Two novel presenilin 1 gene mutations connected with frontotemporal dementia-like clinical phenotype: genetic and bioinformatic assessment

Mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes are associated with early-onset familial Alzheimer's disease (EOAD). There are several reports describing mutations in PSEN1 in cases with frontotemporal dementia (FTD). We identified two novel mutations in the PSEN1 gene: L226F and L424H. The first mutation was detected in a patient with a clinical diagnosis of FTD and a post-mortem diagnosis of AD. The second mutation is connected with a clinical phenotype of variant AD with strong FTD signs. In silico modeling revealed that the mutations, as well as mutations used for comparison (F177L and L424R), change the local structure, stability and/or properties of the transmembrane regions of the presenilin 1 protein (PS1). In contrast, a silent non-synonymous substitution F175S is eclipsed by external residues and has no influence on PS1 interfacial surface. We suggest that in silico analysis of PS1 substitutions can be used to characterize novel PSEN1 mutations, to discriminate between silent polymorphisms and a potential disease-causing mutation. We also propose that PSEN1 mutations should be considered in FTD patients with no MAPT mutations.     

Prevalence of pathogenic mutations in an Italian clinical series of patients with familial dementia

Genetic factors are involved in the aetiology of dementias. Three genes have been identified which, when mutated, cause Familial Alzheimer disease (FAD): the presenilin-1 (PS1), the presenilin-2 (PS2) and the amyloid precursor protein (APP) genes. Together, these mutations are responsible for 30-50% of the cases with autosomal dominant Alzheimer disease (AD), and for about 5% of all AD cases. While over 130 mutations have been identified in PS1, mutations in PS2 and APP are rarer, since only 10 and 22 mutations, respectively, have been found in these FAD genes. Instead, mutations in the MAPT gene were associated with Familial Frontotemporal dementia (FFTD) linked to chromosome 17 (FTDP-17). Frontotemporal dementia (FTD) can occur in a sporadic form, but in 30-50% of cases there is a positive family history of dementia. In this study, we determined the spectrum of mutations and the relative contribution of the above mentioned four genes in our Italian clinical series of patients with a positive family history of dementia.     

A novel presenilin 1 mutation associated with Pick's disease but not beta-amyloid plaques

Familial forms of frontotemporal dementia (FTD) with tauopathy are mostly caused by mutations in the gene encoding the microtubule-associated protein tau (MAPT). However, rare forms of familial tauopathy without MAPT mutations have been reported, suggesting other tauopathy-related genetic defects. Interestingly, two presenilin 1 (PS1) mutations (Leu113Pro and insArg352) recently have been associated with familial FTD albeit without neuropathological confirmation. We report here a novel PS1 mutation in a patient with Pick-type tauopathy in the absence of extracellular beta-amyloid deposits. The mutation is predicted to substitute Gly-->Val at codon position 183 (Gly183Val) and to affect the splice signal at the junction of the sixth exon and intron. Further clinical-genetic investigation showed a positive family history of FTD-like dementia and suggested that Gly183Val is associated with a phenotypically heterogeneous neurodegenerative disorder. Our results suggest PS1 as a candidate gene for Pick-type tauopathy without MAPT mutations.     

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.     

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.     

Genetic analysis in patients with familial and sporadic frontotemporal dementia: two tau mutations in only familial cases and no association with apolipoprotein epsilon4

We screened for tau gene mutations among 24 Japanese (6 familial and 18 sporadic cases) and 4 Polish patients with frontotemporal dementia (FTD) using PCR-SSCP analysis followed by DNA sequencing. We identified 2 missense mutations in exon 10: N279K and P301L in 2 Japanese patients with familial FTD. Additionally 3 DNA polymorphisms: 2 known (3' exon 3 + 9, A --> G and exon 7, codon 176, G --> A) and 1 new (exon 8, codon 185, T --> C) were identified in 1 Polish patient. Tau mutations were not found in subjects with a negative family history suggesting that tau mutations do not account for most sporadic cases of FTD. We also found no association of apolipoprotein E4 allele with FTD.     

Does the pattern of atrophy of the Corpus callosum differ between patients with frontotemporal dementia and patients with Alzheimer's disease?

