Neuropathologic variation in frontotemporal dementia due to the intronic tau 10(+16) mutation

BACKGROUND: An increasing number of recently described tau mutations show considerable clinical heterogeneity. The assessment of this phenotypic variation is of vital importance in the differential diagnosis of neurodegenerative diseases. OBJECTIVE: To assess the neuropathologic heterogeneity in a comprehensive study of 12 brains with a tau mutation at exon 10(+16) (C-to-T) splice site from 9 families. METHODS: A comprehensive neuropathologic examination has been carried out, using a wide range of tau antibodies. RESULTS: All brains showed frontotemporal atrophy of varying severity and pallor of the pigmented nuclei of the brainstem. The histologic changes were more extensive to include other cortical areas, the deep gray matter, and the white matter. The hallmark histologic lesions were the tau-positive neuronal and glial inclusions. In neurons, these ranged from typical neurofibrillary tangles through well-circumscribed inclusions to diffuse cytoplasmic staining. This tau pathology was complemented by the presence of large, abnormal achromatic neurons, neuronal loss, astrocytosis, and superficial status spongiosus. CONCLUSION: The distribution, type, and severity of these histologic abnormalities varied not only from case to case but also within the same brain. These brains with a common tau mutation raise important differential diagnostic problems: cases in the past might have been misdiagnosed as corticobasal degeneration or even atypical Pick disease, disorders with similar, if not identical, phenotypic manifestations.     

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.     

Familial early-onset dementia with tau intron 10 + 16 mutation with clinical features similar to those of Alzheimer disease

BACKGROUND: Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) owing to the tau intron 10 + 16 mutation usually occurs with a prototypical frontotemporal dementia phenotype with prominent disinhibition and affective disturbances. OBJECTIVE: To report a new FTDP-17 pedigree with the tau intron 10 + 16 mutation demonstrating a clinical phenotype suggestive of Alzheimer disease. DESIGN: Case reports. SETTING: Regional neuroscience centers in northwest England. Patients We examined 4 members of a kindred in which 8 individuals were affected in 3 generations. RESULTS: All 4 patients reported memory difficulty. Marked anomia was also present, but behavioral disturbances were conspicuously absent in the early stages of disease. All patients had an initial clinical diagnosis of Alzheimer disease. No mutations were found in the presenilin or amyloid precursor protein genes. Pathologic examination of the proband showed features typical of FTDP-17, and tau gene analysis showed the intron 10 + 16 mutation. CONCLUSIONS: This pedigree illustrates the phenotypic variability of tau intron 10 + 16 mutations. In pedigrees with a clinical diagnosis of Alzheimer disease but without presenilin or amyloid precursor protein gene mutations, tau gene mutations may be found.     

Clinical and genetic features of families with frontotemporal dementia and parkinsonism linked to chromosome 17 with a P301S tau mutation

Summary In 9 patients with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) with a P301S tau mutation, the predominant phenotype was frontotemporal dementia in 3 and parkinsonism in 6. Comparison of the tau genotype/haplotype carrying the mutation and the initial clinical sign showed association between H1/H1 and parkinsonism and between H1/H2 and personality change. Thus, the tau haplotype carrying the mutation and the tau genotype may be related to the clinical phenotype throughout the disease course.     

The tau S305S mutation causes frontotemporal dementia with parkinsonism

Members of families with mutations in the tau gene are known to be heterogeneous in their clinical presentation, ranging from frontotemporal dementia to a clinical picture more resembling corticobasal degeneration or progressive supranuclear palsy. In this report, we describe a new phenotype for the tau S305S mutation, previously described as progressive supranuclear palsy. Clinically, the three affected family members showed alterations in personality and behaviour as well as cognitive decline and late levodopa-resistant parkinsonian symptoms, consistent with the diagnosis of frontotemporal dementia with parkinsonism linked to chromosome 17. One autopsied case displayed degeneration of the frontal and temporal lobes together with extensive tau pathology in both neurones and glial cells. Sarkosyl-soluble and -insoluble tau extracted from frontal cortex revealed a ratio shift with decreased levels of tau with three microtubule-binding repeats and increased levels of tau with four microtubule-binding repeats (4R tau). These findings provide further evidence for the clinical and pathological variation both within and between families with mutations in the tau gene. In addition, they support previous studies which demonstrate that the S305S mutation influences the splicing of tau exon 10 and results in an overproduction of 4R tau.     

