Frontotemporal dementia with trans‐activation response DNA‐binding protein 43 presenting with catatonic syndrome

Catatonia is a clinical syndrome characterized by symptoms such as immobility, mutism, stupor, stereotypy, echophenomena, catalepsy, automatic obedience, posturing, negativism, gegenhalten and ambitendency. This syndrome occurs mostly in mood disorder and schizophrenic patients, and is related to neuronal dysfunction involving the frontal lobe. Some cases of frontotemporal dementia (FTD) with catatonia have been reported, but these cases were not examined by autopsy. Here, we report on a FTD case which showed catatonia after the first episode of brief psychotic disorder. At the age of 58, the patient had a sudden onset of disorganized behavior and meaningless speech. Psychotropic drugs were effective for catatonic symptoms. However, after remission apathy, hyperorality, socially inappropriate behavior, hoarding, and an instinctive grasp reaction appeared and persisted. Brain MRI showed significant atrophy of the bilateral fronto‐temporal lobes. A neuropathological examination revealed extensive trans‐activation response DNA‐binding protein 43 (TDP‐43) positive neurocytoplasmic inclusions and dystrophic neurites in the brain, including the cerebral cortex, basal ganglia, and brainstem. Pathological diagnosis was frontotemporal lobar degeneration (FTLD) with TDP‐43 (FTLD‐TDP) type C, which was also confirmed by the band pattern of C‐terminal fragments of TDP‐43 on western blotting of sarkosyl‐insoluble fractions extracted from the frozen brain. Dysfunction of the thalamus, globus pallidus, supplementary motor area, amygdala and cingulate cortex have been said to be related to the catatonic syndrome. In this case, these areas were affected, showing abnormal TDP‐43‐positive structures. Further studies are expected to confirm further clinical ‐ pathological correlations to FTLD.     

Diagnosis and Management of Behavioral Issues in Frontotemporal Dementia

Frontotemporal lobar degeneration is an umbrella term for several different disorders. In behavioral variant frontotemporal dementia (bvFTD), patients show deterioration in cognition and social behavior. New diagnostic criteria proposed by the International Behavioral Variant FTD Consortium provide greater sensitivity in diagnosing bvFTD. Current pharmacological management of symptoms relies on medications borrowed from treating Alzheimer's disease (AD) and psychiatric disorders. The evidence for using AD medications such as acetylcholinesterase inhibitors is questionable. Psychiatric medications can be helpful. Trazodone or SSRIs can have some efficacy in reducing disinhibition, repetitive behaviors, sexually inappropriate behaviors, and hyperorality. Small doses of atypical antipsychotics may be helpful in decreasing agitation and verbal outbursts. Nonpharmacological management includes caregiver education and support and behavioral interventions. While symptomatic treatments are likely to remain important behavior management tools, targeting the underlying pathology of bvFTD with disease-modifying agents will hopefully be the future of treatment.     

Frontotemporal lobar degeneration: current knowledge and future challenges

Frontotemporal lobar degeneration (FTLD) is one of the most frequent neurodegenerative disorders with a presenile onset. It presents with a spectrum of clinical manifestations, ranging from behavioral and executive impairment to language disorders and motor dysfunction. New diagnostic criteria identified two main cognitive syndromes: behavioral variant frontotemporal dementia (bvFTD) and primary progressive aphasia. Regarding bvFTD, new criteria include the use of biomarkers. According to them, bvFTD can be classified in “possible” (clinical features only), “probable” (inclusion of imaging biomarkers) and “definite” (in the presence of a known causal mutation or at autopsy). Familial aggregation is frequently reported in FTLD, and about 10?% of cases have an autosomal dominant transmission. Microtubule-associated protein tau gene mutations have been the first ones identified, and are generally associated with early onset (40–50?years) and with the bvFTD phenotype. More recently, progranulin gene mutations were recognized in association with the familial form of FTLD and a hexanucleotide repetition in C9ORF72 has been shown to be responsible for familial FTLD and amyotrophic lateral sclerosis. In addition, other genes are linked to rare cases of familiar FTLD. Lastly, a number of genetic risk factors for sporadic forms have also been identified.     