The pattern of callosal atrophy might be useful for the differentiation between frontotemporal dementia (FTD) and Alzheimer's disease (AD) in advanced cases. However, it is unclear whether the pattern of callosal atrophy differs between patients with FTD and patients with AD in mild to moderate stages. Volumetric MR images were recorded from 48 probands (12 with FTD, 12 with late-onset AD, and 24 controls). All patients were in a mild or in a moderate stage. The corpus callosum was divided into five segments. A repeated-measures analysis of variance showed that there was no difference in the pattern of callosal atrophy between the groups. We provide evidence that patients with FTD and patients with late-onset AD do not differ in the pattern of callosal atrophy on condition that: (1) FTD patients and AD patients are in a mild to moderate stage and (2) FTD patients and AD patients differ in age.     

Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are part of a disease spectrum associated with TDP-43 pathology. Strong evidence supporting this is the existence of kindreds with family members affected by FTD, ALS or mixed features of FTD and ALS, referred to as FTD-MND. Some of these families have linkage to chromosome 9, with hexanucleotide expansion mutation in a noncoding region of C9ORF72. Discovery of the mutation defines c9FTD/ALS. Prior to discovery of mutations in C9ORF72, it was assumed that TDP-43 pathology in c9FTD/ALS was uniform. In this study, we examined the neuropathology and clinical features of 20 cases of c9FTD/ALS from a brain bank for neurodegenerative disorders. Included are six patients clinically diagnosed with ALS, eight FTD, one FTD-MND and four Alzheimer-type dementia. Clinical information was unavailable for one patient. Pathologically, the cases all had TDP-43 pathology, but there were three major pathologic groups: ALS, FTLD-MND and FTLD-TDP. The ALS cases were morphologically similar to typical sporadic ALS with almost no extramotor TDP-43 pathology; all had oligodendroglial cytoplasmic inclusions. The FTLD-MND showed predominantly Mackenzie Type 3 TDP-43 pathology, and all had ALS-like pathology in motor neurons, but more extensive extramotor pathology, with oligodendroglial cytoplasmic inclusions and infrequent hippocampal sclerosis. The FTLD-TDP cases had several features similar to FTLD-TDP due to mutations in the gene for progranulin, including Mackenzie Type 1 TDP-43 pathology with neuronal intranuclear inclusions and hippocampal sclerosis. FTLD-TDP patients were older and some were thought to have Alzheimer-type dementia. In addition to the FTD and ALS clinical presentations, the present study shows that c9FTD/ALS can have other presentations, possibly related to age of onset and the presence of hippocampal sclerosis. Moreover, there is pathologic heterogeneity not only between ALS and FTLD, but also within the FTLD group. Further studies are needed to address the molecular mechanism of clinical and pathological heterogeneity of c9FTD/ALS due to mutations in C9ORF72.     

Frontotemporal lobar degeneration with motor neuron disease-type inclusions predominates in 76 cases of frontotemporal degeneration

This report presents the largest series of consecutive, neuropathologically confirmed cases of frontotemporal degeneration (FTD). Prior studies have found dementia lacking distinctive histology (DLDH) to be the most common pathology underlying the clinical diagnosis of FTD. In this series of 76 cases, 29 (38%) were found to have frontotemporal lobar degeneration with motor neuron disease-type inclusions (FTLD-MND-type) or FTLD-MND (with ALS), the most common neuropathological classification in our series. Only eight (11%) were classified as Picks disease. Several cases originally designated as DLDH could be reclassified as FTLD-MND-type based on current recommendations for classification of FTD.     

