Frontotemporal dementia--Part I. History, prevalence, clinical forms

The authors report a comprehensive publication consisting of three parts going into the details of history, prevalence, clinical forms, differential diagnosis, genetics, molecular pathomechanism, pathology, clinical diagnosis and treatment of frontotemporal dementia (FTD). The first part of the present review deals with history, prevalence and clinical forms of FTD. The prototypical FTD with circumscribed atrophy was first described by Arnold Pick; Alois Alzheimer found the intraneural inclusions in the patients' brain. Later it was recognised that many patients had neither the atrophy nor the cellular changes, but genetic mutations have been identified. Frontotemporal dementia is a degenerative condition with unknown etiology in the frontal and anterior temporal lobes of the brain. It is a progressive neurobehavioral syndrome characterized by early decline in social interpersonal conduct, early impairment in the regulation of personal conduct, early emotional blunting, and early loss of insight. There are no reliable epidemiological studies on the prevalence of FTD, but it is well-accepted that FTD is a common cause for dementia before the age of 65 (it constitutes approximately five percent of all irreversible dementias). The nomenclature of the FTD has been confusing and continues to be. Three major clinical syndromes can be identified: 1 frontal variant FTD (dementia of frontal type) in which changes in social behavior and personality predominate, 2. in semantic dementia (progressive fluent aphasia) there is a breakdown in the conceptual database which underlies language production and comprehension, 3. in progressive nonfluent aphasia the phonologic and syntactic components of language are affected. The authors report two cases, which can point to clinical symptoms and forms, and mention the problems of the differential diagnosis and therapy.     

The Neuropsychology of Frontal Variant Frontotemporal Dementia and Semantic Dementia. Introduction to the Special Topic Papers: Part II

The second part of this review, which accompanies 10 special topic articles dedicated to frontotemporal dementia (FTD), describes some of the advances in understanding frontal variant FTD (fvFTD) and semantic dementia, and the theoretical insights gained into normal cognitive processes from the study of these syndromes. Recent work has clarified the neuropsychiatric features that distinguish fvFTD from Alzheimer’s and has begun to spread light on the underlying deficits in social judgement, theory of mind, processing of emotional stimuli and decision making. With regard to central aspects of cognitive processing, such as memory, patients with fvFTD may have a distinctive profile of performance on tests of explicit and implicit memory, and contrary to current views some patients may even have a severe amnesic syndrome. There is also growing evidence that despite relatively well preserved general language skills, patients with fvFTD have particular problems with verb processing. Although there is agreement regarding the key features of semantic dementia, much controversy has surrounded the issue of whether the cognitive findings favour an explanation in terms of progressive breakdown of a central amodal semantic store or differential involvement of verbal and non-verbal systems. Other topics discussed include the impact of semantic breakdown on phonological processes and episodic memory. We also review recent structural and functional neuroimaging findings in semantic dementia.     

The neuropsychology of frontal variant frontotemporal dementia and semantic dementia. Introduction to the special topic papers: Part II

The second part of this review, which accompanies 10 special topic articles dedicated to frontotemporal dementia (FTD), describes some of the advances in understanding frontal variant FTD (fvFTD) and semantic dementia, and the theoretical insights gained into normal cognitive processes from the study of these syndromes. Recent work has clarified the neuropsychiatric features that distinguish fvFTD from Alzheimer's and has begun to spread light on the underlying deficits in social judgement, theory of mind, processing of emotional stimuli and decision making. With regard to central aspects of cognitive processing, such as memory, patients with fvFTD may have a distinctive profile of performance on tests of explicit and implicit memory, and contrary to current views some patients may even have a severe amnesic syndrome. There is also growing evidence that despite relatively well preserved general language skills, patients with fvFTD have particular problems with verb processing. Although there is agreement regarding the key features of semantic dementia, much controversy has surrounded the issue of whether the cognitive findings favour an explanation in terms of progressive breakdown of a central amodal semantic store or differential involvement of verbal and non-verbal systems. Other topics discussed include the impact of semantic breakdown on phonological processes and episodic memory. We also review recent structural and functional neuroimaging findings in semantic dementia.     