Clinical, neuropathological, and genetic characteristics of the novel IVS9+1delG GRN mutation in a patient with frontotemporal dementia

Frontotemporal lobar degeneration (FTLD) refers to a clinically, pathologically, and genetically heterogeneous group of dementias that arises from the degeneration of the frontal and temporal lobes. Mutations in the progranulin gene (GRN) are a major cause of FTLD with TDP-43 inclusions. Herein, we describe the clinical, neuropathological, and genetic findings in a case of autosomal dominant behavioral variant of frontotemporal dementia (bvFTD) with asymmetrical parkinsonism and prominent visuospatial deficits that carries a novel GRN mutation. This case highlights important clinical characteristics that seem to be common in FTLD GRN-associated patients, such as asymmetrical parkinsonism and parietal symptoms, and that are correlated to the pathological involvement of striatum (rather than substantia nigra in our case) and parietal lobe. We also emphasize that plasma progranulin level can be useful to infer about the pathogenicity of new GRN mutations.     

A quantitative study of the neuropathology of 32 sporadic and familial cases of frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP)

R. A. Armstrong, D. Carter and N. J. Cairns (2012) Neuropathology and Applied Neurobiology 38, 25–38 A quantitative study of the neuropathology of 32 sporadic and familial cases of frontotemporal lobar degeneration with TDP‐43 proteinopathy (FTLD‐TDP) Aims: To further characterize the neuropathology of the heterogeneous molecular disorder frontotemporal lobar degeneration (FTLD) with transactive response (TAR) DNA‐binding protein of 43 kDa (TDP‐43) proteinopathy (FTLD‐TDP). Methods: We quantified the neuronal cytoplasmic inclusions, glial inclusions, neuronal intranuclear inclusions, dystrophic neurites, surviving neurones, abnormally enlarged neurones, and vacuoles in regions of the frontal and temporal lobe using a phosphorylation‐independent TDP‐43 antibody in 32 cases of FTLD‐TDP comprising sporadic and familial cases, with associated pathology such as hippocampal sclerosis (HS) or Alzheimer's disease (AD), and four neuropathological subtypes using TDP‐43 immunohistochemistry. Analysis of variance (anova ) was used to compare differences between the various groups of cases. Results: These data from FTLD‐TDP cases demonstrate quantitative differences in pathological features between: (i) regions of the frontal and temporal lobe; (ii) upper and lower cortex; (iii) sporadic and progranulin (GRN) mutation cases; (iv) cases with and without AD or HS; and (v) between assigned subtypes. Conclusions: The data confirm that the dentate gyrus is a major site of neuropathology in FTLD‐TDP and that most laminae of the cerebral cortex are affected. GRN mutation cases are quantitatively different from sporadic cases, while cases with associated HS and AD have increased densities of dystrophic neurites and abnormally enlarged neurones respectively. There is little correlation between the subjective assessment of subtypes and the more objective quantitative data.     

Efficacy of combination treatment of fluvoxamine and tiapride for repetitive behaviors in frontotemporal lobar degeneration

The present study reports a 63‐year‐old right‐handed man with frontotemporal lobar degeneration (FTLD) who manifested severe repetitive and disinhibited behaviors. Combination treatment of fluvoxamine and tiapride decreased the frequency of these behaviors. The results indicate that these drugs are effective for the treatment of repetitive and disinhibited behaviors for patients with FTLD. The behaviors caused by FTLD are discussed in terms of obsessive–compulsive spectrum disorder.     

Frequency of ubiquitin and FUS-positive, TDP-43-negative frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD) is a clinically, genetically and pathologically heterogeneous disorder. Within FTLD with ubiquitin-positive inclusions (FTLD-U), a new pathological subtype named FTLD-FUS was recently found with fused in sarcoma (FUS) positive, TDP-43-negative inclusions, and striking atrophy of the caudate nucleus. The aim of this study was to determine the frequency of FTLD-FUS in our pathological FTLD series, and to describe the clinical, neuroimaging and neuropathological features of FTLD-FUS, especially caudate atrophy. Demographic and clinical data collected prospectively from 387 patients with frontotemporal dementia (FTD) yielded 74 brain specimens. Immunostaining was carried out using a panel of antibodies, including AT-8, ubiquitin, p62, FUS, and TDP-43. Cortical and caudate atrophy on MRI (n = 136) was rated as normal, mild-moderate or severe. Of the 37 FTLD-U cases, 33 were reclassified as FTLD-TDP and four (0.11, 95%: 0.00–0.21) as FTLD-FUS, with ubiquitin and FUS-positive, p62 and TDP-43-negative neuronal intranuclear inclusions (NII). All four FTLD-FUS cases had a negative family history, behavioural variant FTD (bvFTD), and three had an age at onset ≤40 years. MRI revealed mild-moderate or severe caudate atrophy in all, with a mean duration from onset till MRI of 63 months (range 16–119 months). In our total clinical FTD cohort, we found 11 patients (0.03; 95% CI: 0.01–0.05) with bvFTD, negative family history, and age at onset ≤40 years. Caudate atrophy was present in 10 out of 136 MRIs, and included all four FUS-cases. The newly identified FTLD-FUS has a frequency of 11% in FTLD-U, and an estimated frequency of three percent in our clinical FTD cohort. The existence of this pathological subtype can be predicted with reasonable certainty by age at onset ≤40 years, negative family history, bvFTD and caudate atrophy on MRI.     