Familial frontotemporal dementia with a P301L tau mutation in Japan

We have reported the family line with frontotemporal dementia (FTD) in Japan. This family line has so far included four patients. Patient II-1 (man) had a 10 year history of slowly progressive personality and behavioral changes and died at the age of 56. His neuropathological examination showed severe atrophy of the bilateral frontal and temporal cortices with neuronal loss, gliosis and superficial spongiosis. Pick bodies were not found. The neuropathological diagnosis was atypical Pick's disease without Pick bodies or Pick-type in FTD. Patient III-2 is patient II-1's oldest daughter and was taken ill with personality change at the age of 52. She died at the age of 68. Patient III-4 is patient II-1's second daughter. Her onset with strange speech and behavior was at the age of 59. Patient III-5 is patient II-1's oldest son. He also had onset with personality change at the age of 54 and had the P301L mutation in tau. In all III generation cases CT/MRI revealed circumscribed frontotemporal atrophy. Patient III-5's PET/SPECT showed signs of hypoperfusion or hypometabolism in the bilateral frontotemporal areas. This is the first report of familial FTD with the P301L mutation in Japan.     

A novel L266V mutation of the tau gene causes frontotemporal dementia with a unique tau pathology

We report a novel mutation of tau (L266V missense mutation in exon 9) which may cause a type of familial frontotemporal dementia. The brain of a patient showed Pick body-like inclusions and unique tau-positive, argyrophilic astrocytes with stout filaments and naked, round, or irregular argyrophilic inclusions with deposits of both three-repeat and four-repeat tau. Recombinant tau with a L266V mutation showed a reduced ability to promote microtubule assembly, which may be the primary effect of the mutation.     

Late-onset frontotemporal dementia with a novel exon 1 (Arg5His) tau gene mutation

We report a case of frontotemporal dementia and parkinsonism linked to chromosome 17 of 5 years' duration in an 81-year-old man whose brother had died at age 86 years with dementia. In this patient, we found frontal and temporal neuronal loss, glial-predominant tau deposits, progressive supranuclear palsy-like straight tubules, accumulation of 4-repeat-predominant Sarkosyl-insoluble tau, and a novel exon 1 (Arg5His) tau gene mutation. This mutation decreased microtubule-promoting capacity and increased fibrillation of tau in vitro. Thus, we consider that the Arg5His mutation is an authentic tau gene abnormality responsible for the patient's tau pathology and late-onset dementia.     

Clinical features of pathologic subtypes of behavioral--variant frontotemporal dementia

OBJECTIVE: To identify clinical features in behavioral-variant frontotemporal dementia that may help predict tau-positive pathology. METHODS: Clinical and historical features of patients with pathologically confirmed tau-positive and tau-negative frontotemporal lobar degeneration from 1970 to 2006 were retrospectively reviewed in a blinded fashion. The initial clinical features of those patients who eventually met consensus criteria for frontotemporal dementia were examined using univariate and cluster analyses to explore characteristics that may be associated with tau pathology. RESULTS: Fifty-six patients (24 tau-positive cases) were included in the analysis. There was no difference in demographics between the tau-positive and tau-negative cases. Univariate analysis showed that poor planning and/or judgment was more commonly associated with tau-positive pathology (P = .03). Cluster analysis using behavioral characteristics identified 2 groups of patients: cluster 1 contained mainly tau-positive cases (57%) and cluster 2 was mostly tau-negative cases (71%). Poor planning and/or judgment was a common presenting sign in the first group (P < .001), while the second group was more likely to present with impaired regulation of personal conduct (P < .001) and a decline in personal hygiene (P = .005). CONCLUSIONS: Poor planning and/or judgment was associated with behavioral-variant frontotemporal dementia patients who had tau-positive pathology. The constellation of impaired personal conduct and a paucity of dysexecutive symptoms identified tau-negative patients.     

Search for a mutation in the tau gene in a Swiss family with frontotemporal dementia

Frontotemporal dementia (FTD) is considered to have a heterogeneous aetiology. To date the tau gene located on chromosome 17 has been shown to be implicated in the pathogenesis of several FTD families with parkinsonism, the so called FTDP-17 families. The mutations reported so far are located within exons 9 to 13, a region coding for the microtubule-binding sites. They are causing various cytoskeletal disturbances. We are describing here the main clinical and neuropathological features of a Swiss FTD family with members presenting a FTDP-like clinical phenotype. However, if we except two silent polymorphic sites at position 227 and 255 in exon 9, neither a known FTDP-17 mutation nor a novel one was detected in this region of the tau gene. Thus, the existence of a yet unknown mechanism of neurodegeneration, other than via mutations near or within the microtubule-binding sites, or the exon 10 splice sites of the tau gene, has to be considered to explain dementia in this family. A mutation in another gene is still possible.     

