Search

Primary progressive aphasia (PPA) is an overarching term for a heterogeneous group of neurodegenerative diseases which affect language processing. Impaired picture naming has been linked to atrophy of the anterior temporal lobe in the semantic variant of PPA. Although atrophy of the anterior temporal lobe proposedly impairs picture naming by undermining access to semantic knowledge, picture naming also entails object recognition and lexical retrieval. Using multivariate analysis, we investigated whether cortical atrophy relates to different types of naming errors generated during picture naming in 43 PPA patients (13 semantic, 9 logopenic, 11 nonfluent, and 10 mixed variant). Omissions were associated with atrophy of the anterior temporal lobes. Semantic errors, for example, mistaking a rhinoceros for a hippopotamus, were associated with atrophy of the left mid and posterior fusiform cortex and the posterior middle and inferior temporal gyrus. Semantic errors and atrophy in these regions occurred in each PPA subtype, without major between-subtype differences. We propose that pathological changes to neural mechanisms associated with semantic errors occur across the PPA spectrum., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We evaluated the genetic contribution of the T cell-restricted intracellular antigen-1 gene (TIA1) in a European cohort of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) patients. Exonic resequencing of TIA1 in 1120 patients (693 FTD, 341 ALS, 86 FTD-ALS) and 1039 controls identified in total 5 rare heterozygous missense variants, affecting the TIA1 low-complexity domain (LCD). Only 1 missense variant, p.Met290Thr, identified in a familial FTD patient with disease onset at 64 years, was absent from controls yet received a combined annotation-dependent depletion score of 11.42. By contrast, 3 of the 4 variants also detected in unaffected controls, p.Val294Glu, p.Gln318Arg, and p.Ala381Thr, had combined annotation-dependent depletion scores greater than 20. Our findings in a large European patient-control series indicate that variants in TIA1 are not a common cause of ALS and FTD. The observation of recurring TIA1 missense variants in unaffected individuals lead us to conclude that the exact genetic contribution of TIA1 to ALS and FTD pathogenesis remains to be further elucidated., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