Serum neurofilament light chain is a discriminative biomarker between frontotemporal lobar degeneration and primary psychiatric disorders

Journal of Neurology - Due to the significant clinical overlap between frontotemporal lobar degeneration (FTLD) spectrum disorders and late-onset primary psychiatric disorders (PPD), diagnostic...     

An autopsy case of frontotemporal lobar degeneration with the appearance of fused in sarcoma inclusions (basophilic inclusion body disease) clinically presenting corticobasal syndrome

We describe an autopsy case of basophilic inclusion body disease (BIBD), a subtype of frontotemporal lobar degeneration (FTLD) with the appearance of fused in sarcoma (FUS) inclusions (FTLD‐FUS), clinically presenting corticobasal syndrome (CBS). A 54‐year‐old man initially developed worsening of stuttering and right hand clumsiness. Neurological examinations revealed rigidity in the right upper and lower extremities, buccofacial apraxia, and right‐side dominant limb‐kinetic and ideomotor apraxia. Neuroimaging showed asymmetric left‐dominant brain atrophy and a cerebral blood flow reduction in the ipsilateral frontal region. At 56 years, his apraxia had advanced, and ideational apraxia was observed. Furthermore, the asymmetry in the limb‐kinetic and ideomotor apraxia had disappeared, and both conditions had become bilateral. He had a new onset of aphasia. His symptoms progressed and he died 9 years after the initial symptoms. The brain weighed 955 g. Diffuse brain atrophy was most obvious in the bilateral frontotemporal regions. The atrophy of the left superior frontal and precentral gyri and bilateral basal ganglia was remarkable. Histologically, there was a marked loss of neurons with gliosis in the affected areas, where basophilic neuronal cytoplasmic inclusions were observed. The inclusions were immunoreactive for FUS, p62, and TATA‐binding protein‐associated factor 15 (TAF15), but not for phosphorylated tau, transactive response DNA‐binding protein of 43 kDa (TDP‐43), neurofilament protein, or Ewing sarcoma (EWS). From these pathological findings, this case was diagnosed as having BIBD as an FTLD‐FUS variant. Spinal cord lower motor neurons were spared in number, similar to primary lateral sclerosis. Mutations in FUS were undetectable. Common background pathologies for CBS include corticobasal degeneration, Alzheimer's disease, PSP, FTLD with phosphorylated TDP‐43 inclusions (FTLD‐TDP), Pick's disease, Lewy body disease and CJD. However, FTLD‐FUS (BIBD) has been rarely reported. Our case suggested further pathological heterogeneity in CBS than had previously been reported. It is necessary to consider FTLD‐FUS (BIBD) as a background pathology for CBS in the future.     

Clinical entity of frontotemporal dementia with motor neuron disease

Non‐Alzheimer‐type dementias occur in association with a variety of pathological conditions that include a group of diseases characterized by atrophy of the frontal and temporal lobes. Frontotemporal dementia (FTD) is a clinical entity that comprises at least two distinct diseases: Pick's disease with Pick bodies and frontotemporal lobar degeneration with ubiquitin‐positive inclusions (FTLD‐U). The vast majority of FTLD‐U is now referred to as FTLD‐TDP, following the recent discovery of TAR DNA‐binding protein of 43 kDa (TDP‐43) as the major constituent of the ubiquitin‐positive inclusions. FTLD‐TDP, but not Pick's disease with Pick bodies, is often associated with motor neuron disease (MND). MND is a group of diseases in which the central nervous system lesions were long believed to be confined to the motor neuron system. In other words, MND was not considered to be associated with other neurological symptoms such as dementia. Nevertheless, more than 200 FTD cases associated with clinical MND have been reported in Japan since 1964. Neuropathologically, MND in such FTD cases was essentially similar to MND in cases without dementia. The combination of FTD and MND was so characteristic that we considered these cases comprise a unique clinicopathological subgroup of FTD. FTD with MND and the classical MND without dementia share the occurrence of ubiquitinated TDP‐43‐positive inclusions, a finding that could be a key to unlock the pathological backgrounds of both diseases.     

