http://repub.eur.nl/res/aut/12509/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/33317/ 2011-09-01T00:00:00Z Based on the recent literature and collective experience, an international consortium developed revised guidelines for the diagnosis of behavioural variant frontotemporal dementia. The validation process retrospectively reviewed clinical records and compared the sensitivity of proposed and earlier criteria in a multi-site sample of patients with pathologically verified frontotemporal lobar degeneration. According to the revised criteria, 'possible' behavioural variant frontotemporal dementia requires three of six clinically discriminating features (disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behaviours, hyperorality and dysexecutive neuropsychological profile). 'Probable' behavioural variant frontotemporal dementia adds functional disability and characteristic neuroimaging, while behavioural variant frontotemporal dementia 'with definite frontotemporal lobar degeneration' requires histopathological confirmation or a pathogenic mutation. Sixteen brain banks contributed cases meeting histopathological criteria for frontotemporal lobar degeneration and a clinical diagnosis of behavioural variant frontotemporal dementia, Alzheimer's disease, dementia with Lewy bodies or vascular dementia at presentation. Cases with predominant primary progressive aphasia or extra-pyramidal syndromes were excluded. In these autopsy-confirmed cases, an experienced neurologist or psychiatrist ascertained clinical features necessary for making a diagnosis according to previous and proposed criteria at presentation. Of 137 cases where features were available for both proposed and previously established criteria, 118 (86) met 'possible' criteria, and 104 (76) met criteria for 'probable' behavioural variant frontotemporal dementia. In contrast, 72 cases (53) met previously established criteria for the syndrome (P<0.001 for comparison with 'possible' and 'probable' criteria). Patients who failed to meet revised criteria were significantly older and most had atypical presentations with marked memory impairment. In conclusion, the revised criteria for behavioural variant frontotemporal dementia improve diagnostic accuracy compared with previously established criteria in a sample with known frontotemporal lobar degeneration. Greater sensitivity of the proposed criteria may reflect the optimized diagnostic features, less restrictive exclusion features and a flexible structure that accommodates different initial clinical presentations. Future studies will be needed to establish the reliability and specificity of these revised diagnostic guidelines. http://repub.eur.nl/res/pub/34193/ 2011-07-01T00:00:00Z Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ≤ 10-3. We found significant previously unidentified signals (P < 5 × 10-8) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component. http://repub.eur.nl/res/pub/34220/ 2011-05-01T00:00:00Z We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ĝ‰Currency sign 1 × 10-5. We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10-17; including ADGC data, meta P = 5.0 × 10-21) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10-14; including ADGC data, meta P = 1.2 × 10-16) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10-4; including ADGC data, meta P = 8.6 × 10-9), CD33 (GERAD+, P = 2.2 × 10-4; including ADGC data, meta P = 1.6 × 10-9) and EPHA1 (GERAD+, P = 3.4 × 10-4; including ADGC data, meta P = 6.0 × 10-10). http://repub.eur.nl/res/pub/24481/ 2009-04-01T00:00:00Z Frontotemporal lobar degeneration (FTLD) is now recognised as a common form of early onset dementia. Up to 40% of patients have a family history of disease demonstrating a large genetic component to its etiology. Linkage to chromosome 9p21 has recently been reported in families with this disorder. We undertook a large scale two-stage linkage disequilibrium mapping approach of this region in the Manchester FTLD cohort. We identified association of ubiquitin associated protein 1 (UBAP1; OR 1.42 95% CI 1.08-1.88, P = 0.013) with FTLD in this cohort and we replicated this finding in an additional two independent cohorts from the Netherlands (OR 1.33 95% CI 1.04-1.69, P = 0.022), the USA (OR 1.4 95% CI 1.02-1.92, P = 0.032) and a forth Spanish cohort approached significant association (OR 1.45 95% CI 0.97-2.17, P = 0.064). However, we failed to replicate in a fifth cohort from London (OR 0.99 95% CI 0.72-1.37, P = 0.989). Quantitative analysis of UBAP1 mRNA extracted from tissue from the Manchester cases demonstrated a significant reduction of expression from the disease-associated haplotype. In addition, we identified a case of familial FTLD that demonstrated colocalisation of UBAP1 and TDP-43 in the neuronal cytoplasmic inclusions in the brain of this individual. Our data for the first time identifies UBAP1 as a genetic risk factor for FTLD and suggests a mechanistic relationship between this protein and TDP-43. http://repub.eur.nl/res/pub/5886/ 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.