Clinical features of frontotemporal dementia

What was once called Pick's disease has three major anatomic variants. With all three, frontotemporal brain is selectively injured whereas posterior cortical regions are spared. These three clinical patterns include a bifrontal, slightly asymmetric subtype with more involvement of the right frontotemporal region called frontotemporal dementia or the frontal variant of FTD (fvFTD), a temporal-predominant subtype called the temporal variant of FTD or semantic dementia (SD), and a left frontal-predominant subtype called progressive nonfluent aphasia (PNFA). The three anatomic groups help to classify distinctive clinical syndromes with unique features. Careful study of these subtypes of frontotemporal dementia, using combinations of new quantitative neuroimaging, behavioral and physiological measures are yielding important information about the functioning of the brain's frontal and temporal regions. As we come to better understand the biologic basis for the three FTD clinical syndromes, new classification schemas may emerge, but our current clinical criteria serve as a strong guide to the diagnosis and separation of FTD from Alzheimer disease and other dementias.     

Microtubule associated protein (tau) gene variability in patients with frontotemporal dementia

Frontotemporal dementia represents up to 10% of all dementias and is, next to Alzheimer's disease and Lewy body disease, the third most common cause of degenerative dementia. The term "frontotemporal dementia" covers a range of conditions, including Pick's disease, frontal lobe degeneration and dementia associated with motor neurone disease. Neuropathologically FTD is characterised by atrophy of the frontal and temporal lobes of the cerebral cortex, often with additional subcortical changes. Both familial and more frequently sporadic forms of FTD can be recognised. Recently, mutations in the microtubule-associated protein (tau) gene have been found in families with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). The identification of mutations in the tau gene indicates that the protein plays a central role in the process of neurodegeneration. Epidemiology of frontotemporal dementias in Poland remains still unknown. A prevalence of tau mutations among Polish patients has not been established yet. Here, we report results of a mutational analysis of the tau gene among Polish FTD patients. No pathogenic mutation was found in the analysed sample. The study confirmed that the frequency of tau mutations is very low and depends strongly on the clinical criteria used to select patients. Mutations in the tau gene account only for a small number of FTD cases with a clear autosomal dominant pattern of disease inheritance. Therefore there should exist additionalgenetic and non-genetic factors contributing to the pathogenesis of both familial (linked and non-linked to chromosome 17) and sporadic forms of FTD.     

Association between tau H2 haplotype and age at onset in frontotemporal dementia

BACKGROUND: The frontotemporal dementia (FTD) syndromes have been associated with the microtubule-associated tau protein since tau gene mutations have been demonstrated to be the cause of FTD and parkinsonism linked to chromosome 17. In cases of FTD without tau gene mutations, however, it is unclear whether genetic variability in the tau gene is associated with the development or modulation of FTD. OBJECTIVE: To determine whether genetic variability in tau and apolipoprotein E (ApoE) modulates and contributes to the development of FTD.Design and Patients The distribution of tau gene haplotypes and the ApoE genotype were investigated in 86 patients with well-characterized FTD and 50 control subjects. RESULTS: No difference in the distribution of the tau H1 and H2 haplotypes between FTD cases and controls was observed, whereas the ApoE epsilon4 allele was more frequent in FTD cases. The presence of at least 1 tau H2 allele was found to be significantly associated with an earlier age of onset in patients with FTD. The association between the H2 allele and age at onset was not related to family history, clinical presentation, or ApoE genotype. CONCLUSION: These findings support a role of tau protein in modulating disease phenotype by influencing the age at onset in these FTD cases.     

Clinical and molecular aspects of frontotemporal dementia

Frontotemporal dementia (FTD) is a neurodegenerative disease and next to Alzheimer's disease and vascular dementia, the third most common cause of early-onset progressive dementia. FTD leads to neurodegeneration in the frontal and temporal neocortex and usually encompasses both sides of the frontal and anterior temporal lobes. Psychologically, FTD is characterized by personality changes such as lack of insight, inappropriate behaviour, disinhibition, apathy, executive disabilities and a decline in cognitive functions, with large clinical and neuropathological variations among cases. Neuropathological characteristics include gliosis or microvacuolation of cortical nerve cells. Inclusions staining for tau protein and/or ubiquitin are also common findings. Both sporadic and hereditary forms of FTD have been identified and 30-50% of the FTD cases have a familial background. So far, at least three genetic loci for FTD have been identified, at human chromosomes 3, 9 and 17 in familial forms of the disease. A large number of the familial forms have been linked to chromosome 17q21 and referred to as frontotemporal dementia and Parkinsonism linked to chromosome 17. In the majority of these families, pathogenic mutations in the tau gene were identified. However, tau mutations seem to be a rare cause of disease in the general FTD population. Thus, other genes and/or environmental factors are yet to be identified, which will give further clues to this complex and heterogeneous disorder.     

Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review

Frontotemporal dementia (FTD) is the second most common young-onset dementia and is clinically characterised by progressive behavioural change, executive dysfunction and language difficulties. Three clinical syndromes, behavioural variant FTD, semantic dementia and progressive non-fluent aphasia, form part of a clinicopathological spectrum named frontotemporal lobar degeneration (FTLD). The classical neuropsychological phenotype of FTD has been enriched by tests exploring Theory of Mind, social cognition and emotional processing. Imaging studies have detailed the patterns of atrophy associated with different clinical and pathological subtypes. These patterns offer some diagnostic utility, while measures of progression of atrophy may be of use in future trials. 30-50% of FTD is familial, and mutations in two genes, microtubule associated protein tau and Progranulin (GRN), account for about half of these cases. Rare defects in VCP, CHMP2B, TARDP and FUS genes have been found in a small number of families. Linkage to chromosome 9p13.2-21.3 has been established in familial FTD with motor neuron disease, although the causative gene is yet to be identified. Recent developments in the immunohistochemistry of FTLD, and also in amyotrophic lateral sclerosis (ALS), have led to a new pathological nomenclature. The two major groups are those with tau-positive inclusions (FTLD-tau) and those with ubiquitin-positive and TAR DNA-binding protein of 43 kDa (TDP-43) positive inclusions (FTLD-TDP). Recently, a new protein involved in familial ALS, fused in sarcoma (FUS), has been found in FTLD patients with ubiquitin-positive and TDP-43-negative inclusions. In this review, the authors discuss recent clinical, neuropsychological, imaging, genetic and pathological developments that have changed our understanding of FTD, its classification and criteria. The potential to establish an early diagnosis, predict underlying pathology during life and quantify disease progression will all be required for disease-specific therapeutic trials in the future.     

Language,executive function and social cognition in the diagnosis of frontotemporal dementia syndromes

Abstract

Frontotemporal dementia (FTD) represents a spectrum of non-Alzheimer's degenerative conditions associated with focal atrophy of the frontal and/or temporal lobes. Frontal and temporal regions of the brain have been shown to be strongly involved in executive function, social cognition and language processing and, thus, deficits in these domains are frequently seen in patients with FTD or may even be hallmarks of a specific FTD subtype (i.e. relatively selective and progressive language impairment in primary progressive aphasia). In this review we have attempted to delineate how language, executive function, and social cognition may contribute to the diagnosis of FTD syndromes, namely the behavioural variant FTD as well as the language variants of FTD including the three subtypes of primary progressive aphasia (PPA): non-fluent/agrammatic, semantic and logopenic. This review also addresses the extent to which deficits in these cognitive areas contribute to the differential diagnosis of FTD versus Alzheimer’s disease (AD). Finally, early clinical determinants of pathology are briefly discussed and contemporary challenges to the diagnosis of FTD are presented.     

Frontotemporal dementia

Frontotemporal dementia (FTD) is an uncommon but important form of degenerative disease. It may make up 50% of dementia cases presenting before age 60. The symptoms are related to the anatomic areas affected. Neary divided the clinical syndromes into "frontotemporal dementia," "progressive nonfluent aphasia," and "semantic dementia." However, the pathology may extend beyond the frontal and temporal lobes and additional symptoms may be found. Although most cases are sporadic, some cases are genetic. The best-known genetic mutation causing FTD is frontotemporal dementia with parkinsonism, linked to the microtubule-associated protein tau on chromosome 17. There are other known genes and chromosome loci related to FTD. The most common pathology found is frontotemporal degeneration with ubiquitin inclusions. In contrast, FTD with Pick bodies is rare. Although there are strategies to help patients and their families, there is no known treatment for the disease.     

Frequency of tau gene mutations in familial and sporadic cases of non-Alzheimer dementia