Senile onset frontotemporal lobar degeneration with TAR‐DNA binding protein 43 proteinopathy primarily presenting with wasteful habits

We present an autopsied case of a senile Japanese woman with sporadic frontotemporal lobar degeneration (FTLD) presenting as frontotemporal dementia. Disease onset was at the age of 70 and presented as a behaviour disorder, particularly involving wasteful habits. The patient had repeated incidents of making expensive purchases and then had difficulty making payments. Following these symptoms, she showed other changes of character such as lethargy and apathy. She gradually showed signs of parkinsonism including rigidity and bradykinesia, and in the terminal stage, an akinetic mutism state with quadriplegia in flexion was observed. Head magnetic resonance imaging revealed severe frontotemporal lobe atrophy with severe lateral ventricular dilatation and frontal white matter degeneration. At autopsy, the brain weighed 930 g and the frontotemporal cerebral cortex showed neuron loss with gliosis, tissue rarefaction and spongiform change, particularly in the superficial layers. Pathologic degeneration was more severe in the anterior portion of the frontal lobe with extensive white matter degeneration. Immunostaining for phosphorylated TAR‐DNA binding protein 43 (TDP‐43) revealed numerous neuronal cytoplasmic inclusions and extensive short dystrophic neuritis, particularly in the frontotemporal cortex. Many TDP‐43‐positive cytoplasmic inclusions were also observed in the dentate gyrus of the hippocampus. The patient was pathologically diagnosed with FTLD with TDP‐43‐positive inclusions (FTLD‐TDP) without motor neuron disease. The immunohistochemical findings corresponded to type A of the FTLD‐TDP pathology classification system.     

Neuropathological background of phenotypical variability in frontotemporal dementia

Frontotemporal lobar degeneration (FTLD) is the umbrella term encompassing a heterogeneous group of pathological disorders. With recent discoveries, the FTLDs have been show to classify nicely into three main groups based on the major protein deposited in the brain: FTLD-tau, FTLD-TDP and FTLD-FUS. These pathological groups, and their specific pathologies, underlie a number of well-defined clinical syndromes, including three frontotemporal dementia (FTD) variants [behavioral variant frontotemporal dementia (bvFTD), progressive non-fluent aphasia, and semantic dementia (SD)], progressive supranuclear palsy syndrome (PSPS) and corticobasal syndrome (CBS). Understanding the neuropathological background of the phenotypic variability in FTD, PSPS and CBS requires large clinicopathological studies. We review current knowledge on the relationship between the FTLD pathologies and clinical syndromes, and pool data from a number of large clinicopathological studies that collectively provide data on 544 cases. Strong relationships were identified as follows: FTD with motor neuron disease and FTLD-TDP; SD and FTLD-TDP; PSPS and FTLD-tau; and CBS and FTLD-tau. However, the relationship between some of these clinical diagnoses and specific pathologies is not so clear cut. In addition, the clinical diagnosis of bvFTD does not have a strong relationship to any FTLD subtype or specific pathology and therefore remains a diagnostic challenge. Some evidence suggests improved clinicopathological association of bvFTD by further refining clinical characteristics. Unlike FTLD-tau and FTLD-TDP, FTLD-FUS has been less well characterized, with only 69 cases reported. However, there appears to be some associations between clinical phenotypes and FTLD-FUS pathologies. Clinical diagnosis is therefore promising in predicting molecular pathology.     