Cerebrospinal fluid profile in frontotemporal dementia and Alzheimer's disease

We assessed cerebrospinal fluid (CSF) levels of tau and other biomarkers of neurodegenerative disease. CSF tau levels vary widely in reports of frontotemporal dementia (FTD). CSF samples were assayed for tau, amyloid beta1-42 (A1-42), and the isoprostane 8,12-iso-iPF2a-VI (iP) prospectively in 64 patients with FTD, retrospectively in 26 autopsied cases with FTD or Alzheimer's disease (AD), and in 13 healthy seniors. To validate our observations in vivo, we correlated CSF tau levels with cortical atrophy in 17 FTD patients using voxel-based morphometry analyses of high-resolution magnetic resonance imaging. CSF levels of tau, Abeta1-42, and iP differed significantly in FTD compared with AD. Individual patient analyses showed that 34% of FD patients had significantly low levels of CSF tau, although this was never seen in AD. A discriminant analysis based on CSF levels of tau, Abeta1-42, and iP was able to classify 88.5% of these patients in a manner that corresponds to their clinical or autopsy diagnosis. Magnetic resonance imaging studies showed that CSF tau levels correlate significantly with right frontal and left temporal cortical atrophy, brain regions known to be atrophic in patients with autopsy-proved FTD. We conclude that CSF tau levels are significantly reduced in many patients with FTD.     

Frontotemporal lobar degeneration and ubiquitin immunohistochemistry

We set out to determine the frequency of the different pathologies underlying frontotemporal degeneration (FTD) in our brain bank series, by reviewing all cases of pathologically diagnosed FTD over the last 12 years. We identified and reviewed 29 cases of FTD and classified them using the most recent consensus criteria with further histological analysis of 6 initially unclassifiable cases. Detailed histological analysis of these 6 cases revealed variable numbers of ubiquitin-positive (tau and alpha-synuclein-negative) inclusions in 5 cases, consistent with the diagnosis of frontotemporal lobar degeneration with ubiquitin-only-immunoreactive neuronal changes (FTLD-U). As a consequence of the current re-evaluation, 18 (62%) of the 29 cases with FTD have underlying pathology consistent with FTLD-U. Therefore in our brain bank series of frontotemporal degeneration, most cases were non-tauopathies with FTLD-U accounting for 62% of all the diagnoses.     

Neuronal intranuclear inclusions distinguish familial FTD-MND type from sporadic cases

Ubiquitin-immunoreactive (ub-ir) neuronal cytoplasmic inclusions are characteristically found in the extramotor cortex in patients with motor neuron disease (MND) and dementia (MND-dementia) and in a subset of patients with frontotemporal dementia (FTD) without motor symptoms (FTD-MND type). Recently, ub-ir neuronal intranuclear inclusions have been described in a small number of patients with familial FTD-MND type. To better define the sensitivity and specificity of this pathological change, we examined postmortem tissue from 14 patients with FTD-MND type (8 familial, 6 sporadic), 10 cases of MND-dementia (5 familial, 5 sporadic) and 19 cases of MND with no history of cognitive dysfunction (2 familial, 17 sporadic). Numerous intranuclear inclusions were found in multiple anatomic sites in 6/8 cases of familial FTD-MND. Rare intranuclear inclusions were present in the hippocampal dentate granule cells in 1 case of familial MND-dementia. No sporadic cases had intranuclear inclusions. These findings suggest that intranuclear inclusions are specific for familial FTD and may identify a subset of families with a common genetic basis. Although intranuclear inclusions are most characteristic of families with pure FTD, they may also be found in some pedigrees with both FTD and MND, further supporting the hypothesis that FTD-MND type and MND-dementia represent a clinicopathological spectrum of disease.     

Tau isoform expression in frontotemporal dementia without tau deposition

In many cases of sporadic frontotemporal dementia (FTD) and in FTD caused by tau mutations (FTDP-17) there is disruption of the normal splicing of tau leading to the aberrant expression of tau isoforms and neurodegeneration. This suggests a central role for tau in the pathogenesis of FTD. However, more than half the cases of sporadic FTD show no tau deposition. We question whether altered expression is also involved in the pathogenesis of tau-negative FTD. Real-time polymerase chain reaction was used to investigate tau isoform expression in tau-negative FTD and age-matched controls. There were no differences in total tau mRNA or 4R versus 3R isoform expression. Our study suggests that perturbed tau mRNA expression is unlikely to be involved in the pathogenesis of tau-negative FTD.     

Inheritance of frontotemporal dementia.

