Phenotypic variation in frontotemporal dementia and parkinsonism linked to chromosome 17

Hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) caused by mutations in the tau gene shows a wide range in age at onset, several distinct clinical presentations, and a spectrum of tau pathology. Although the clinical and pathological phenotype often correlate with the location of the mutation, there also exists considerable interfamilial and intrafamilial phenotypical variation. Not all families with FTDP-17 do have mutations and deposition of hyperphosphorylated tau in the brain, but show ubiquitin-positive, tau-negative inclusions. Future research should focus on the role of other genetic and environmental factors in this form of FTDP-17, whereas the responsible gene defect(s) has still to be identified for hereditary FTD without tau mutations.     

Tau negative frontal lobe dementia at 17q21: significant finemapping of the candidate region to a 4.8 cM interval

We report the results of a genome-wide search in a four-generation pedigree with autosomal dominant early-onset dementia (mean onset age: 64.9 years, range 53-79 years). In this family we previously excluded the known Alzheimer's disease genes based on linkage analysis and mutation screening of the amyloid precursor protein gene (exons 16 and 17) and the presenilin 1 and 2 genes. In addition we excluded mutations in the prion protein gene and exons 9-13 of the microtubule associated protein tau (MAPT) gene. We obtained conclusive linkage with chromosome 17q21 markers with a maximum multi-point LOD score of 5.51 at D17S951 and identified a candidate region of 4.8 cM between D17S1787 and D17S958 containing MAPT. Recent clinical and neuropathological follow-up of the family showed that the phenotype most closely resembled frontotemporal dementia (FTD) characterized by dense ubiquitin-positive neuronal inclusions that were tau negative. Extensive mutation analysis of MAPT identified 38 sequence variations in exons, introns, untranslated regions and the 5' regulatory sequence, however none was comprised within the disease haplotype. Although our findings do not entirely exclude a mutation in a yet unanalyzed region of MAPT, the apparent absence of MAPT mutations combined with the lack of tau pathology is highly suggestive for another defective gene at 17q21 responsible for FTD in this family.     

FTDP-17: an early-onset phenotype with parkinsonism and epileptic seizures caused by a novel mutation.

Recently, mutations in the tau gene on chromosome 17 were found causative for autosomal dominantly inherited frontotemporal dementia and parkinsonism (FTDP-17). We describe a family carrying a missense mutation at nucleotide 1137 C --> T, resulting in the amino acid substitution P301S. Methods of investigations include clinical, electrophysiological, and imaging techniques. This kindred presents with a novel phenotype characterized by an early onset of rapidly progressive frontotemporal dementia and parkinsonism in combination with epileptic seizures. We define the dopaminergic deficits as being predominantly presynaptic by the use of single-photon emission computed tomography with a dopamine transporter ligand. The association of this early-onset phenotype with P301S mutation is not entirely consistent with current criteria for the diagnosis of frontotemporal dementias and may encourage the search for tau mutations in diseases similar but not identical to FTDP-17. Also, the change from proline to serine suggests that this mutation might contribute to tau hyperphosphorylation.     

New developments in frontotemporal dementia and parkinsonism linked to chromosome 17

PURPOSE OF REVIEW: The identification of tau mutations in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) has revealed invaluable information regarding the role of the tau protein in neurodegenerative disease. Over the past year several new mutations have been identified, and experimental studies have provided further insight into the mechanism of neurodegeneration due to tau mutations and possible interactions with amyloid pathology. RECENT FINDINGS: Extensive clinical and pathological variation is seen in patients with different types of mutation, as well as in patients with the same mutation. Mutations may be found in patients with frontotemporal dementia (FTD), parkinsonism, progressive supranuclear palsy and corticobasal degeneration, justifying mutation analysis in familial cases of these disorders. Genetic heterogeneity exists in frontotemporal dementia, because a number of FTDP-17 families have neither tau mutations nor tau pathology. Genetic linkage has been found in familial FTD (chromosome 3), FTD with amyotrophic lateral sclerosis (9q21-q22), and FTD with inclusion body myopathy (9q13.3-p12). Tau deposits may consist of mainly mutated protein, or of mutated and wild-type protein in equal amounts, depending on the mutation. Recent animal studies show that amyloid-beta deposition may accelerate formation of neurofibrillary tangles. SUMMARY: Hopefully, the identification of responsible genetic defects and associated proteins will be helpful in improving our understanding of the role of the tau protein in the common neurodegenerative process of frontotemporal degeneration.     