Atypical parkinsonian syndromes: a general neurologist's perspective

The differential diagnosis of atypical parkinsonian syndromes is challenging. These severe and often rapidly progressive neurodegenerative disorders are clinically heterogeneous and show significant phenotypic overlap. Here, clinical, imaging, neuropathological and genetic features of multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration and frontotemporal lobar degeneration (FTLD) are reviewed. The terms corticobasal degeneration and FTLD refer to pathologically confirmed cases of corticobasal syndrome and frontotemporal dementia (FTD). Frontotemporal lobar degeneration clinically presents as the behavioral variant FTD, semantic variant primary progressive aphasia (PPA), non‐fluent agrammatic variant PPA, logopenic variant PPA and FTD associated with motor neuron disease. While progressive supranuclear palsy and corticobasal syndrome have been called Parkinson‐plus syndromes in the past, they are now classified as FTD‐related disorders, reflecting that they pathologically differ from α‐synucleinopathies like multiple system atrophy and Parkinson disease. The contribution of genetic factors to atypical parkinsonian syndromes is increasingly recognized. Genes involved in the etiology of FTLD include MAPT, GRN and C9orf72. Novel neuroimaging techniques, including tau positron emission tomography imaging, are being investigated. Multimodal magnetic resonance imaging approaches and automated magnetic resonance imaging volume segmentation techniques are being evaluated for optimized differential diagnosis. Current treatment options are symptomatic, and disease modifying therapies are under active investigation.     

The behavioral variant of frontotemporal dementia: linking neuropathology to social cognition

The behavioral variant of frontotemporal dementia (bvFTD) is one of the most frequent neurodegenerative disorders with a presenile onset. It is characterized by a long phase of subclinical behavioral changes and social conduct disorders, associated with a progressive modification of personality. Recently, an international consortium of experts developed revised guidelines for its clinical diagnosis, which highlight the supportive role of biomarkers in the diagnostic process. According to new criteria, bvFTD can be classified in “possible” (requiring three of six specific clinical features), “probable” (in the presence of functional disability and typical neuroimaging features), and “with definite frontotemporal lobar degeneration” (requiring the presence of a known causal mutation or a histopathological confirmation). Familial aggregation is frequently reported in bvFTD and frontotemporal lobar degeneration in general, with an autosomal dominant transmission in about 10 % cases. The aim of this paper is to review and discuss recent advances in the knowledge of clinical, neuropsychological, and imaging features of bvFTD. We also briefly summarize the available genetic information about the frontotemporal lobar degeneration spectrum.     

Clinical phenotypes and genetic biomarkers of FTLD

Frontotemporal lobar degeneration (FTLD) is the most frequent neurodegenerative disorder with a presenile onset. It presents with a spectrum of clinical manifestations, ranging from behavioural and executive impairment to language disorders and motor dysfunction. New diagnostic criteria identified two main cognitive syndromes: behavioural variant frontotemporal dementia (bvFTD) and primary progressive aphasia (PPA). Regarding bvFTD, new criteria that include the use of biomarkers have been proposed. According to them, bvFTD can be classified in "possible" (clinical features only), "probable" (inclusion of imaging biomarkers) and "definite" (in the presence o f a known causal mutation or at autopsy). Concerning autosomal dominant mutations, microtubule associated protein tau gene mutations have been the first ones identified and are generally associated with early onset bvFTD phenotype. More recently, progranulin gene mutations were recognized in association with familial form of FTLD. In addition, other genes are linked to rare cases of familial FTLD, primarily the newly discovered C9ORF72 hexanucleotide expansion repeats. As regards PPA, new consensus criteria identify three syndromes: primary non-fluent aphasia, semantic variant of PPA and logopenic aphasia, which seems to be associated, in the majority of cases, with underlying Alzheimer's disease pathology. In this review, new criteria, including MRI, cerebrospinal fluid and genetic biomarkers, will be presented and discussed.     

Progressive nonfluent aphasia: A rare clinical subtype of FTLD‐TDP in Japan

Progressive nonfluent aphasia (PNFA) is a clinical subtype of frontotemporal lobar degeneration (FTLD). FTLD with tau accumulation (FTLD‐tau) and FTLD with TDP‐43 accumulation (FTLD‐TDP) both cause PNFA. We reviewed clinical records of 29 FTLD‐TDP cases in the brain archive of our institute and found only one case of PNFA. The patient was an 81‐year‐old male at death. There was no family history of dementia or aphasia. He presented with slow, labored and nonfluent speech at age 75. Behavioral abnormality and movement disorders were absent. MRI at age 76 demonstrated atrophy of the perisylvian regions, including the inferior frontal gyrus, insular gyrus and superior temporal gyrus. The atrophy was more severe in the left hemisphere than the right. On post mortem examinations, neuronal loss was evident in these regions as well as in the substantia nigra. There were abundant TDP‐43‐immunoreactive neuronal cytoplasmic inclusions and round or irregular‐shaped structures in the affected cerebral cortices. A few dystrophic neurites and neuronal intranuclear inclusions were also seen. FTLD‐TDP showing PNFA seems to be rare but does exist in Japan, similar to that in other countries.     