BACKGROUND: Mutations in the tau gene have been reported in families with frontotemporal dementia (FTD) linked to chromosome 17. It remains uncertain how commonly such mutations are found in patients with FTD or non-Alzheimer dementia with or without a positive family history. OBJECTIVE: To determine the frequency of tau mutations in patients with non-Alzheimer dementia. PATIENTS AND METHODS: One hundred one patients with non-Alzheimer, nonvascular dementia, most thought to have FTD. Of these, 57 had a positive family history of dementia. Neuropathologic findings were available in 32. The tau gene was sequenced for all exons including flanking intronic DNA, portions of the 3' and 5' untranslated regions, and at least 146 base pairs in the intron following exon 10. RESULTS: Overall, the frequency of the tau mutations was low, being 5.9% (6/101) in the entire group. No mutations were found in the 44 sporadic cases. However, 6 (10.5%) of the 57 familial cases and 4 (33%) of the 12 familial cases with tau pathologic findings had mutations in the tau gene. The most common mutation was P301L. CONCLUSIONS: We conclude that tau mutations are uncommon in a neurology referral population with non-Alzheimer dementia, even in those with a clinical diagnosis of FTD. However, a positive family history and/or tau pathologic findings increase the likelihood of a tau mutation. There must be other genetic and nongenetic causes of FTD and non-Alzheimer dementia, similar to the etiologic heterogeneity present in Alzheimer disease.     

The tau R406W mutation causes progressive presenile dementia with bitemporal atrophy

Frontotemporal dementia (FTD) and Alzheimer's disease (AD) are two frequent causes of dementia that share both clinical and neuropathological features. Common to both disorders are the neurofibrillary tangles consisting of aggregations of hyperphosphorylated tau protein. Recently, a number of different pathogenic mutations in the tau gene have been identified in families with FTD and parkinsonism linked to chromosome 17 (FTDP-17). In the present study, a Swedish family with presenile degenerative dementia with bitemporal atrophy was screened for mutations in the tau gene. As a result, the R406W mutation in exon 13 was identified in all affected cases. This mutation has previously been reported in two different FTDP-17 families of Dutch and Midwestern American origin. Common features to these two kindreds and our family are the late age at onset and long duration of the disease. Our pedigree as well as the American one show early memory impairment and pronounced temporal lobar atrophy similar to AD, while the Dutch cases show more FTD features. This further illustrates the large clinical variability among cases with tau mutations and stresses the importance of genetic classification in addition to the traditional clinical classification of neurodegenerative disorders.     

Tau protein in frontotemporal dementia linked to chromosome 3 (FTD-3)

Recent work on frontotemporal dementia (FTD) has revealed the existence of at least 3 genetically distinct groups of inherited FTD: FTDP-17, FTD and motor neuron disease linked to chromosome 9, and FTD linked to chromosome 3 (FTD-3). Tau, on chromosome 17, is the only gene where mutations have been identified and its involvement in FTD has been firmly established. The genes on chromosome 9 and chromosome 3 associated with familial forms of FTD remain to be identified. Abnormal aggregates of tau protein characterize the brain lesions of FTDP-17 patients and ubiquitin inclusions have been found in FTD with motor neuron disease linked to chromosome 9. In this study the frontal cortices of 3 FTD-3 patients from a unique Danish family were examined for characteristic neuropathological features. In these brains tau inclusions were present in neurons and some glial cells in the absence of beta-amyloid deposits. The presence of filamentous tau protein in the frontal cortex of these patients suggests a possible link between tau and the genetic defect present on chromosome 3 and associated with FTD-3, although the limited amount of tau deposits observed makes it difficult to define this as a tauopathy.     

Review: Clinical,genetic and neuroimaging features of frontotemporal dementia

Frontotemporal dementia (FTD) is a heterogeneous group of disorders causing neurodegeneration within a network of areas centred on the frontal and temporal lobes. Clinically, patients present with behavioural symptoms (behavioural variant FTD) or language disturbance (primary progressive aphasia), although there is an overlap with motor neurone disease and atypical parkinsonian disorders. Whilst neuroimaging commonly reveals abnormalities in the frontal and temporal lobes, a closer review identifies a more complex picture with variable asymmetry of neuronal loss, widespread subcortical involvement and in many cases more posterior cortical atrophy. An autosomal‐dominant genetic disorder is found in around a third of people with mutations in progranulin, C9orf72 and the microtubule‐associated protein tau being the commonest causes. In the other two‐thirds, the disorder is sporadic, although recent genome‐wide association studies have started to identify genetic risk factors within this group. Much of this knowledge has been understood only in the past 10 years and so this review will discuss the current knowledge about the clinical, genetic and neuroimaging features of FTD.     