Progranulin mutations in ubiquitin-positive frontotemporal dementia linked to chromosome 17q21

Two genetically distinct types of frontotemporal dementia (FTD) are linked to chromosome 17q21. FTD with parkinsonism (FTDP-17) results from mutations in the gene encoding microtubule associated protein tau (MAPT) and is associated with tau deposition in the patient's brain. An increasing number of FTD families are linked to 17q21 in the absence of a demonstrable MAPT mutation. Brains of these patients do not show tau deposits, but tau-negative intra- and perinuclear inclusions of unknown composition that are immunoreactive to ubiquitin (FTDU-17). These ubiquitin inclusions are located in the cytoplasm or nucleus of predominantly neuronal cells of affected brain regions. By extensive segregation analyses in conclusively linked FTDU-17 families, the candidate region was reduced to a 6.2 Mb segment containing MAPT; however, genomic sequencing of MAPT in FTDU-17 patients excluded disease-causing mutations. Further, the linked region was characterized by the presence of multiple low-copy repeat regions associated with genomic instability. However, we excluded genomic rearrangements as the cause of FTDU-17. Subsequent sequencing of positional candidate genes identified loss-of-function mutations in the gene encoding progranulin (PGRN), a growth factor involved in multiple physiological processes such as cellular proliferation and survival and tissue repair, and pathological processes including tumorigenesis. In a Belgian FTD patient series, the prevalence of PGRN mutations was 3.5 times higher than that of MAPT mutations underscoring a major role for PGRN in FTD pathogenesis. Together, mutation data provided convincing evidence that PGRN haploinsufficiency leads to neurodegeneration because of reduced PGRN-mediated neuronal survival. The PGRN protein is not deposited in the ubiquitin-positive inclusions, the nature of which remains unknown. Due to the functions of PGRN in neuronal survival and the clinicopathological overlaps between FTD and other dementias it is likely that reduced PGRN expression is associated with the progression of other neurodegenerative brain diseases including Alzheimer's disease. These findings open promising novel targets for therapeutic intervention against neurodegeneration.     

The novel MAPT mutation K298E: mechanisms of mutant tau toxicity, brain pathology and tau expression in induced fibroblast-derived neurons

Frontotemporal lobar degeneration (FTLD) consists of a group of neurodegenerative diseases characterized by behavioural and executive impairment, language disorders and motor dysfunction. About 20–30 % of cases are inherited in a dominant manner. Mutations in the microtubule-associated protein tau gene (MAPT) cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17T). Here we report a novel MAPT mutation (K298E) in exon 10 in a patient with FTDP-17T. Neuropathological studies of post-mortem brain showed widespread neuronal loss and gliosis and abundant deposition of hyperphosphorylated tau in neurons and glia. Molecular studies demonstrated that the K298E mutation affects both protein function and alternative mRNA splicing. Fibroblasts from a skin biopsy of the proband taken at post-mortem were directly induced into neurons (iNs) and expressed both 3-repeat and 4-repeat tau isoforms. As well as contributing new knowledge on MAPT mutations in FTDP-17T, this is the first example of the successful generation of iNs from skin cells retrieved post-mortem.     

Frontotemporal dementia with tauopathy: A review and preliminary immunohistochemical study of tau kinases and phosphatases

Recent work has shown that frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) is caused by tau gene mutations. Several different exonic and intronic mutations in the tau gene heve been found in many families with FTDP-17. Patients with tau gene mutations show a wide variety of clinicopathological conditions, such as frontotemporal dementia, corticobasal degeneration, multiple system tauopathy with presenile dementia, pallido-ponto-nigral degeneration, disinhibition-dementia-parkinsonism-amyotrophy complex, and progressive sub-cortical gliosis. A Japanese family of frontotemporal dementia with a missense mutation S305N in exon 10 of the tau gene is reported. Post-mortem examination of the brain revealed ring-shaped neurofibrillary tangles (NFT) partially surrounding the nucleus, which were most prominent in the frontal, temporal, insular, and postcentral cortices, as well as in the dentate gyrus. Cortical NFT were restricted primarily to layer II. The missense mutation S305N did not reduce the ability of tau to promote microtubule assembly. Instead, it increased splicing of exon 10. Weak immunoreactivities of kinases for tau phosphorylation were found in late-stage NFT in the dentate gyrus, whereas strong immunoreactivities were seen in early stage NFT in the temporal cortex. PP2B was present in temporal NFT. Although anti-PP2A antibody labeled neurons, NFT were not stained, which suggests that the activity of this phosphatase might be decreased in NFT.     

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.     

Comparison of extent of tau pathology in patients with frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration with Pick bodies and early onset Alzheimer's disease

In order to gain insight into the pathogenesis of frontotemporal lobar degeneration (FTLD), the mean tau load in frontal cortex was compared in 34 patients with frontotemporal dementia linked to chromosome 17 (FTDP-17) with 12 different mutations in the tau gene (MAPT), 11 patients with sporadic FTLD with Pick bodies and 25 patients with early onset Alzheimer's disease (EOAD). Tau load was determined, as percentage of tissue occupied by stained product, by image analysis of immunohistochemically stained sections using the phospho-dependent antibodies AT8, AT100 and AT180. With AT8 and AT180 antibodies, the amount of tau was significantly (P < 0.001 in each instance) less than that in EOAD for both FTDP-17 (8.5% and 10.0% respectively) and sporadic FTLD with Pick bodies (16.1% and 10.0% respectively). With AT100, the amount of tau detected in FTDP-17 was 54% (P < 0.001) of that detected in EOAD, but no tau was detected in sporadic FTLD with Pick bodies using this particular antibody. The amount of insoluble tau deposited within the brain in FTDP-17 did not depend in any systematic way upon where the MAPT mutation was topographically located within the gene, or on the physiological or structural change generated by the mutation, regardless of which anti-tau antibody was used. Not only does the amount of tau deposited in the brain differ between the three disorders, but the pattern of phosphorylation of tau also varies according to disease. These findings raise important questions relating to the role of aggregated tau in neurodegeneration - whether this represents an adaptive response which promotes the survival of neurones, or whether it is a detrimental change that directly, or indirectly, brings about the demize of the affected cell.     

The effect of tau genotype on clinical features in FTDP-17

The clinical phenotype of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) varies. This variability is seen not only between kindreds with different mutations but also in families sharing the same mutation. Inheritance of tau haplotype (H1) and genotype (H1/H1) has been established as a risk factor for some neurodegenerative disorders with parkinsonism. We assessed the effect of tau polymorphism on the clinical features of FTDP-17 in 61 cases from 30 separately ascertained families with four different tau mutations, including P301L, +16, N279K, and P301S. There were no significant differences of age at symptomatic onset and disease duration between H1/H1 and H1/H2 genotypes. The comparison between tau genotype and type of initial clinical sign showed an association between the H1/H1 genotype and parkinsonian phenotype and between the H1/H2 genotype and frontotemporal dementia phenotype (OR=11.7; 95% confidence interval, 1.4-98.7; P=0.008). Our results suggest that tau genotype does not influence the disease course. However, it may predispose to a specific clinical sign in the early stage of FTDP-17.     

