Frequency of tau mutations in three series of non-Alzheimer's degenerative dementia.
ABSTRACT Splice-site and missense mutations have been identified in tau associated with frontotemporal dementia with parkinsonism linked to chromosome 17. In this study we assessed the genetic contribution of tau mutations to three patient series with non-Alzheimer's (non-AD) degenerative dementia. The groups included (1) a community-based dementia series from Minnesota, MN; (2) a referral series with clinicopathological tauopathy; and (3) a pathologically confirmed familial frontotemporal dementia series from Manchester, UK. Comparing the three clinical series: in the stringently diagnosed Manchester frontotemporal dementia series, tau mutations were present in 13.6% of cases (three splice-site mutations); in the clinicopathological referral series that used more general inclusion criteria, 3 cases with P301L mutations were observed, which represents a lower mutation frequency of 3.6% (9.4% in familial cases); in contrast, tau mutations were not detected in the Minnesota community-based dementia series, suggesting the occurrence of these mutations in dementia generally is rare (<0.2%). These data identify the prevalence of mutations in three different clinical settings and indicate that this figure is sensitive to the diagnostic criteria used in each patient series.
SourceAvailable from: Rivka Ravid[Show abstract] [Hide abstract]
ABSTRACT: Since 1994, a population-based study of frontotemporal dementia (FTD) in The Netherlands has aimed to ascer-tain all patients with FTD, and ®rst prevalence esti-mates based on 74 patients were reported in 1998. Here, we present new prevalence estimates after expan-sion of our FTD population to 245 patients, with emphasis on the prevalence in the province Zuid-Holland where the main study centre is located. All neurologists and physicians in nursing homes received a yearly postal enquiry about suspected FTD cases. FTD was diagnosed in 245 patients according to the Lund-Manchester criteria, supported by neuroimaging and neuropsychology. tau mutation analysis was performed in a subgroup of 154 patients (63%), and 40 out of 98 patients (41%) who died during follow-up were autop-sied during the course of the study. The prevalence of FTD in the province Zuid-Holland was 3.6 per 100 000 at age 50±59 years, 9.4 per 100 000 at age 60±69 years and 3.8 per 100 000 at age 70±79 years. The median age at onset of the 245 patients (51% female) was 58.0 years (range 33±80 years). Dementia in one or more ®rst-degree family members was found in 43% of patients and mutation analysis of the tau gene showed mutations in 34 patients (19 P301L, ®ve L315R, four G272V, four R406W, one DK280 and one S320F), all with a positive family history for dementia (14% of the total population, 32% of patients with a positive family history). Pathological ®ndings in the 40 autopsied patients consisted of dementia lacking distinctive histol-ogy in 22%, FTD with ubiquitin-positive inclusions in 33%, Pick's disease in 15% and tauopathy in the remaining 30% of patients, with tau mutations identi-®ed in more than half of the latter patients. We con-clude that the prevalence of FTD in The Netherlands is higher than previously reported, con®rming that FTD is more common than was previously thought. The ®nding of tau mutations in 32% of patients with a positive fam-ily history for dementia justi®es mutation screening in FTD patients with a positive family history, while tau mutations in non-familiar cases are rare. Abbreviations: DLDH = dementia lacking distinctive histology; FTD = frontotemporal dementia; MND = motoneuron disease; NBB = The Netherlands Brain Bank
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ABSTRACT: Hereditary frontotemporal dementia (FTD) associated with mutations in the Microtubule Associated Protein Tau gene (MAPT) is a protean disorder. Three neuropathologic subtypes can be recognized, based on the presence of inclusions made of tau isoforms with 3 and 4 repeats, predominantly 3 repeats and mostly 4 repeats. This is relevant for establishing a correlation between structural magnetic resonance imaging and positron emission tomography using tracers specific for aggregated tau. Longitudinal studies will be essential to determine the evolution of anatomical alterations from the asymptomatic stage to the various phases of disease following the onset of symptoms.Neuropathology and Applied Neurobiology 12/2014; 41(1). DOI:10.1111/nan.12213
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ABSTRACT: Pathological accumulation of the microtubule-associated protein tau, in the form of neurofibrillary tangles, is a major hallmark of Alzheimer's disease, the most prevalent neurodegenerative condition worldwide. In addition to Alzheimer's disease, a number of neurodegenerative diseases, called tauopathies, are characterized by the accumulation of aggregated tau in a variety of brain regions. While tau normally plays an important role in stabilizing the microtubule network of the cytoskeleton, its dissociation from microtubules and eventual aggregation into pathological deposits is an area of intense focus for therapeutic development. Here we discuss the known cellular factors that affect tau aggregation, from post-translational modifications to molecular chaperones.Cellular and Molecular Life Sciences CMLS 02/2015; 72(10). DOI:10.1007/s00018-015-1839-9