Frontotemporal lobar degeneration: clinical and pathological relationships

Frontotemporal lobar degeneration (FTLD) encompasses a heterogeneous group of clinical syndromes that include frontotemporal dementia (FTD), frontotemporal dementia with motor neurone disease (FTD/MND), progressive non-fluent aphasia (PNFA), semantic dementia (SD) and progressive apraxia (PAX). Clinical phenotype is often assumed to be a poor predictor of underlying histopathology. Advances in immunohistochemistry provide the opportunity to re-examine this assumption. We classified pathological material from 79 FTLD brains, blind to clinical diagnosis, according to topography of brain atrophy and immunohistochemical characteristics. There were highly significant relationships to clinical syndrome. Atrophy was predominantly frontal and anterior temporal in FTD, frontal in FTD/MND, markedly asymmetric perisylvian in PNFA, asymmetric bitemporal in SD and premotor, parietal in PAX. Tau pathology was found in half of FTD and all PAX cases but in no FTD/MND or SD cases and only rarely in PNFA. FTD/MND, SD and PNFA cases were ubiquitin and TDP-43 positive. SD cases were associated with dystrophic neurites without neuronal cytoplasmic or intranuclear inclusions (FTLD-U, type 1), FTD/MND with numerous neuronal cytoplasmic inclusions (FTLD-U, type 2 ) and PNFA with neuronal cytoplasmic inclusions, dystrophic neurites and neuronal intranuclear inclusions (FTLD-U, type 3). MAPT mutations were linked to FTD and PGRN mutations to FTD and PNFA. The findings demonstrate predictable relationships between clinical phenotype and both topographical distribution of brain atrophy and immunohistochemical characteristics. The findings emphasise the importance of refined delineation of both clinical and pathological phenotype in furthering understanding of FTLD and its molecular substrate.     

Frontotemporal dementia: one disease, or many?: probably one, possibly two

Accumulating evidence suggest that frontotemporal dementia is best viewed as a clinical syndrome even though there are distinct presentations of the behavioral variety, progressive aphasia, semantic dementia, corticobasal degeneration and progressive supranuclear palsy. Similarly the pathology should be regarded as a spectrum even though histological varieties are distinguished. More than half of FTD pathology is associated with ubiquitin positive and tau negative inclusions that are common in ALS. However the majority of FTD cases do not have ALS clinically and relatively few ALS cases develop FTD. The pathological and biochemical varieties can be dichotomized as tau positive and tau negative pathology and biochemistry. The genetics of the tau positive variety is associated with tau mutations and so far the tau negative variety is not, although some are linked to chromosome-17 also. There is a corresponding clinical dichotomy combining the behavioral variety of FTD presentation with semantic dementia and usually ubiquitin positive tau negative pathology on one hand and the association of primary progressive aphasia and cortical basal degeneration/PSP syndrome with tau positive pathology on the other. The overlap between them is too great to establish two separate diseases.     

Total tau and phosphorylated tau 181 levels in the cerebrospinal fluid of patients with frontotemporal dementia due to P301L and G272V tau mutations

BACKGROUND: Frontotemporal dementia (FTD) is a pathologically heterogeneous group of presenile neurodegenerative disorders, with or without the deposition of hyperphosphorylated tau protein in affected brain regions. Mutations in the tau gene have been found in the familial form of FTD, linked to chromosome 17q21-22, showing a spectrum of tauopathy. OBJECTIVE: To evaluate levels of total tau, phosphorylated tau 181 (Ptau-181), and amyloid-beta1-42 in the cerebrospinal fluid (CSF) of patients with FTD, with special emphasis on FTD due to tau mutations. DESIGN: Case-control study. SETTING: Outpatient neurology clinics at 2 university medical centers, in Rotterdam and Amsterdam (the Netherlands). PATIENTS: Twenty-six patients with FTD (9 with tau mutations 7 P301L and 2 G272V), 18 patients with Alzheimer disease (AD), and 13 nondemented controls. METHODS: Total tau, Ptau-181, and amyloid-beta1-42 levels in CSF, obtained by lumbar puncture, were determined by sandwich enzyme-linked immunosorbent assay. Patients were diagnosed after clinical examination, neuropsychologic evaluation, and neuroimaging. Differences between patient groups were statistically evaluated using nonparametric tests. RESULTS: Although CSF levels of total tau were mildly increased in FTD patients compared with nondemented controls (P =.05), median CSF total tau levels were low in the subgroup with tau mutations compared with AD patients. Furthermore, CSF levels of Ptau-181 and amyloid-beta1-42 were not different in FTD patients, including the patients with tau mutations, compared with nondemented controls. CONCLUSIONS: The tauopathy in P301L and G272V does not appear to be associated with an evident increase in CSF levels of Ptau-181 in FTD patients with these tau mutations, in contrast with findings in patients with AD.     

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.