Frontotemporal dementia and tauopathy

The presence of abundant neurofibrillary lesions made of hyperphosphorylated tau proteins is the characteristic neuropathology of a subset of neurodegenerative disorders classified as "tauopathies." The discovery of mutations in the tau gene in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) constitutes convincing evidence that tau proteins play a key role in the pathogenesis of neurodegenerative disorders. Moreover, it now is known that the most common form of sporadic frontotemporal dementia (FTD), which is characterized by frontotemporal neuron loss, gliosis, and microvacuolar change, also is a tauopathy caused by a loss of tau protein expression. Thus, these discoveries have begun to change the classification and the neuropathologic diagnosis of FTD and tauopathies, as well as current understanding of the disease mechanisms underlying them. Although transgenic mice expressing wild-type human tau or variants thereof with an FTDP-17 mutation result in tau pathologies and brain degeneration similar to that seen in human tauopathies, the precise mechanisms leading to the onset and progression of neurodegenerative disorders remain incompletely understood. Here, we review current understanding of human neurodegenerative tauopathies and prospects for translative recent insights about these into therapeutic interventions to prevent or ameliorate them.     

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.     

Frontotemporal dementia with novel tau pathology and a Glu342Val tau mutation

It is unclear how tau gene mutations cause frontotemporal dementia (FTD) with parkinsonism linked to chromosome 17 (FTDP-17), but those in exon 10 (E10) or the following intron may be pathogenic by altering E10 splicing, perturbing the normal 1:1 ratio of four versus three microtubule-binding repeat tau (4R:3R tau ratio) and forming tau inclusions. We report on a 55-year old woman with frontotemporal dementia and a family history of FTDP-17 in whom we found a novel E12 (Glu342Val) tau gene mutation, prominent frontotemporal neuron loss, intracytoplasmic tau aggregates, paired helical tau filaments, increased 4R tau messenger RNA, increased 4R tau without E2 or E3 inserts, decreased 4R tau with these inserts, and a 4R:3R tau ratio greater than 1 in gray and white matter. Thus, this novel Glu342Val mutation may cause FTDP-17 by unprecedented mechanisms that alter splicing of E2, E3, and E10 to preferentially increase 4R tau without amino terminal inserts and promote aggregation of tau filaments into cytopathic inclusions.     

Phenotypic heterogeneity within a new family with the MAPT p301s mutation

Mutations in the gene encoding the microtubule-associated protein tau (MAPT) cause frontotemporal dementia and parkinsonism linked to chromosome 17. Clinical variability is seen not only among families with different mutations, but also among family members with the same mutation. We investigated a newly identified familial frontotemporal dementia and parkinsonism family. The disease was of early onset and was inherited as an autosomal dominant trait. Clinically, parkinsonism was the prominent and often early feature, and it preceded dementia. Three autopsied cases shared involvement predominantly in the frontal and temporal lobes and also in the subcortical nuclei, including substantia nigra, globus pallidus, and subthalamic nucleus, that microscopically consisted of neuronal loss, microvacuolation, and astrocytic fibrosis. Immunohistochemistry demonstrated neuropil threads, ballooned cells, and glial fibrillary tangles. Sequencing analysis of the MAPT gene showed an alteration in one allele, resulting in a P301S substitution. These findings suggest that the MAPT P301S mutation can cause pathologically subcortical-predominant, neuropil thread-rich, tau-containing lesions, which could result in consistent parkinsonism. Our study confirms the notion that the phenotype observed in affected individuals from P301S MAPT mutation families is heterogeneous and is broader than the phenotypes seen to date in affected family members carrying other MAPT mutations.     

Frequency of tau mutations in familial and sporadic frontotemporal dementia and other tauopathies

Abstract. Tau gene mutations with insoluble Tau neuropathology have been identified in pedigrees with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Other neurodegenerative diseases, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), are also characterised by insoluble Tau neuropathology. This study sought to determine the nature and frequency of tau gene mutations in an affected proband cohort of patients within this spectrum of neurodegenerative diseases. Sixty-four individuals with clinical features consistent with FTD and other tauopathies were referred over a three year period. There was neuropathological confirmation of disease in 30%. Individuals were screened for mutations in the coding region and flanking intronic regions of the tau gene by direct sequencing of PCR products. Four confirmed tau gene mutations were identified representing 6.3 % for the total affected proband cohort. Tau gene mutations were found in three of twelve (25%) of the cases with a family history of dominantly inherited frontotemporal dementia, but in only one of 25 cases without a family history (4 %). Although tauopathies have been considered to result from genetic defects, screening for tau gene mutations in sporadic cases is not likely to identify pathogenic mutations.     