We investigated the genetic role of sortilin (SORT1) in frontotemporal dementia (FTD). SORT1 is the neuronal receptor for granulin, encoded by the progranulin gene (GRN), a major causal gene for inherited FTD. In Belgian cohorts of 636 FTD patients and 1066 unaffected control individuals, we identified 5 patient-only nonsynonymous rare variants in SORT1. Rare variant burden analysis showed a significant increase in rare coding variants in patients compared to control individuals (p = 0.04), particularly in the β-propeller domain (p = 0.04), with 2 rare variants located in the predicted binding site for GRN (p = 0.001). We extended these observations by analyzing 3 independent patient/control cohorts sampled in Spain, Italy, and Portugal by partners of the European Early-Onset Dementia Consortium, together with 1155 FTD patients and 1161 control persons. An additional 7 patient-only nonsynonymous variants were observed in SORT1 in European patients. Meta-analysis of the rare nonsynonymous variants in the Belgian and European patient/control cohorts revealed a significant enrichment in FTD patients (p = 0.006), establishing SORT1 as a genetic risk factor for FTD., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Mutation screening and phenotypic profiling of 2 amyotrophic lateral sclerosis-(ALS) and frontotemporal dementia-(FTD) associated genes, CHCHD10 and TUBA4A, were performed in a Belgian cohort of 459 FTD, 28 FTD-ALS, and 429 ALS patients. In CHCHD10, we identified a novel nonsense mutation (p.Gln108*) in a patient with atypical clinical FTD and pathology-confirmed Parkinson's disease (1/459, 0.22%) leading to loss of transcript. We further observed 3 previously described missense variants (p.Pro34Ser, p.Pro80Leu, and p.Pro96Thr) that were also present in the matched control series. In TUBA4A, we detected a novel frameshift mutation (p.Arg64Glyfs*90) leading to a truncated protein in 1 FTD patient (1/459 of 0.22%) with family history of Parkinson's disease and cognitive impairment, and a novel missense mutation (p.Thr381Met) in 2 sibs with familial ALS and memory problems (1 index patient/429, 0.23%) in whom we previously identified a pathogenic Chromosome 9 open reading frame 72 repeat expansion mutation. The present study confirms the role of CHCHD10 and TUBA4A in the FTD-ALS spectrum, although genetic variations in these 2 genes are extremely rare in the Belgian population and often associated with symptomatology of related neurodegenerative diseases including Parkinson's disease and Alzheimer's disease., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Age-related microstructural differences have been detected using diffusion tensor imaging (DTI). Although DTI is sensitive to the effects of aging, it is not specific to any underlying biological mechanism, including demyelination. Combining multiexponential T2 relaxation (MET2) and multishell diffusion MRI (dMRI) techniques may elucidate such processes. Multishell dMRI and MET2 data were acquired from 59 healthy participants aged 17-70 years. Whole-brain and regional age-associated correlations of measures related to multiple dMRI models (DTI, diffusion kurtosis imaging [DKI], neurite orientation dispersion and density imaging [NODDI]) and myelin-sensitive MET2 metrics were assessed. DTI and NODDI revealed widespread increases in isotropic diffusivity with increasing age. In frontal white matter, fractional anisotropy linearly decreased with age, paralleled by increased "neurite" dispersion and no difference in myelin water fraction. DKI measures and neurite density correlated well with myelin water fraction and intracellular and extracellular water fraction. DTI estimates remain among the most sensitive markers for age-related alterations in white matter. NODDI, DKI, and MET2 indicate that the initial decrease in frontal fractional anisotropy may be due to increased axonal dispersion rather than demyelination., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Meta-analysis of existing genome-wide association studies on Alzheimer's disease (AD) showed subgenome-wide association of an intronic variant in the sequestosome 1 (SQSTM1) gene with AD. We performed targeted resequencing of SQSTM1 in Flanders-Belgian AD patients selected to be enriched for a genetic background (n = 435) and geographically matched nonaffected individuals (n = 872) to investigate the role of both common and rare SQSTM1 variants. Results were extended to the European early-onset dementia cohorts (926 early-onset Alzheimer's disease [EOAD] patients and 1476 nonaffected individuals). Of the 61 detected exonic variants in SQSTM1, the majority were rare (n = 57). Rare variant (minor allele frequency <0.01) burden analysis did not reveal an increased frequency of rare variants in EOAD patients in any of the separate study populations nor when meta-analyzing all cohorts. Common variants p.D292= and p.R312= showed nominal association with AD (odds ratiop.D292= = 1.11 [95% confidence interval = 1-1.22], p = 0.04), only when including the Flanders-Belgian cohort in the meta-analysis. We cannot exclude a role of SQSTM1 genetic variability in late-onset AD, but our data indicate that SQSTM1 does not play a major role in the etiology of EOAD., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Homozygous mutations in exon 2 of TREM2, a gene involved in Nasu-Hakola disease, can cause frontotemporal dementia (FTD). Moreover, a rare TREM2 exon 2 variant (p.R47H) was reported to increase the risk of Alzheimer's disease (AD) with an odds ratio as strong as that for APOEε4. We systematically screened the TREM2 coding region within a Belgian study on neurodegenerative brain diseases (1216 AD patients, 357 FTD patients, and 1094 controls). We observed an enrichment of rare variants across TREM2 in both AD and FTD patients compared to controls, most notably in the extracellular IgV-set domain (relative risk = 3.84 [95% confidence interval = 1.29-11.44]; p = 0.009 for AD; relative risk = 6.19 [95% confidence interval = 1.86-20.61]; p = 0.0007 for FTD). None of the rare variants individually reached significant association, but the frequency of p.R47H was increased ~ 3-fold in both AD and FTD patients compared to controls, in line with previous reports. Meta-analysis including 11 previously screened AD cohorts confirmed the association of p.R47H with AD (p = 2.93×10(-17)). Our data corroborate and extend previous findings to include an increased frequency of rare heterozygous TREM2 variations in AD and FTD, and show that TREM2 variants may play a role in neurodegenerative diseases in general., (Copyright © 2014 Elsevier Inc. All rights reserved.)