A new case of frontotemporal dementia and parkinsonism resulting from an intron 10 +3-splice site mutation in the tau gene: clinical and pathological features

Hereditary frontotemporal dementia and parkinsonism (FTDP) linked to chromosome 17 (FTDP-17) constitutes a new form of tauopathy, and mutations in the tau gene have recently been reported in some affected families. This report presents clinical and neuropathological data from a member of a British family (SOT 254) with a history of dementia and movement disorder. The medical history of the affected patient, a woman aged 44 years, was reviewed, and a detailed post-mortem examination of the brain was undertaken. A panel of well characterized phosphorylation-dependent and independent anti-tau antibodies was used to assess tau pathology, and inclusions were examined by electron microscopy. Neuronal loss and gliosis were widely distributed, but most severe in neocortical regions, and were associated with abundant neuronal and glial tau inclusions which consisted of a mixture of paired helical filaments (PHFs), similar to those in Alzheimer's disease, and distinct twisted ribbon-like filaments. Genomic DNA was obtained from post-mortem tissue from the index patient, and blood from two unaffected members of the same family. For the index case only, sequencing of intronic sequences flanking exon 10 of the tau gene identified a G to A transition at position +3 of the splice-donor site downstream of exon 10, identical to that reported in multiple system tauopathy with presenile dementia (MSTD). The clinical, neuropathological and genetic findings strongly suggest that SOT 254 represents a new example of FTDP-17 resulting from a mutation in the tau gene. These results are compared with those reported for other FTDP-17 families, i.e. for MSTD.     

Biochemical and pathological characterization of frontotemporal dementia due to a Leu266Val mutation in microtubule-associated protein tau in an African American individual

Frontotemporal dementia (FTD) is a clinically heterogeneous disorder characterized by alterations in language and/or behavior, often in association with Parkinsonism or motor neuron disease. A familial form of FTD is associated with mutations in the microtubule-associated protein tau (MAPT) gene. We report here on the clinical, neuroimaging, cerebral spinal fluid biomarker, genetic, biochemical and postmortem neuropathological analyses of a case of familial FTD with a Leu266Val MAPT mutation which results in a very early age of onset and a rapid course of disease. This is also the first reported case of any MAPT mutation in an individual of African American ethnicity. Grant Acknowledgement: The research reported here was supported by grants AG17586, AG10124, NS44266, K08 NS14108, and K08 AG20073 from the National Institutes on Aging and Neurological Disorders and Stroke of the National Institutes of Health, Department of Health and Human Services.     

Association between the extended tau haplotype and frontotemporal dementia

BACKGROUND: Recent studies have shown an association between an extended tau haplotype (H1) that covers the entire human tau gene and progressive supranuclear palsy or, more inconsistently, other neurodegenerative disorders, such as corticobasal degeneration, Parkinson disease, Alzheimer disease, and frontotemporal dementia (FTD). In addition, disease-causing mutations in the tau gene on chromosome 17 have been detected in some families with autosomal dominant FTD and parkinsonism. In FTD, the pathological accumulation of the microtubule-associated protein tau suggests that the tau gene may be a genetic risk factor for this disorder. OBJECTIVE: To confirm or refute the association between the H1 haplotype or the H1H1 genotype of the tau gene and FTD. DESIGN: Case-control study. SETTING: Neurology departments of 12 French university hospitals. PARTICIPANTS: One hundred unrelated patients with FTD and 79 controls. METHODS: Tau genotype (contiguous polymorphisms in exons 1, 7, and 13 and in intron 9 used to reconstruct the extended haplotypes H1 and H2). Clinical examination, psychometric testing, laboratory tests, computed tomography and magnetic resonance imaging, single-photon emission computed tomography, and electroencephalography for patients with FTD. RESULTS: The H1H1 genotype was significantly overrepresented in patients with FTD compared with controls (62% vs 46%; P=.01, 1-sided; odds ratio adjusted for age and sex, 1.95). After stratification according to apolipoprotein E (APOE) genotype, we found a significant interaction between APOE and tau genotypes (P=.03). CONCLUSIONS: This study of the largest series of patients with FTD confirms the primary role of tau in FTD and establishes that the H1 haplotype of the tau gene and the E2 allele of APOE interact by an unknown mechanism that increases the risk of FTD.