The novel <Emphasis Type="Italic">Tau</Emphasis> mutation G335S: clinical,neuropathological and molecular characterization

Mutations in Tau cause the inherited neurodegenerative disease, frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). Known coding region mutations cluster in the microtubule-binding region, where they alter the ability of tau to promote microtubule assembly. Depending on the tau isoforms, this region consists of three or four imperfect repeats of 31 or 32 amino acids, each of which contains a characteristic and invariant PGGG motif. Here, we report the novel G335S mutation, which changes the PGGG motif of the third tau repeat to PGGS, in an individual who developed social withdrawal, emotional bluntness and stereotypic behavior at age 22, followed by disinhibition, hyperorality and ideomotor apraxia. Abundant tau-positive inclusions were present in neurons and glia in the frontotemporal cortex, hippocampus and brainstem. Sarkosyl-insoluble tau showed paired helical and straight filaments, as well as more irregular rope-like filaments. The pattern of pathological tau bands was like that of Alzheimer disease. Experimentally, the G335S mutation resulted in a greatly reduced ability of tau to promote microtubule assembly, while having no significant effect on heparin-induced assembly of recombinant tau into filaments.     

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.     

Frontotemporal dementia and parkinsonism linked to chromosome 17

Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is an autosomal dominant neurodegenerative disorder caused by mutations in the MAPT gene which encodes the microtubule-associated protein tau. This hereditary tauopathy is a rare clinical syndrome, affecting approximately two hundred kindreds and about six hundred individuals bearing thirty nine known MAPT mutations. The disorder is thought to be related to the altered proportion of tau protein isoforms or the ability of tau to bind to microtubules and to promote microtubule assembly and organization. The clinical presentation of FTDP-17 includes behavioral, cognitive and motor abnormalities. This disorder has both a variable course and phenotype. Gross neuropathological examination reveals brain atrophy, especially of the frontal and temporal lobes, and selective atrophy of the basal ganglia and brainstem nuclei. The major microscopic features of FTDP-17 demonstrate the presence of neurofibrillary tangles, neuropil threads and glial inclusions composed of insoluble tau protein. Distribution and amount of tau deposits vary, depending on the type of MAPT mutation. The definitive diagnosis of FTDP-17 requires a set of clinical and pathological features combined with a molecular genetic analysis. Currently, there is no known effective treatment for FTDP-17.     

Frontotemporal lobar degeneration – tau as a pied piper?

Frontotemporal lobar degeneration (FTLD) is the second most-common form of cortical dementia in the presenium after Alzheimer disease. Clinically three disease entities can be distinguished: frontotemporal dementia, semantic dementia, and primary progressive aphasia. The underlying neuropathology can be classified into disorders with tau pathology (including Pick disease, corticobasal degeneration, progressive supranuclear palsy, and familial frontotemporal dementia with parkinsonism linked to chromosome 17 – FTDP-17), and into disorders that lack tau abnormalities (including dementia lacking distinctive histology and motor neuron disease inclusion dementia). The recent discovery of tau gene mutations in FTDP-17 brought tau to the center stage, but led to the erroneous trend of collectively grouping all forms of FTLD as tauopathies. However, clinicopathological and genetic studies strongly suggest that the majority of sporadic and familial FTLD cases are not associated with tau pathology and/or tau gene mutations. Furthermore, recent studies have linked several autosomal dominantly inherited familial frontotemporal dementia cases to a variety of gene loci on different chromosomes. Thus, this review is intended to summarize our current knowledge about the sporadic and familial FTLD disorders that lack tau pathology, and shall further strengthen the view that FTLD is heterogeneous, both in terms of clinicopathological phenotypes as well as genetic backgrounds. Electronic Publication