We previously described an intragenic functional copy number variation (CNV) in complement receptor 1 (CR1) that is associated with Alzheimer disease (AD) risk. A recent study, however, reported a rare CR1 coding variant p.Ser1610Thr (rs4844609) associated with AD susceptibility, explaining the effect of genome wide association (GWA) top single nucleotide polymorphism rs6656401. We assessed the role of the Ser1610Thr variant in AD pathogenesis and the effect on AD-related endophenotypes in a Flanders-Belgian cohort. We evaluated whether this rare variant rather than the CR1 CNV could explain the association of CR1 in our population. The Ser1610Thr variant was not associated with AD, memory impairment, total tau, amyloid β(1-42) or tau phosphorylated at threonine 181 levels. It did not explain (part of) the association of genome wide association top single-nucleotide polymorphisms rs3818361/rs6656401, nor of the CR1 CNV, with AD in our cohort, whereas the CR1 CNV and rs3818361/rs6656401 represented the same association signal. These findings question a role for the Ser1610Thr variant in AD risk and related endophenotypes, and reaffirm our previous observation that the CR1 CNV could be the true functional risk factor explaining the association between CR1 and AD., (Copyright © 2013 Elsevier Inc. All rights reserved.)

C9orf72 G4C2 repeat expansion is a major cause of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Its role in Alzheimer's disease (AD) is less clear. We assessed the prevalence of G4C2 pathogenic repeat expansions in Flanders-Belgian patients with clinical AD or mild cognitive impairment (MCI). In addition, we studied the effect of non-pathogenic G4C2 repeat length variability on susceptibility to AD, and on AD cerebrospinal fluid (CSF) biomarker levels. A pathogenic repeat expansion was identified in 5 of 1217 AD patients (frequency <1%). No pathogenic expansions were observed in patients with MCI (n = 200) or control individuals (n = 1119). Nonpathogenic repeat length variability was not associated with AD, risk of conversion to AD in MCI individuals, or CSF biomarker levels. We conclude that pathogenic C9orf72 G4C2 repeat expansions can be detected in clinical AD patients and could act as a contributor to AD pathogenesis. Non-pathogenic repeat length variability did not affect risk of AD or MCI, nor AD biomarker levels in CSF, indicating that C9orf72 is not a direct AD risk factor., (Copyright © 2013 Elsevier Inc. All rights reserved.)

UBQLN2 and PFN1 were recently associated with amyotrophic lateral sclerosis (ALS). We investigated a role for these ALS genes in frontotemporal lobar degeneration (FTLD). We screened 328 FTLD, 17 FTLD-ALS, and 157 ALS patients. Patients originated from Flanders-Belgium except for 26 Bulgarian ALS patients. The frequency of UBQLN2 and PFN1 genetic variants in the FTLD patients was low at 0.30% and 0.91% respectively. Moreover, the biological relevance to disease of the variants was questionable. In UBQLN2, we identified p.S346C outside of the PXX domain in 1 FTLD patient. Yet, a closely located serine substitution, p.S340I, was observed in a neurologically healthy control individual. In PFN1, we observed the previously reported p.E117G mutation in 3 FTLD patients and in 3 control individuals. In the ALS patient cohort, we detected UBQLN2 variants in 1.27% of patients. These involved 2 novel UBQLN2 missense mutations, p.S400G and p.P440L, that were also present in unaffected relatives (i.e., the p.S400G carrier's son [70 years] and daughter [65 years]) and the p.P440L carrier's mother (67 years). No mutations were observed in PFN1. In summary, we conclude that genetic variations in UBQLN2 and PFN1 in a predominantly Flanders-Belgian cohort of FTLD and ALS patients are extremely rare., (Copyright © 2013 Elsevier Inc. All rights reserved.)