BACKGROUND: Previous studies of families with fronto-temporal dementia (FTD) support an autosomal dominant inheritance pattern, but most studies have described genetic transmission in individual families specifically selected for the presence of multiple affected individuals. OBJECTIVE: To investigate the familial presentation and inheritance of FTD and related disorders among a large group of FTD index cases unselected for family history of dementia. DESIGN AND SETTING: We interviewed family members and reviewed medical records and autopsy reports at a university hospital and a university-affiliated hospital to determine the frequency of familial FTD and the most likely mode of inheritance. Characteristic families with the disorder are described, along with the history, clinical findings, and neuroimaging results in affected members of these families. PATIENTS AND PARTICIPANTS: The 42 index cases of FTD had a mean age of onset of 56.1 years (range, 40-69 years). Of these patients, 21 (50%) were women. All but one of the patients were white. Participants included male and female spouses and children of the index cases. family member with an FTD spectrum disorder and were considered familial cases. The majority (17 [89%]) of familial FTD cases showed a pattern consistent with dominant inheritance. If depression is excluded, familial cases decrease from 19 (45%) to 17 (40%), of which 15 (88%) showed a dominant transmission pattern. The initial presentations in the nonindex familial cases varied but most frequently consisted of personality and behavioral changes that preceded cognitive impairment (19 [43%]), followed by psychiatric illness (14 [33%]), dementia without behavioral change (5 [11%]), amyotrophic lateral sclerosis (5 [11%]), and parkinsonism (2[5%]). Two of the affected nonindex cases had dual presenting diagnoses. The average age of onset was 56.1 years and did not differ significantly between familial and nonfamilial cases. Onset of FTD-related symptoms occurred after the age of 65 years in only 4(10%) of 42 index cases and 3 (5%) of 60 affected relatives. CONCLUSIONS: Familial FTD is usually inherited in an autosomal dominant pattern. The initial onset is insidious, often consisting of mood and behavioral changes occurring in presenile years that are often erroneously attributed to other nonneurologic causes. Although the precise incidence of FTD in North America is not known, it is one of the most common presenile dementias.     

Evaluation of the NINCDS-ADRDA criteria in the differentiation of Alzheimer's disease and frontotemporal dementia

OBJECTIVES: The diagnosis of Alzheimer's disease (AD) is now reliant on the use of NINCDS-ADRDA criteria. Other diseases causing dementia are being increasingly recognised--for example, frontotemporal dementia (FTD). Historically, these disorders have not been clearly demarcated from AD. This study assesses the capability of the NINCDS-ADRDA criteria to accurately distinguish AD from FTD in a series of pathologically proved cases. METHODS: The case records of 56 patients (30 with AD, 26 with FTD) who had undergone neuropsychological evaluation, brain imaging, and ultimately postmortem, were assessed in terms of whether at initial diagnosis the NINCDS-ADRDA criteria were successful in diagnosing those patients who had AD and excluding those who did not. RESULTS: (1) The overall sensitivity of the NINCDS-ADRDA criteria in diagnosing "probable" AD from 56 patients with cortical dementia (AD and FTD) was 0.93. However, the specificity was only 0.23; most patients with FTD also fulfilled NINCDS-ADRDA criteria for AD. (2) Cognitive deficits in the realms of orientation and praxis significantly increased the odds of a patient having AD compared with FTD, whereas deficits in problem solving significantly decreased the odds. Neuropsychological impairments in the domains of attention, language, perception, and memory as defined in the NINCDS-ADRDA statement did not contribute to the clinical differentiation of AD and FTD. CONCLUSION: NINCDS-ADRDA criteria fail accurately to differentiate AD from FTD. Suggestions to improve the diagnostic specificity of the current criteria are made.     

Progranulin mutations and amyotrophic lateral sclerosis or amyotrophic lateral sclerosis-frontotemporal dementia phenotypes

Objective

Mutations in the progranulin (PGRN) gene were recently described as the cause of ubiquitin positive frontotemporal dementia (FTD). Clinical and pathological overlap between amyotrophic lateral sclerosis (ALS) and FTD prompted us to screen PGRN in patients with ALS and ALS–FTD.

Methods

The PGRN gene was sequenced in 272 cases of sporadic ALS, 40 cases of familial ALS and in 49 patients with ALS–FTD.

