disease (PiD) or non-PiD tau [26–28]. 

The small number of reported FUS positive FTD cases 

thus far have presented with bvFTD [6,29]. 

GENETICS 

Up to 40% of patients with FTD may have a family 

history of dementia [1,30,31], but the high community 

prevalence of non-FTD dementia may account for a 

significant proportion of this family history. Patients 

with an autosomal dominant pattern (several affected 

first degree relatives across two generations) are much 

rarer, perhaps only accounting for 10% of FTD cas- 

es [32]. Known mutations can now be demonstrated 

in the majority of patients with this pattern of inheritance. 

Overall, mutations of the microtubule associated 

phosphoprotein tau (MAPT) and the progranulin 

(PRGN) gene each account for 5–11% of total FTD cases 

[32–35]. Although associated with TDP-43 pathology, 

PGRN mutations are not usually identified in patients 

with familial ALS [36]. Mutations of the gene 

encoding for TDP-43 (TARBP), recognized as a cause 

of familial ALS, have also been identified in cases of 

FTD-ALS [37], and rarely in FTD [38]. Rare genetic 

mutations causing FTD include valosin containing protein 

(VCP) and charged multivesicular body protein 2B 

(CHMP-2B). Mutation in the VCP gene causes FTD in 

association with inclusion body myopathy and Paget 

disease of bone [39], whereas the CHMP-2B gene mutation 

is confined to a large Danish cohort with FTD 

and other very rare patients with ALS [40]. In a recent 

study of patients with familial ALS due to FUS mutations, 

one mutation carrier presented with FTD [24]. 

The overall incidence of FUS mutations in FTD patients 

is currently unknown, however, no cases were 

identified in a recent mutation screening study of 225 

FTD patients [32]. 

In addition to autosomal dominant inheritance of 

FTD, familial clusters of FTD and ALS are reported. 

Within these clusters, one individual may develop FTD 

and another ALS, or a third individual may develop 

FTD and subsequently ALS. Several linkage studies of 

FTD-ALS clusters have indicated a common locus in 

the region of chromosome 9p13.2–21.3 [41–44], but 

the responsible gene has not yet been identified. 

CLINICAL PHENOTYPES OF FTD 

Behavioral variant FTD 

Approximately half of patients with FTD present 

with the bvFTD [45]. The symptom profile reflects progressive 

disintegration of the neural circuits involved in 

social cognition, emotion regulation, motivation, and 

decision making [46–48]. The orbitomesial frontal cortex, 

insula, and amygdala are increasingly recognized 

as key structures undergoing degeneration [49]. The 

behavioral and personality changes of bvFTD develop 

insidiously and may initially be mistaken for symptoms 

of depression [50,51]. Over time, symptoms accumulate 

and become more obvious. Patients usually lack 

insight into their cognitive symptoms and often dismiss 

carer or family concerns as unfounded. Apathy is al-


most universal and manifests as inertia, reduced motivation, 

lack of interest in previous hobbies, and progressive 

social isolation. Disinhibition often coexists 

with apathy, and may manifest as impulsive actions, 

tactless or sexually inappropriate remarks, and socially 

embarrassing behavior. Changes in eating habits are 

common, with a narrowed repertoire of favored foods 

and meals. Patients may become gluttonous with food 

hoarded and even snatched from others. Excessive 

weight gain is common. Repetitive or stereotypic behaviors 

may be apparent and patients may perseverate, 

frequently repeating phrases, stories or favorite jokes. 

Patients often lack empathy and an inappropriately subdued 

grief reaction is a common early symptom. Mental 

rigidity is common and patients may have difficulty 

adapting to new situations or routines. Psychotic 

features (delusions and or hallucinations) are relatively 

unusual overall [52], but in cases of FTD associated 

with ALS psychotic features have been reported in up 

to 50% of patients [53]. Uncommonly, patients may 

present with symptoms suggestive of dementia with 

Lewy bodies such as hallucinations, fluctuating cognition, 

and parkinsonism [54]. 

Language disturbance may be present, most commonly 

characterized by adynamism, but does not dominate 

the clinical picture. Impaired executive function, 

manifest as difficulties in planning, organization, and 

goal-setting, is common. Unlike AD, episodic memory 

is preserved in the early stages of bvFTD and visuospatial 

deficits are not prominent. 

It is increasingly apparent that not all patients with 

the clinical features of bvFTD actually progress to frank 

dementia [55]. Such patients are almost always men 

and a proportion remain stable over many years or 

actually improve [56,57]. Over recent years a number 

of features have emerged that distinguish these 

non-progressive or phenocopy cases, for example, they 

show normal structural and functional imaging brain 

imaging [55,56,58]. The etiology of the phenocopy 

syndrome is a matter of debate. A proportion of patients 

appear to have a developmental personality disorder 

in the Asperger’s spectrum (personal observation). 

Some may have a chronic low grade mood disorder, but 

others remain a mystery. 

The most commonly used diagnostic criteria for 

bvFTD, the Neary criteria [59], have recently come under 

criticism and are currently under review [60]. It is 

anticipated that the revised criteria will distinguish possible/probable 

and definite bvFTD, be easier and more 

flexible to apply with clearer operational definitions, 

and will include imaging and genetic findings. 

Progressive Non-Fluent Aphasia (PNFA) 

In PNFA, the presenting features reflect the breakdown 

of processes vital for effortless verbal communication, 

centering on Broca’s area, the anterior insula 

and the perisylvian structures. While some patients 

have a predominantly motor speech disorder (or apraxia 

of speech), others have mainly syntactic problems [61]. 

Their speech is labored and they often stumble over 

certain words, make grammatical errors, and have variable 

degrees of dysarthria. Word-finding difficulty and 

word pauses are common, further contributing to reduced 

speech fluency. Phonemes, the most elemental 

components of verbal language, may be inappropriately 

selected or substituted, and such phonemic errors 

and paraphrasias are common. For example, the patient 

with PNFA may say “kanbaroo” rather than “kangaroo” 

or “wrisk” rather than “whisk”. Minor naming difficulties 

are apparent, but the severe anomia as encountered 

with SD is not a feature. Word repetition is typically 

impaired, particularly when attempting multisyllabic 

words such as “hippopotamus”, “chrysanthemum”, 

or “methodist episcopal” but comprehension of word 

meaning is preserved. Syntax (sentence construction) 

may be impaired and patients use simplified grammar 

with occasional inflectional errors and omissions, but 

severe agrammatism is uncommon. Although typically 

not reported by patients, sentence comprehension is 

often impaired. This is best observed when testing sequencing 

of tasks with more complex sentence structures, 

for example “Touch the pen after handing me the 

razor”. 

