Boeve, B.

Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions (Article)

2010-03-01T00:00:00Z

Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP). FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 × 10 11; odds ratio, minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 × 10 4). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.

Survival profiles of patients with frontotemporal dementia and motor neuron disease (Article)

2009-11-01T00:00:00Z

Background: Frontotemporal dementia and amyotrophic lateral sclerosis are neurodegenerative diseases associated with TAR DNA-binding protein 43- and ubiquitin-immunoreactive pathologic lesions. Objective: To determine whether survival is influenced by symptom of onset in patients with frontotemporal dementia and amyotrophic lateral sclerosis. Design, Setting, and Patients: Retrospective review of patients with both cognitive impairment and motor neuron disease consecutively evaluated at 4 academic medical centers in 2 countries. Main Outcome Measures: Clinical phenotypes and survival patterns of patients. Results: A total of 87 patients were identified, including 60 who developed cognitive symptoms first, 19 who developed motor symptoms first, and 8 who had simultaneous onset of cognitive and motor symptoms. Among the 59 deceased patients, we identified 2 distinct subgroups of patients according to survival. Long-term survivors had cognitive onset and delayed emergence of motor symptoms after a long monosymptomatic phase and had significantly longer survival than the typical survivors (mean, 67.5 months vs 28.2 months, respectively; P<.001). Typical survivors can have simultaneous or discrete onset of cognitive and motor symptoms, and the simultaneous-onset patients had shorter survival (mean, 19.2 months) than those with distinct cognitive or motor onset (mean, 28.6 months) (P=.005). Conclusions: Distinct patterns of survival profiles exist in patients with frontotemporal dementia and motor neuron disease, and overall survival may depend on the relative timing of the emergence of secondary symptoms.

Apolipoprotein E genotype does not affect the age of onset of dementia in families with define tau mutations (Article)

1999-02-05T00:00:00Z

We have assessed whether apolipoprotein E (ApoE) genotype influences the age of onset of dementia in a series of families with frontal temporal dementia with defined mutations in the tau gene. In contrast to the situation in Alzheimer's disease (AD), we could find no evidence that the age of onset of disease was influenced by the ApoE genotype.