Results

Missense changes were identified in an ALS–FTD patient (p.S120Y) and in a single case of limb onset sporadic ALS (p.T182M), although the pathogenicity of these variants remains unclear.

Conclusion

PGRN mutations are not a common cause of ALS phenotypes.Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder predominantly involving motor neurons leading to paralysis and death within 3–5 years from symptom onset. The pathogenic mechanism leading to motor neuron degeneration is unknown in the majority of cases. Frontotemporal dementia (FTD) is a degenerative disorder of the frontal and anterior temporal lobes.¹ Clinical, pathological and genetic data suggest that ALS and FTD form a spectrum of disease.² Approximately 5% of ALS patients have FTD (ALS–FTD)³ and approximately half of patients with “classical” ALS have subtle frontal and temporal lobe cognitive impairment.⁴ Many FTD cases similarly develop symptoms of motor neuron involvement during the course of their illness⁵ and up to one third of FTD patients without overt motor symptoms have loss of anterior horn cells with characteristic ubiquitin inclusions in surviving motor neurons on autopsy.⁶Recently, mutations in the progranulin (PGRN) gene have been described as the cause of ubiquitin positive FTD.^7,8 The overlap between ALS and FTD prompted us to screen 272 cases of sporadic ALS, 40 familial ALS cases and 49 patients diagnosed with ALS–FTD for mutations in this gene.     

Similar early clinical presentations in familial and non-familial frontotemporal dementia

BACKGROUND: It is unclear whether there are early clinical features that can distinguish between patients with familial and non-familial frontotemporal dementia (FTD). OBJECTIVE: To compare the clinical features of FTD cases who have tau gene mutations with those of cases with a family history of FTD but no tau gene mutation, and with sporadic cases with neither feature. METHODS AND RESULTS: Comparisons of the behavioural, cognitive, and motor features in 32 FTD patients (five positive for tau gene mutations, nine familial but tau negative, and 18 tau negative sporadic) showed that age of onset and duration to diagnosis did not differ between the groups. Apathy was not observed in tau mutation positive cases, and dysexecutive signs were more frequent in familial tau mutation negative cases. Memory deficits and behavioural changes were common in all groups. CONCLUSIONS: In comparison with other neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease, neither tau gene mutations nor strong familial associations confer earlier disease susceptibility.     

Thalamic nuclei in frontotemporal dementia: Mediodorsal nucleus involvement is universal but pulvinar atrophy is unique to C9orf72

Thalamic atrophy is a common feature across all forms of FTD but little is known about specific nuclei involvement. We aimed to investigate in vivo atrophy of the thalamic nuclei across the FTD spectrum. A cohort of 402 FTD patients (age: mean(SD) 64.3(8.2) years; disease duration: 4.8(2.8) years) was compared with 104 age‐matched controls (age: 62.5(10.4) years), using an automated segmentation of T1‐weighted MRIs to extract volumes of 14 thalamic nuclei. Stratification was performed by clinical diagnosis (180 behavioural variant FTD (bvFTD), 85 semantic variant primary progressive aphasia (svPPA), 114 nonfluent variant PPA (nfvPPA), 15 PPA not otherwise specified (PPA‐NOS), and 8 with associated motor neurone disease (FTD‐MND), genetic diagnosis (27 MAPT, 28 C9orf72, 18 GRN), and pathological confirmation (37 tauopathy, 38 TDP‐43opathy, 4 FUSopathy). The mediodorsal nucleus (MD) was the only nucleus affected in all FTD subgroups (16–33% smaller than controls). The laterodorsal nucleus was also particularly affected in genetic cases (28–38%), TDP‐43 type A (47%), tau‐CBD (44%), and FTD‐MND (53%). The pulvinar was affected only in the C9orf72 group (16%). Both the lateral and medial geniculate nuclei were also affected in the genetic cases (10–20%), particularly the LGN in C9orf72 expansion carriers. Use of individual thalamic nuclei volumes provided higher accuracy in discriminating between FTD groups than the whole thalamic volume. The MD is the only structure affected across all FTD groups. Differential involvement of the thalamic nuclei among FTD forms is seen, with a unique pattern of atrophy in the pulvinar in C9orf72 expansion carriers.