Semantic Dementia (SD) 

Although the predominant features of SD are anomia 

and impaired word comprehension, there is breakdown 

of the amodal knowledge system, the hub of which is 

located in the anterior temporal lobe. In contrast to 

PNFA, SD presents with progressive fluent aphasia and 

word comprehension deficits. Initially patients may report 

“loss of memory for words” or difficulty remembering 

the names of people. Anomia, the inability to 

name objects, is an integral component of SD with 

the names of infrequently used objects usually affected 

first. For example, the patient may be unable to name 

a stethoscope but is able to name a pen. As SD progresses, 

the names of more common objects become 

difficult to produce and patients often resort to circumlocutions 

to express their meaning. For example, when 

asked to name a can opener, a patient with SD may


say “it’s a special device for opening cans”, rather than 

“a can opener”. As anomia progresses, less frequently 

used words are replaced by more common generalizations 

such as “thing” or “stuff” and sub-category 

naming becomes more difficult. For example, breeds 

of dog such as “beagle”, “labrador” or “poodle” may 

all be referred to as “dog” and then all four-legged animals 

are likely to be called “dog” or “cat”. Progressive 

deficits in word meaning become apparent over time 

and can be assessed by asking the patient to “repeat and 

define” a word. Patients with SD are generally able 

to repeat a word without difficulty, but are unable to 

define it (“Hippopotamus? What is that? I’m sure I 

used to know”). Word comprehension difficulties are 

also apparent when the patient attempts to read. Patients 

typically show surface dyslexia, where irregular 

English words with specific and unpredictable pronunciation 

rules are incorrectly read aloud [62–64]. For 

example, the patient with SD may pronounce the word 

“pint” as though it rhymed with “mint”. Other irregular 

words such as “soot”, “yacht” or “colonel” also present 

difficulties. Although behavioral symptoms are not the 

dominant clinical feature of SD, a number of changes 

in personality and behavior are observed. Patients may 

become emotionally withdrawn, apathetic, disinhibited, 

show stereotyped and rigid behaviors or develop a 

preference for sweet foods. Less frequently, patients 

with SD develop more right greater than left sided anterior 

temporal atrophy, and consequently display several 

distinct clinical features. Difficulty in recognizing 

faces, or prosapagnosia, is frequent and behavioral 

symptoms are more common in right temporal SD than 

in classic SD [65–68]. 

Logopenic Progressive Aphasia (LPA) 

Not all cases of primary progressive aphasia can be 

neatly classified as either PNFA or SD. In recent years, 

a third group of patients with progressive aphasia characterized 

by hesitant speech with prominent word finding 

difficulty, anomia, intact word but impaired sentence 

repetition and markedly impaired auditory verbal 

short-term memory has been described [69,70]. This 

syndrome, called logopenic progressive aphasia (LPA), 

while sharing some clinical features with PNFA and 

SD, appears to represent an atypical variant of AD, 

rather than a clinical phenotype of FTD [71]. 

ASSESSMENT 

The bedside or clinic cognitive assessment involves 

a detailed patient and informant interview, simple testing 

of cognitive domains, and a neurological examination 

[72,73]. It is preferable to interview the patient 

and informant separately in order to confirm or 

elaborate on elements of the history which may prove 

sensitive or embarrassing. Even in advanced cases an 

assessment of insight, spontaneous speech, and social 

interaction can usually be attempted. As the interview 

proceeds, speech fluency, word-finding difficulties or 

pauses, and phonemic paraphrasias are noted. Other 

symptoms such as apraxia or visuospatial disturbance 

should also be explored. A family history of dementia, 

mental illness, or ALS should be sought and clarified 

when identified. 

Cognition can be assessed surprisingly well in the 

clinic or at the bedside [72,73]. Naming and semantic 

knowledge should be examined using pictures or, 

even better, toy animals and household objects, but it is 

important to use both familiar and less familiar items. 

Comprehension of simple commands and grammatical 

understanding, often mildly abnormal in patients with 

PNFA, should be examined with multi-step commands 

such as “Touch the razor and then the scissors” or “Give 

me the razor after you have touched the pencil”. Single 

word repetition is often impaired in PNFA. In contrast, 

patients with SD are generally able to repeat but 

not define the word. Reading aloud may reveal surface 

dyslexia, a feature of SD. Executive function is 

assessed with verbal fluency tests (letter and category), 

proverb interpretation, or testing the patient’s ability to 

inhibit alternating hand movements. 

The bedside cognitive assessment should be complemented 

with a neuropsychological examination, which 

is reviewed elsewhere [73,74]. The Mini-Mental Status 

Examination (MMSE), although commonly used in 

clinical practice, it is insensitive to the cognitive deficits 

encountered in FTD [75]. The Addenbrooke’s Cognitive 

Examination (ACE-R) incorporates elements of 

the MMSE, but includes a more thorough assessment of 

language (with fluency, naming, and semantic knowledge 

tasks), visuospatial ability, and memory, is effective 

in the distinction of FTD from AD [76,77]. The 

ACE-R is freely available online for clinical use [78]. 

Traditional neuropsychological assessments are not 

particularly sensitive to the deficits in social cognition 

encountered in patients with FTD, especially early 

bvFTD [79]. However, a new generation of tasks testing 

complex decision making [80,81],emotion process-


ing [49,82,83], sarcasm detection [49,84], and “Theory 

of Mind” [80,85] have been developed to address this. 

Similarly, new tasks have been developed to demonstrate 

and characterize the speech output and semantic 

deficits encountered in PNFA and SD [86]. 

Physical examination may be normal in patients with 

FTD. In some cases of bvFTD, or rarely PNFA, features 

of motor neurone dysfunction such as hyper-reflexia, 

muscle wasting, weakness, fasciculations, or dysarthria 

may be detected [3]. Other patients, particularly those 

with PNFA, may demonstrate the parkinsonian features 

of corticobasal syndrome or progressive supranuclear 

palsy such as rigidity, bradykinesia, gait disturbance, 

and eye movement abnormalities [87–90]. 

NEUROIMAGING 

Neuroimaging has been increasingly applied to the 

assessment of patients with FTD. Structural imaging, 

most typically with magnetic resonance imaging 

(MRI), reveals relatively well circumscribed, but varied, 

frontal and temporal lobe atrophy. The distribution 

of frontal and temporal atrophy observed on MRI correlates 

with the clinical phenotype [91]. In bvFTD, bilateral 

frontal and temporal atrophy is encountered [58], 

with the orbitofrontal cortex, superior frontal gyrus, 

temporal pole, insula, entorhinal cortex, hippocampus, 

and the head of the caudate affected [92,93]. Sophisticated 

MRI imaging techniques have identified dysfunction 

of differing neural circuits in FTD phenotypes [94], 

and selective vulnerabilities of specific circuits may 

underpin the clinical features and distribution of neuropathologic 

appearance of FTD [95]. For example, 

selective atrophy of the anterior cingulate cortex and 

anterior insula, corresponding with the location of von 

Economo neurons – a unique neuron type identified 

in humans and higher primates, has been identified in 

early bvFTD using MR techniques [96]. The neural 

correlates of behavioral symptoms have been studied 

using voxel based morphometry. For example, apathy 

has been associated with atrophy of right dorsolateral 

frontal structures, whereas disinhibition has been 

associated with grey matter loss of the right temporal 

lobe, particularly of the amygdala and hippocampus 

[97]. White matter changes on diffusion tensor 

imaging (DTI) have also been correlated with symptoms 

in bvFTD. For example, the superior longitudinal 

fasciculus has been linked with behavioral symptoms 

in bvFTD [98]. 

In PNFA, atrophy is most marked in the left superior 

temporal and inferior frontal lobes, as well as 

the left insula [17,99,100]. SD is characterized by 

asymmetrical temporal lobe atrophy (worse on the left 

than the right) with atrophy of the perirhinal cortex, 

as well as the parahippocampal, fusiform, and inferior 

temporal gyri [17,99]. Functional imaging with 

F 18 fluorodeoxyglucose positron emission tomography 

(FDG-PET) in FTD reveals frontal and temporal hypometabolism, 

and FDG-PET is a useful adjunct in the 

distinction of FTD from other dementias [101–103]. 

Recently, the use of carbon 11-labeled Pittsburgh compound 

B positron emission tomography (PiB-PET) has 

been used to distinguish atypical presentations of AD 

from FTD [99]. Patients with AD pathology demonstrate 

increased PiB binding, but patients with FTD do 

not [71,104,105]. Positron emission tomography ligands 

to detect tau, TDP-43, or FUS pathology are not 

currently available. 

TREATMENT 

Currently there are no disease specific treatment interventions 

for FTD. Consequently, treatment largely 

remains supportive and involves a combination of 

non-pharmacological and pharmacological measures, 

aimed at reducing the effect of troublesome behaviors 

[106]. The impact of FTD on family members is 

enormous with high levels of stress and burden [107, 

108]. Carer education and support are essential and 

have been enhanced by the publication of a free booklet, 

“Understanding Younger Onset Dementia” [78]. 

The role of pharmacological interventions in FTD remains 

uncertain, and only small and often conflicting 

treatment trials have been conducted thus far. Selective 

serotonin reuptake inhibitors (SSRIs) such as paroxetine 

have been used to treat disinhibition and challenging 

behaviors, but evidence for their use remains contradictory 

[109,110]. Atypical antipsychotics such as 

olanzepine have been used for behaviors unresponsive 

to SSRIs or in patients with prominent delusions [111]. 

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 

behavioral disturbance and carer stress with rivastigmine 

[112], however, deterioration in neuropsychiatric 

symptoms without cognitive improvement was demonstrated 

with donepezil [113].


Table 1 

Clinical features of FTD phenotypes 

Characteristic Behavioral FTD (bvFTD) Progressive Non-Fluent Aphasia 

(PNFA) 

Heritability ++ + +/- 

Behavior – Severe Apathy 

– Disinhibition 

– Reduced empathy 

– Stereotyped behavior and perseveration 

– Changed food preference, 

weight gain 

– Literal proverb interpretation 

– Mental rigidity 

– Executive dysfunction 

– Relatively preserved in early 

stages 

Language – Adynamism – Non-Fluent speech 

– Hesitancy 

– Apraxia of Speech 

– Phoenemic errors 

– Syntactic errors 

– Mild anomia 

– Impaired single word and sentence 

repetition 

MRI features – Frontal atrophy 

– Orbitomesial 

– Temporal atrophy 

– Temporal pole 

– Hippocampus 

– Amygdala 

– Caudate (head) 

– Severe left temporal atrophy ∗ 

– Perisylvian 

% Tau positive cases < 50% 70% < 10% 

% TDP-43 cases < 50% 30% > 90% 

% FUS positive cases 5–10% Unknown Unknown 

∗ Features of the right temporal variant of SD. 

OUTSTANDING ISSUES 

Although disease specific treatments for FTD are not 

available, the development of anti-tau therapies in the 

context of AD holds promise for future FTD therapeutics 

[114]. Should specific anti-tau or anti-TDP-43 

therapies be developed, the ability to predict underlying 

neuropathologic processes at an early stage will become 

crucial [115]. Careful refinement of FTD phenotypes 

is one attempt to achieve this. For instance, 

it is clear that SD is associated with TDP-43 pathology 

[116] but has very low heritability and gene mutations 

are consequently rare [32]. PNFA, by contrast, 

appears to be more commonly associated with 

tau pathology, especially when apraxia of speech is 

present [117]. Sensitive and specific biomarkers are 

clearly needed. CSF biomarkers such as total tau and 

ratios of tau to amyloid-β42 have been demonstrated to 

distinguish FTD from AD in vivo [118,119], but their 

utility in individual cases is unproven. Serum TDP- 

Semantic Dementia (SD) 

– Preference for sweet foods, (late) 

– Apathy (late)* 

– Disinhibition (late)* 

– Impaired facial recognition* 

– Fluent speech 

– Severe anomia 

– Circumlocutions to express meaning 

– Surface dyslexia 

– Normal word and sentence repetition 

– Bilateral anterior temporal atrophy 

(usually left > right) 

– Perirhinal cortex 

– Fusiform gyrus 

– Inferior temporal gyrus 

43 has also been studied as a potential biomarker for 

FTD and ALS [120–122]. Serum progranulin levels, 

which are low in patients with PGRN mutations [123], 

may provide a useful screening test for these mutations. 

PET and MRI imaging may support the clinical 

diagnosis of FTD, to distinguish FTD from AD 

and to aid FTD phenotype classification [99,102,124, 

125]. Accurate prediction of underlying pathology is 

likely to require a combined approach using a range of 

investigative techniques. 

CONCLUSION 

Developments in the field of FTD are proceeding 

rapidly. Consequently, efforts to revise the diagnostic 

criteria, taking into account clinical features, genetic, 

imaging, and pathologic characteristics are underway. 

The revised criteria will hopefully allow the distinction 

of “phenocopy” FTD patients from those with progres-


sive dementia. The shared clinical, genetic, and pathological 

features of FTD and ALS have provided new 

insights into both disorders which together form a single 

clinicopathological spectrum. Although tau positive 

intraneuronal inclusions were identified initially, 

TDP-43 positive inclusions are now recognized as the 

most frequent underlying histopathology in FTD and 

ALS. The observed familial clusters of FTD and ALS 

have not yet been definitively explained. Furthermore, 

the incidence of subclinical motor dysfunction in FTD, 

or cognitive symptoms in ALS, has not yet been definitively 

established and is the subject of further study. 

The combination of FTD and ALS is associated with 

a poorer prognosis, but whether the prognosis of TDP- 

43 positive cases differs significantly from tau positive 

FTD cases remains controversial. Moreover, the role 

of neuropsychologic examination in the assessment of 

ALS patients is yet to be established. The need for 

suitable biomarkers in life of distinctive pathological 

entities, and their relationship to prognosis, is clear and 

will be necessary for the future development of disease 

specific treatments. 

ACKNOWLEDGMENTS 

Dr. James R. Burrell gratefully acknowledges the 

support of the National Health and Medical Research 

Council of Australia and the Motor Neurone Disease 

Research Institute of Australia. 

Professor John R. Hodges is in receipt of an Australian 

Research Council Federation Fellowship Grant. 

Authors’ dislcosures available online (http://www.jalz.com/disclosures/view.php?id=317). 

REFERENCES 

[1] Ratnavalli E, Brayne C, Dawson K, Hodges JR (2002) The 

prevalence of frontotemporal dementia. Neurology 58, 1615- 

1621. 

[2] Rosso SM, Kaat LD, Baks T, Joosse M, de Koning I, Pijnenburg 

Y, de Jong D, Dooijes D, Kamphorst W, Ravid R, 

Niermeijer MF, Verheij F, Kremer HP, Scheltens P, van Duijn 

CM, Heutink P, van Swieten JC (2003) Frontotemporal dementia 

in The Netherlands: patient characteristics and prevalence 

estimates from a population-based study. Brain 126, 

2016-2022. 

[3] Lomen-Hoerth C, Anderson T, Miller B (2002) The overlap 

of amyotrophic lateral sclerosis and frontotemporal dementia. 

Neurology 59, 1077-9. 

[4] Cairns N, Bigio E, Mackenzie I, Neumann M, Lee V, Hatanpaa 

K, White C, Schneider J, Grinberg L, Halliday G, Duyckaerts 

C, Lowe J, Holm I, Tolnay M, Okamoto K, Yokoo 

H, Murayama S, Woulfe J, Muñoz D, Dickson D, Ince P, 

Trojanowski J, Mann D (2007) Neuropathologic diagnostic 

and nosologic criteria for frontotemporal lobar degeneration: 

consensus of the Consortium for Frontotemporal Lobar Degeneration. 

Acta Neuropathol 114, 5-22. 

[5] Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi 

MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark 

CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, 

Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, 

Lee VM (2006) Ubiquitinated TDP-43 in frontotemporal lobar 

degeneration and amyotrophic lateral sclerosis. Science 

314, 130-133. 

[6] Neumann M, Rademakers R, Roeber S, Baker M, Kretzschmar 

HA, Mackenzie IRA (2009) A new subtype of frontotemporal 

lobar degeneration with FUS pathology. Brain 

132, 2922-2931. 

[7] Taniguchi S, McDonagh AM, Pickering-Brown SM, Umeda 

Y, Iwatsubo T, Hasegawa M, Mann DMA (2004) The neuropathology 

of frontotemporal lobar degeneration with respect 

to the cytological and biochemical characteristics of 

tau protein. Neuropathol Appl Neurobiol 30, 1-18. 

[8] Mott RT, Dickson DW, Trojanowski JQ, Zhukareva V, Lee 

VM, Forman M, Van Deerlin V, Ervin JF, Wang D, Schmechel 

DE, Hulette CM (2005) Neuropathologic, biochemical, and 

molecular characterization of the frontotemporal dementias. 

J Neuropathol Exp Neurol 64, 420-428. 

[9] Geser F, Martinez-Lage M, Robinson J, Uryu K, Neumann 

M, Brandmeir NJ, Xie SX, Kwong LK, Elman L, McCluskey 

L, Clark CM, Malunda J, Miller BL, Zimmerman EA, Qian 

J, Van Deerlin V, Grossman M, Lee VM, Trojanowski JQ 

(2009) Clinical and Pathological Continuum of Multisystem 

TDP-43 Proteinopathies. Arch Neurol 66, 180-189. 

[10] Mackenzie IRA, Foti D, Woulfe J, Hurwitz TA (2008) 

Atypical frontotemporal lobar degeneration with ubiquitinpositive, 

TDP-43-negative neuronal inclusions. Brain 131, 

1282-1293. 

[11] Mendez MF, Selwood A, Mastri AR, Frey WH (1993) Pick’s 

disease versus Alzheimer’s disease: A comparison of clinical 

characteristics. Neurology 43, 289-292. 

[12] Varma AR, Snowden JS, Lloyd JJ, Talbot PR, Mann DMA, 

Neary D (1999) Evaluation of the NINCDS-ADRDA criteria 

in the differentiation of Alzheimer’s disease and frontotemporal 

dementia. J Neurol Neurosurg Psychiatry 66, 184-188. 

[13] Hodges JR, Davies R, Xuereb J, Kril J, Halliday G (2003) 

Survival in frontotemporal dementia. Neurology 61, 349-54. 

[14] Roberson ED, Hesse JH, Rose KD, Slama H, Johnson JK, 

Yaffe K, Forman MS, Miller CA, Trojanowski JQ, Kramer 

JH, Miller BL (2005) Frontotemporal dementia progresses to 

death faster than Alzheimer disease. Neurology 65, 719-725. 

[15] Snowden J, Neary D, Mann D (2007) Frontotemporal lobar 

degeneration: clinical and pathological relationships. Acta 

Neuropathol 114, 31-38. 

[16] Hodges JR Patterson K (2007) Semantic dementia: a unique 

clinicopathological syndrome. Lancet Neurol 6, 1004-1014. 

[17] Rohrer JD, Warren JD, Modat M, Ridgway GR, Douiri A, 

Rossor MN, Ourselin S, Fox NC (2009) Patterns of cortical 

thinning in the language variants of frontotemporal lobar 

degeneration. Neurology 72, 1562-1569. 

[18] Josephs KA, Holton JL, Rossor MN, Godbolt AK, Ozawa T, 

Strand K, Khan N, Al-Sarraj S, Revesz T (2004) Frontotemporal 

lobar degeneration and ubiquitin immunohistochemistry. 

Neuropathol Appl Neurobiol 30, 369-373. 

[19] Neumann M, Tolnay M, Mackenzie IR (2009) The Molecular 

Basis of Frontotemporal Dementia. Expert Rev Mol Med 11, 

e23.


[20] Belzil VV, Valdmanis PN, Dion PA, Daoud H, Kabashi E, 

Noreau A, Gauthier J, for the S2D team, Hince P, Desjarlais 

A, Bouchard J-, Lacomblez L, Salachas F, Pradat P-, Camu 

W, Meininger V, Dupre N, Rouleau GA (2009) Mutations in 

FUS cause FALS and SALS in French and French Canadian 

populations. Neurology 73, 1176-1179. 

[21] Ticozzi N, Silani V, LeClerc AL, Keagle P, Gellera C, Ratti 

A, Taroni F, Kwiatkowski TJ, McKenna-Yasek DM, Sapp 

PC, Brown RH, Landers JE (2009) Analysis of FUS gene 

mutation in familial amyotrophic lateral sclerosis within an 

Italian cohort. Neurology 73, 1180-1185. 

[22] Kwiatkowski TJ, Bosco DA, LeClerc AL, Tamrazian E, Vanderburg 

CR, Russ C, Davis A, Gilchrist J, Kasarskis EJ, 

Munsat T, Valdmanis P, Rouleau GA, Hosler BA, Cortelli 

P, de Jong PJ, Yoshinaga Y, Haines JL, Pericak-Vance MA, 

Yan J, Ticozzi N, Siddique T, McKenna-Yasek D, Sapp PC, 

Horvitz HR, Landers JE, Brown RH (2009) Mutations in 

the FUS/TLS gene on chromosome 16 cause familial amyotrophic 

lateral sclerosis. Science 323, 1205-1208. 

[23] Vance C, Rogelj B, Hortobágyi T, De Vos KJ, Nishimura AL, 

Sreedharan J, Hu X, Smith B, Ruddy D, Wright P, Ganesalingam 

J, Williams KL, Tripathi V, Al-Saraj S, Al-Chalabi 

A, Leigh PN, Blair IP, Nicholson G, de Belleroche J, Gallo J, 

Miller CC, Shaw CE (2009) Mutations in FUS, an RNA processing 

protein, cause familial amyotrophic lateral sclerosis 

type 6. Science 323, 1208-1211. 

[24] Blair IP, Williams KL, Warraich ST, Durnall JC, Thoeng AD, 

Manavis J, Blumbergs PC, Vucic S, Kiernan MC, Nicholson 

GA (2009) FUS mutations in amyotrophic lateral sclerosis: 

clinical, pathological, neurophysiological and genetic 

analysis. J Neurol Neurosurg Psychiatry, in press. 

[25] Lagier-Tourenne C Cleveland DW (2009) Rethinking ALS: 

The FUS about TDP-43. Cell 136, 1001-1004. 

[26] Shi J, Shaw C, Plessis D, Richardson A, Bailey K, Julien 

C, Stopford C, Thompson J, Varma A, Craufurd D, Tian J, 

Pickering-Brown S, Neary D, Snowden J, Mann D (2005) 

Histopathological changes underlying frontotemporal lobar 

degeneration with clinicopathological correlation. Acta Neuropathol 

110, 501-512. 

[27] Hodges JR, Davies RR, Xuereb JH, Casey B, Broe M, Bak 

TH, Kril JJ, Halliday GM (2004) Clinicopathological correlates 

in frontotemporal dementia. Ann Neurol 56, 399-406. 

[28] Lladó A, Sánchez-Valle R, Rey MJ, Ezquerra M, Tolosa 

E, Ferrer I, Molinuevo JL (2008) Clinicopathological and 

genetic correlates of frontotemporal lobar degeneration and 

corticobasal degeneration. J Neurol 255, 488-494. 

[29] Seelaar H, Klijnsma K, de Koning I, van der Lugt A, Chiu W, 

Azmani A, Rozemuller A, van Swieten J (2010) Frequency 

of ubiquitin and FUS-positive, TDP-43-negative frontotemporal 

lobar degeneration. J Neurol 257, 747-753. 

[30] Rosso SM, Kaat LD, Baks T, Joosse M, de Koning I, Pijnenburg 

Y, de Jong D, Dooijes D, Kamphorst W, Ravid R, 

Niermeijer MF, Verheij F, Kremer HP, Scheltens P, van Duijn 

CM, Heutink P, van Swieten JC (2003) Frontotemporal dementia 

in The Netherlands: patient characteristics and prevalence 

estimates from a population-based study. Brain 126, 

2016-2022. 

[31] Stevens M, van Duijn C, Kamphorst W, de Knijff P, Heutink 

P, van Gool W, Scheltens P, Ravid R, Oostra B, Niermeijer M, 

van Swieten J (1998) Familial aggregation in frontotemporal 

dementia. Neurology 50, 1541-1545. 

[32] Rohrer JD, Guerreiro R, Vandrovcova J, Uphill J, Reiman D, 

Beck J, Isaacs AM, Authier A, Ferrari R, Fox NC, Mackenzie 

I, Warren JD, de Silva R, Holton J, Revesz T, Hardy J, Mead 

S, Rossor MN (2009) The heritability and genetics of frontotemporal 

lobar degeneration. Neurology 73, 1451-1456. 

[33] Seelaar H, Kamphorst W, Rosso SM, Azmani A, Masdjedi 

R, de Koning I, Maat-Kievit JA, Anar B, Kaat LD, Breedveld 

GJ, Dooijes D, Rozemuller JM, Bronner IF, Rizzu P, van 

Swieten JC (2008) Distinct genetic forms of frontotemporal 

dementia. Neurology 71, 1220-1226. 

[34] Poorkaj P, Grossman M, Steinbart E, Payami H, Sadovnick A, 

Nochlin D, Tabira T, Trojanowski JQ, Borson S, Galasko D, 

Reich S, Quinn B, Schellenberg G, Bird TD (2001) Frequency 

of Tau Gene Mutations in Familial and Sporadic Cases of 

Non-Alzheimer Dementia. Arch Neurol 58, 383-387. 

[35] Gass J, Cannon A, Mackenzie IR, Boeve B, Baker M, Adamson 

J, Crook R, Melquist S, Kuntz K, Petersen R, Josephs 

K, Pickering-Brown SM, Graff-Radford N, Uitti R, Dickson 

D, Wszolek Z, Gonzalez J, Beach TG, Bigio E, Johnson N, 

Weintraub S, Mesulam M, White CL, Woodruff B, Caselli 

R, Hsiung G, Feldman H, Knopman D, Hutton M, Rademakers 

R (2006) Mutations in progranulin are a major cause of 

ubiquitin-positive frontotemporal lobar degeneration. Hum 

Mol Genet 15, 2988-3001. 

[36] Schymick JC, Yang Y, Andersen PM, Vonsattel JP, Greenway 

M, Momeni P, Elder J, Chiò A, Restagno G, Robberecht 

W, Dahlberg C, Mukherjee O, Goate A, Graff-Radford N, 

Caselli RJ, Hutton M, Gass J, Cannon A, Rademakers R, 

Singleton AB, Hardiman O, Rothstein J, Hardy J, Traynor BJ 

(2007) Progranulin mutations and amyotrophic lateral sclerosis 

or amyotrophic lateral sclerosis-frontotemporal dementia 

phenotypes. J Neurol Neurosurg Psychiatry 78, 754-756. 

[37] Benajiba L, Le Ber I, Camuzat A, Lacoste M, Thomas- 

Anterion C, Couratier P, Legallic S, Salachas F, Hannequin 

D, Decousus M, Lacomblez L, Guedj E, Golfier V, Camu 

W, Dubois B, Campion D, Meininger V, Brice A (2009) 

TARDBP mutations in motoneuron disease with frontotemporal 

lobar degeneration. Ann Neurol 65, 470-473. 

[38] Borroni B, Bonvicini C, Alberici A, Buratti E, Agosti C, 

Archetti S, Papetti A, Stuani C, Di Luca M, Gennarelli M, 

Padovani A (2009) Mutation within TARDBP leads to frontotemporal 

dementia without motor neuron disease. Hum 

Mutat 30, E974-983. 

[39] Watts GDJ, Wymer J, Kovach MJ, Mehta SG, Mumm S, 

Darvish D, Pestronk A, Whyte MP, Kimonis VE (2004) Inclusion 

body myopathy associated with Paget disease of bone 

and frontotemporal dementia is caused by mutant valosincontaining 

protein. Nat Genet 36, 377-381. 

[40] Parkinson N, Ince PG, Smith MO, Highley R, Skibinski G, 

Andersen PM, Morrison KE, Pall HS, Hardiman O, Collinge 

J, Shaw PJ, Fisher EC, on behalf of the MRC Proteomics 

in ALS Study and the FReJA Consortium (2006) ALS phenotypes 

with mutations in CHMP2B (charged multivesicular 

body protein 2B). Neurology 67, 1074-1077. 

[41] Hosler BA, Siddique T, Sapp PC, Sailor W, Huang MC, Hossain 

A, Daube JR, Nance M, Fan C, Kaplan J, Hung W, 

McKenna-Yasek D, Haines JL, Pericak-Vance MA, Horvitz 

HR, Brown RH (2000) Linkage of Familial Amyotrophic 

Lateral Sclerosis With Frontotemporal Dementia to Chromosome 

9q21–q22. JAMA 284, 1664-1669. 

[42] Morita M, Al-Chalabi A, Andersen PM, Hosler B, Sapp P, 

Englund E, Mitchell JE, Habgood JJ, de Belleroche J, Xi J, 

Jongjaroenprasert W, Horvitz HR, Gunnarsson L-, Brown RH 

(2006) A locus on chromosome 9p confers susceptibility to 

ALS and frontotemporal dementia. Neurology 66, 839-844. 

[43] Vance C, Al-Chalabi A, Ruddy D, Smith BN, Hu X, Sreedharan 

J, Siddique T, Schelhaas HJ, Kusters B, Troost D, Baas


F, de Jong V, Shaw CE (2006) Familial amyotrophic lateral 

sclerosis with frontotemporal dementia is linked to a locus 

on chromosome 9p13.2–21.3. Brain 129, 868-876. 

[44] Le Ber I, Camuzat A, Berger E, Hannequin D, Laquerriere 

A, Golfier V, Seilhean D, Viennet G, Couratier P, Verpillat P, 

Heath S, Camu W, Martinaud O, Lacomblez L, Vercelletto 

M, Salachas F, Sellal F, Didic M, Thomas-Anterion C, Puel 

M, Michel B, Besse C, Duyckaerts C, Meininger V, Campion 

D, Dubois B, Brice A, For the French Research Network 

on FTD/FTD-MND (2009) Chromosome 9p-linked families 

with frontotemporal dementia associated with motor neuron 

disease. Neurology 72, 1669-1676. 

[45] Johnson JK, Diehl J, Mendez MF, Neuhaus J, Shapira JS, 

Forman M, Chute DJ, Roberson ED, Pace-Savitsky C, Neumann 

M, Chow TW, Rosen HJ, Förstl H, Kurz A, Miller BL 

(2005) Frontotemporal Lobar Degeneration: Demographic 

Characteristics of 353 Patients. Arch Neurol 62, 925-930. 

[46] Kipps CM, Mioshi E, Hodges JR (2009) Emotion, social 

functioning and activities of daily living in frontotemporal 

dementia. Neurocase 15, 182-189. 

[47] Zamboni G, Huey ED, Krueger F, Nichelli PF, Grafman J 

(2008) Apathy and disinhibition in frontotemporal dementia: 

Insights into their neural correlates. Neurology 71, 736-742. 

[48] Huey ED, Goveia EN, Paviol S, Pardini M, Krueger F, Zamboni 

G, Tierney MC, Wassermann EM, Grafman J (2009) 

Executive dysfunction in frontotemporal dementia and corticobasal 

syndrome. Neurology 72, 453-459. 

[49] Kipps CM, Nestor PJ, Acosta-Cabronero J, Arnold R, Hodges 

JR (2009) Understanding social dysfunction in the behavioural 

variant of frontotemporal dementia: the role of 

emotion and sarcasm processing. Brain 132(Pt3), 592-603. 

[50] Gustafson L (1987) Frontal lobe degeneration of non- 

Alzheimer type. II. Clinical picture and differential diagnosis. 

Arch Gerontol Geriatr 6, 209-223. 

[51] Pasquier F, Lebert F, Lavenu I, Guillaume B (1999) The 

clinical picture of frontotemporal dementia: diagnosis and 

follow-up. Dement Geriatr Cogn Disord 10(Suppl 1), 10-14. 

[52] Mendez MF, Shapira JS, Woods RJ, Licht EA, Saul RE 

(2008) Psychotic symptoms in frontotemporal dementia: 

prevalence and review. Dement Geriatr Cogn Disord 25, 206- 

211. 

[53] Lillo, P, Garcin, B, Bak TH, Hornberger M, Hodges JR (2010) 

Neurobehavioral features in frontotemporal dementia with 

amyotrophic lateral sclerosis. Arch Neurol 67, 826-830. 

[54] Claassen DO, Parisi JE, Giannini C, Boeve BF, Dickson 

DW, Josephs KA (2008) Frontotemporal Dementia Mimicking 

Dementia With Lewy Bodies. Cogn Behav Neurol 21, 

157-163. 

[55] Kipps CM, Nestor PJ, Fryer TD, Hodges JR (2007) Behavioural 

variant frontotemporal dementia: not all it seems? 

Neurocase 13, 237-247. 

[56] Davies RR, Kipps CM, Mitchell J, Kril JJ, Halliday GM, 

Hodges JR (2006) Progression in frontotemporal dementia: 

identifying a benign behavioral variant by magnetic resonance 

imaging. Arch Neurol 63, 1627-1631. 

[57] Hornberger M, Shelley BP, Kipps CM, Piguet O, Hodges 

JR (2009) Can progressive and non-progressive behavioural 

variant frontotemporal dementia be distinguished at presentation? 

J Neurol Neurosurg Psychiatry 80, 591-593. 

[58] Kipps CM, Hodges JR, Fryer TD, Nestor PJ (2009) Combined 

magnetic resonance imaging and positron emission tomography 

brain imaging in behavioural variant frontotemporal 

degeneration: refining the clinical phenotype. Brain 132, 

2566-2578. 

[59] Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, 

Black S, Freedman M, Kertesz A, Robert PH, Albert M, 

Boone K, Miller BL, Cummings J, Benson DF (1998) Frontotemporal 

lobar degeneration: A consensus on clinical diagnostic 

criteria. Neurology 51, 1546-1554. 

[60] Rascovsky K, Hodges JR, Kipps CM, Johnson JK, Seeley 

WW, Mendez MF, Knopman D, Kertesz A, Mesulam M, 

Salmon DP, Galasko D, Chow TW, DeCarli C, Hillis A, 

Josephs K, Kramer JH, Weintraub S, Grossman M, Gorno- 

Tempini M, Miller BM (2007) Diagnostic criteria for the behavioral 

variant of frontotemporal dementia (bvFTD): current 

limitations and future directions. Alzheimer Dis Assoc 

Disord 21, S14-18. 

[61] Knibb JA, Woollams AM, Hodges JR, Patterson K (2009) 

Making sense of progressive non-fluent aphasia: an analysis 

of conversational speech. Brain 132, 2734-2746. 

[62] Hodges J, Patterson K, Oxbury S, Funnell E (1992) Semantic 

dementia. Progressive fluent aphasia with temporal lobe 

atrophy. Brain 115, 1783-1806. 

[63] Wilson SM, Brambati SM, Henry RG, Handwerker DA, 

Agosta F, Miller BL, Wilkins DP, Ogar JM, Gorno-Tempini 

ML (2009) The neural basis of surface dyslexia in semantic 

dementia. Brain 132, 71-86. 

[64] Brambati SM, Ogar J, Neuhaus J, Miller BL, Gorno-Tempini 

ML (2009) Reading disorders in primary progressive aphasia: 

a behavioral and neuroimaging study. Neuropsychologia 47, 

1893-1900. 

[65] Thompson SA, Patterson K, Hodges JR (2003) Left/right 

asymmetry of atrophy in semantic dementia: Behavioralcognitive 

implications. Neurology 61, 1196-1203. 

[66] Chan D, Anderson V, Pijnenburg Y, Whitwell J, Barnes J, 

Scahill R, Stevens JM, Barkhof F, Scheltens P, Rossor MN, 

Fox NC (2009) The clinical profile of right temporal lobe 

atrophy. Brain 132, 1287-1298. 

[67] Seeley WW, Bauer AM, Miller BL, Gorno-Tempini ML, 

Kramer JH, Weiner M, Rosen HJ (2005) The natural history 

of temporal variant frontotemporal dementia. Neurology 64, 

1384-1390. 

[68] Josephs KA, Whitwell JL, Knopman DS, Boeve BF, Vemuri 

P, Senjem ML, Parisi JE, Ivnik RJ, Dickson DW, Petersen 

RC, Jack CR (2009) Two distinct subtypes of right temporal 

variant frontotemporal dementia. Neurology 73, 1443-1450. 

[69] Gorno-Tempini ML, Brambati SM, Ginex V, Ogar J, 

Dronkers NF, Marcone A, Perani D, Garibotto V, Cappa SF, 

Miller BL (2008) The logopenic/phonological variant of primary 

progressive aphasia. Neurology 71, 1227-1234. 

[70] Gorno-Tempini ML, Dronkers NF, Rankin KP, Ogar JM, 

Phengrasamy L, Rosen HJ, Johnson JK, Weiner MW, Miller 

BL (2004) Cognition and anatomy in three variants of primary 

progressive aphasia. Ann Neurol 55, 335-346. 

[71] Rabinovici GD, Furst AJ, O’Neil JP, Racine CA, Mormino 

EC, Baker SL, Chetty S, Patel P, Pagliaro TA, Klunk WE, 

Mathis CA, Rosen HJ, Miller BL, Jagust WJ (2007) 11C-PIB 

PET imaging in Alzheimer disease and frontotemporal lobar 

degeneration. Neurology 68, 1205-1212. 

[72] Kipps CM Hodges JR (2005) Cognitive assessment for clinicians. 

J Neurol Neurosurg Psychiatry 76(Suppl 1), i22-30. 

[73] Hodges JR (2007) Cognitive Assessment for Clinicians, Oxford 

University Press, USA. 

[74] Hodges JR (2007) Frontotemporal Dementia Syndromes, 

Cambridge University Press, UK. 

[75] Gregory CA, Orrell M, Sahakian B, Hodges JR (1997) Can 

frontotemporal dementia and Alzheimer’s disease be differ-


entiated using a brief battery of tests? Int J Geriatr Psychiatry 

12, 375-383. 

[76] Mathuranath PS, Nestor PJ, Berrios GE, Rakowicz W, 

Hodges JR (2000) A brief cognitive test battery to differentiate 

Alzheimer’s disease and frontotemporal dementia. Neurology 

55, 1613-1620. 

[77] Mioshi E, Dawson K, Mitchell J, Arnold R, Hodges JR (2006) 

The Addenbrooke’s Cognitive Examination Revised (ACE- 

R): a brief cognitive test battery for dementia screening. Int 

J Geriatr Psychiatry 21, 1078-1085. 

[78] Frontier: Frontotemporal Dementia Research Group, http:// 

www.ftdrg.org/, Accessed 10 March 2010. 

[79] Gregory CA, Serra-Mestres J, Hodges JR (1999) Early diagnosis 

of the frontal variant of frontotemporal dementia: 

how sensitive are standard neuroimaging and neuropsychologic 

tests? Neuropsychiatry Neuropsychol Behav Neurol 12, 

128-135. 

[80] Torralva T, Kipps CM, Hodges JR, Clark L, Bekinschtein 

T, Roca M, Calcagno ML, Manes F (2007) The relationship 

between affective decision-making and theory of mind in the 

frontal variant of fronto-temporal dementia. Neuropsychologia 

45, 342-349. 

[81] Torralva T, Roca M, Gleichgerrcht E, Bekinschtein T, Manes 

F (2009) A neuropsychological battery to detect specific executive 

and social cognitive impairments in early frontotemporal 

dementia. Brain 132, 1299-1309. 

[82] Keane J, Calder AJ, Hodges JR, Young AW (2002) Face and 

emotion processing in frontal variant frontotemporal dementia. 

Neuropsychologia 40, 655-665. 

[83] Rankin KP, Gorno-Tempini ML, Allison SC, Stanley CM, 

Glenn S, Weiner MW, Miller BL (2006) Structural anatomy 

of empathy in neurodegenerative disease. Brain 129, 2945- 

2956. 

[84] Rankin KP, Salazar A, Gorno-Tempini ML, Sollberger M, 

Wilson SM, Pavlic D, Stanley CM, Glenn S, Weiner MW, 

Miller BL (2009) Detecting sarcasm from paralinguistic 

cues: Anatomic and cognitive correlates in neurodegenerative 

disease. NeuroImage 47, 2005-2015. 

[85] Gregory C, Lough S, Stone V, Erzinclioglu S, Martin L, 

Baron-Cohen S, Hodges JR (2002) Theory of mind in 

patients with frontal variant frontotemporal dementia and 

Alzheimer’s disease: theoretical and practical implications. 

Brain 125, 752-764. 

[86] Hodges JR, Martinos M, Woollams AM, Patterson K, Adlam 

AR (2008) Repeat and Point: differentiating semantic 

dementia from progressive non-fluent aphasia. Cortex 44, 

1265-1270. 

[87] Diehl-Schmid J, Schulte-Overberg J, Hartmann J, Förstl H, 

Kurz A, Häussermann P (2007) Extrapyramidal signs, primitive 

reflexes and incontinence in fronto-temporal dementia. 

Eur J Neurol 14, 860-864. 

[88] Padovani A, Agosti C, Premi E, Bellelli G, Borroni B 

(2007) Extrapyramidal symptoms in Frontotemporal Dementia: 

Prevalence and clinical correlations. Neurosci Lett 422, 

39-42. 

[89] Garbutt S, Matlin A, Hellmuth J, Schenk AK, Johnson JK, 

Rosen H, Dean D, Kramer J, Neuhaus J, Miller BL, Lisberger 

SG, Boxer AL (2008) Oculomotor function in frontotemporal 

lobar degeneration, related disorders and Alzheimer’s 

disease. Brain 131, 1268-1281. 

[90] Meyniel C, Rivaud-Péchoux S, Damier P, Gaymard B (2005) 

Saccade impairments in patients with fronto-temporal dementia. 

J Neurol Neurosurg Psychiatry 76, 1581-1584. 

[91] Pereira J, Williams GB, Acosta-Cabronero J, Pengas G, Spi- 

llantini MG, Xuereb JH, Hodges JR, Nestor PJ (2009) Atrophy 

patterns in histologic vs clinical groupings of frontotemporal 

lobar degeneration. Neurology 72, 1653-1660. 

[92] Looi J, Lindberg O, Zandbelt B, Ostberg P, Andersen C, 

Botes L, Svensson L, Wahlund L (2008) Caudate nucleus 

volumes in frontotemporal lobar degeneration: differential 

atrophy in subtypes. AJNR Am J Neuroradiol 29, 1537-1543. 

[93] Lindberg O, Ostberg P, Zandbelt B, Oberg J, Zhang Y, Andersen 

C, Looi J, Bogdanovic N, Wahlund L (2009) Cortical 

morphometric subclassification of frontotemporal lobar 

degeneration. AJNR Am J Neuroradiol 30, 1233-1239. 

[94] Seeley WW, Crawford RK, Zhou J, Miller BL, Greicius MD 

(2009) Neurodegenerative diseases target large-scale human 

brain networks. Neuron 62, 42-52. 

[95] Seeley WW (2008) Selective functional, regional, and neuronal 

vulnerability in frontotemporal dementia. Curr Opin 

Neurol 21, 701-707. 

[96] Seeley WW, Carlin DA, Allman JM, Macedo MN, Bush 

C, Miller BL, DeArmond SJ (2006) Early frontotemporal 

dementia targets neurons unique to apes and humans. Ann 

Neurol 60, 660-667. 

[97] Zamboni G, Huey ED, Krueger F, Nichelli PF, Grafman J 

(2008) Apathy and disinhibition in frontotemporal dementia: 

Insights into their neural correlates. Neurology 71, 736-742. 

[98] Borroni B, Brambati SM, Agosti C, Gipponi S, Bellelli G, 

Gasparotti R, Garibotto V, Di Luca M, Scifo P, Perani D, 

Padovani A (2007) Evidence of white matter changes on 

diffusion tensor imaging in frontotemporal dementia. Arch 

Neurol 64, 246-251. 

[99] Gorno-Tempini ML, Dronkers NF, Rankin KP, Ogar JM, 

Phengrasamy L, Rosen HJ, Johnson JK, Weiner MW, Miller 

BL (2004) Cognition and anatomy in three variants of primary 

progressive aphasia. Ann Neurol 55, 335-346. 

[100] Nestor PJ, Graham NL, Fryer TD, Williams GB, Patterson K, 

Hodges JR (2003) Progressive non-fluent aphasia is associated 

with hypometabolism centred on the left anterior insula. 

Brain 126, 2406-2418. 

[101] Herholz K (2003) PET studies in dementia. Ann Nucl Med 

17, 79-89. 

[102] Foster NL, Heidebrink JL, Clark CM, Jagust WJ, Arnold SE, 

Barbas NR, DeCarli CS, Scott Turner R, Koeppe RA, Higdon 

R, Minoshima S (2007) FDG-PET improves accuracy 

in distinguishing frontotemporal dementia and Alzheimer’s 

disease. Brain 130, 2616-2635. 

[103] Panegyres PK, Rogers JM, McCarthy M, Campbell A, Wu 

J (2009) Fluorodeoxyglucose-Positron Emission Tomography 

in the differential diagnosis of early-onset dementia: a 

prospective, community-based study. BMC Neurol 9, 41. 

[104] Wiley CA, Lopresti BJ, Venneti S, Price J, Klunk WE, 

DeKosky ST, Mathis CA (2009) Carbon 11-labeled Pittsburgh 

Compound B and Carbon 11-Labeled (R)-PK11195 

positron emission tomographic imaging in Alzheimer disease. 

Arch Neurol 66, 60-67. 

[105] Ng SY, Villemagne VL, Masters CL, Rowe CC (2007) Evaluating 

atypical dementia syndromes using positron emission 

tomography with Carbon 11 labeled Pittsburgh Compound 

B. Arch Neurol 64, 1140-1144. 

[106] Boxer AL Boeve BF (2007) Frontotemporal dementia treatment: 

current symptomatic therapies and implications of 

recent genetic, biochemical, and neuroimaging studies. 

Alzheimer Dis Assoc Disord 21, S79-S87. 

[107] Bristow M, Cook R, Erzinclioglu S, Hodges J (2008) Stress, 

distress and mucosal immunity in carers of a partner with 

fronto-temporal dementia. Aging Ment Health 12, 595-604.


[108] Mioshi E, Bristow M, Cook R, Hodges JR (2009) Factors 

underlying caregiver stress in frontotemporal dementia and 

Alzheimer’s disease. Dement Geriatr Cogn Disord 27, 76-81. 

[109] Moretti R, Torre P, Antonello RM, Cazzato G, Bava A (2003) 

Frontotemporal dementia: paroxetine as a possible treatment 

of behavior symptoms. A randomized, controlled, open 14month 

study. Eur Neurol 49, 13-19. 

[110] Deakin J, Rahman S, Nestor P, Hodges J, Sahakian B (2004) 

Paroxetine does not improve symptoms and impairs cognition 

in frontotemporal dementia: a double-blind randomized 

controlled trial. Psychopharmacology (Berl) 172, 400-408. 

[111] Moretti R, Torre P, Antonello RM, Cazzato G, Griggio S, 

Bava A (2003) Olanzapine as a treatment of neuropsychiatric 

disorders of Alzheimer’s disease and other dementias: a 24month 

follow-up of 68 patients. Am J Alzheimers Dis Other 

Demen 18, 205-214. 

[112] Moretti R, Torre P, Antonello RM, Cattaruzza T, Cazzato G, 

Bava A (2004) Rivastigmine in frontotemporal dementia: an 

open-label study. Drugs Aging 21, 931-937. 

[113] Mendez MF, Shapira JS, McMurtray A, Licht E (2007) Preliminary 

findings: behavioral worsening on donepezil in patients 

with frontotemporal dementia. Am J Geriatr Psychiatry 

15, 84-87. 

[114] Schneider A Mandelkow E (2008) Tau-Based Treatment 

Strategies in Neurodegenerative Diseases. Neurotherapeutics 

5, 443-457. 

[115] Sonnen JA, Montine KS, Quinn JF, Kaye JA, Breitner JC, 

Montine TJ (2008) Biomarkers for cognitive impairment and 

dementia in elderly people. Lancet Neurol 7, 704-714. 

[116] Hodges JR, Mitchell J, Dawson K, Spillantini MG, Xuereb 

JH, McMonagle P, Nestor PJ, Patterson K (2009) Semantic 

dementia: demography, familial factors and survival in a 

consecutive series of 100 cases. Brain 133(Pt 1), 300-306. 

[117] Josephs KA, Duffy JR, Strand EA, Whitwell JL, Layton KF, 

Parisi JE, Hauser MF, Witte RJ, Boeve BF, Knopman DS, 

Dickson DW, Jack CR, Petersen RC (2006) Clinicopathological 

and imaging correlates of progressive aphasia and 

apraxia of speech. Brain 129, 1385-1398. 

[118] Bian H, Van Swieten JC, Leight S, Massimo L, Wood E, 

Forman M, Moore P, de Koning I, Clark CM, Rosso S, Trojanowski 

J, Lee VM, Grossman M (2008) CSF biomarkers 

in frontotemporal lobar degeneration with known pathology. 

Neurology 70, 1827-1835. 

[119] Kapaki E, Paraskevas GP, Papageorgiou SG, Bonakis A, 

Kalfakis N, Zalonis I, Vassilopoulos D (2008) Diagnostic 

value of CSF biomarker profile in frontotemporal lobar degeneration. 

Alzheimer Dis Assoc Disord 22, 47-53. 

[120] Foulds P, McAuley E, Gibbons L, Davidson Y, Pickering- 

Brown SM, Neary D, Snowden JS, Allsop D, Mann DMA 

(2008) TDP-43 protein in plasma may index TDP-43 brain 

pathology in Alzheimer’s disease and frontotemporal lobar 

degeneration. Acta Neuropathol 116, 141-146. 

[121] Foulds P, Davidson Y, Mishra M, Hobson D, Humphreys 

K, Taylor M, Johnson N, Weintraub S, Akiyama H, Arai T, 

Hasegawa M, Bigio E, Benson F, Allsop D, Mann D (2009) 

Plasma phosphorylated-TDP-43 protein levels correlate with 

brain pathology in frontotemporal lobar degeneration. Acta 

Neuropathol 118, 647-658. 

[122] Kasai T, Tokuda T, Ishigami N, Sasayama H, Foulds P, 

Mitchell DJ, Mann DMA, Allsop D, Nakagawa M (2009) 

Increased TDP-43 protein in cerebrospinal fluid of patients 

with amyotrophic lateral sclerosis. Acta Neuropathol 117, 

55-62. 

[123] Finch N, Baker M, Crook R, Swanson K, Kuntz K, Surtees 

R, Bisceglio G, Rovelet-Lecrux A, Boeve B, Petersen RC, 

Dickson DW, Younkin SG, Deramecourt V, Crook J, Graff- 

Radford NR, Rademakers R (2009) Plasma progranulin levels 

predict progranulin mutation status in frontotemporal dementia 

patients and asymptomatic family members. Brain 

132, 583-591. 

[124] Krueger C, Dean D, Rosen H, Halabi C, Weiner M, Miller B, 

Kramer J (2009) Longitudinal rates of lobar atrophy in frontotemporal 

dementia, semantic dementia, and Alzheimer’s 

disease. Alzheimer Dis Assoc Disord 24, 43-48. 

[125] Small GW, Bookheimer SY, Thompson PM, Cole GM, 

Huang S, Kepe V, Barrio JR (2008) Current and future uses 

of neuroimaging for cognitively impaired patients. Lancet 

Neurol 7, 161-172.

From FUS to Fibs: What's New in Frontotemporal ... - IOS Press

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