Non-Alzheimer's disease dementias: anatomic, clinical, and molecular correlates.

OBJECTIVE: To review the clinical and molecular features of non-Alzheimer's disease (non-AD) dementias, focusing on disorders associated with tau pathology (that is, frontotemporal lobar degeneration [FTLD], corticobasal ganglionic degeneration [CBD], and progressive supranuclear palsy [PSP]) or on disorders with synuclein pathology (that is, dementia with Lewy bodies [DLB] and multisystem atrophy [MSA]). We also discuss the pharmacologic treatment of these disorders. METHODS: We report a selective review of the literature on FTLD, CBD, PSP, DLB, and MSA. RESULTS: The non-AD dementias can present with a wide variety of cognitive and behavioural symptoms. Through common clinical features and shared molecular etiologies, neurodegenerative disorders previously thought to be distinct are now classified into tauopathies and synucleinopathies. CONCLUSIONS: The unique cognitive and behavioural manifestations of the non-AD dementias can be mistaken for psychiatric disorders. Improved detection of tauopathies and synucleinopathies and their differentiation from AD is possible.     

Review: An update on clinical,genetic and pathological aspects of frontotemporal lobar degenerations

The development of our understanding of frontotemporal dementia (FTD) has gathered pace over the last 10 years. After taking a back seat to Alzheimer's disease for many years FTD has emerged as a significant group of heterogeneous diseases often affecting people under the age of 65. FTD has also been brought into the spotlight as the major disease entities of the group have clinical, genetic and pathological links to motor neuron disease/amyotrophic lateral sclerosis, indicating that they form a disease spectrum. In this review, we overview how the pathological concept of frontotemporal lobar degeneration (FTLD) and the clinical concept of FTD evolved and show that FTLD, once thought of as a single disorder, represents a heterogeneous group of diseases with overlapping clinical symptoms, multiple causative genes and varying underlying pathology. We also provide a brief summary of the clinical manifestations, summarize the major genetic aspects and describe the main pathological features seen in the different subtypes of FTLD. We also summarize the correlations that exist between clinical presentations and pathological variants. An overview of the main pathogenic mechanisms is also provided.     

Profiles of white matter tract pathology in frontotemporal dementia

Despite considerable interest in improving clinical and neurobiological characterisation of frontotemporal dementia and in defining the role of brain network disintegration in its pathogenesis, information about white matter pathway alterations in frontotemporal dementia remains limited. Here we investigated white matter tract damage using an unbiased, template‐based diffusion tensor imaging (DTI) protocol in a cohort of 27 patients with the behavioral variant of frontotemporal dementia (bvFTD) representing both major genetic and sporadic forms, in relation both to healthy individuals and to patients with Alzheimer's disease. Widespread white matter tract pathology was identified in the bvFTD group compared with both healthy controls and Alzheimer's disease group, with prominent involvement of uncinate fasciculus, cingulum bundle and corpus callosum. Relatively discrete and distinctive white matter profiles were associated with genetic subgroups of bvFTD associated with MAPT and C9ORF72 mutations. Comparing diffusivity metrics, optimal overall separation of the bvFTD group from the healthy control group was signalled using radial diffusivity, whereas optimal overall separation of the bvFTD group from the Alzheimer's disease group was signalled using fractional anisotropy. Comparing white matter changes with regional grey matter atrophy (delineated using voxel based morphometry) in the bvFTD cohort revealed co‐localisation between modalities particularly in the anterior temporal lobe, however white matter changes extended widely beyond the zones of grey matter atrophy. Our findings demonstrate a distributed signature of white matter alterations that is likely to be core to the pathophysiology of bvFTD and further suggest that this signature is modulated by underlying molecular pathologies. Hum Brain Mapp 35:4163–4179, 2014. © 2014 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc.