[Show abstract][Hide abstract] ABSTRACT: The Tubulin Alpha 4a (TUBA4A) gene has been recently associated with amyotrophic lateral sclerosis. Interestingly, some of the mutation carriers were also diagnosed with frontotemporal degeneration (FTD) or mild cognitive impairment. With the aim to investigate the role of TUBA4A in FTD, we screened TUBA4A in a series of 814 FTD patients from Spain. Our data did not disclose any nonsense or missense variant in the cohort, thus suggesting that TUBA4A mutations are not associated with FTD.
Neurobiology of Aging 11/2015; DOI:10.1016/j.neurobiolaging.2015.10.030 · 5.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The MAPT H1 haplotype has been linked to several disorders, but its relationship with Alzheimer's disease (AD) remains controversial. A rare variant in MAPT (p.A152T) has been linked with frontotemporal dementia (FTD) and AD. We genotyped H1/H2 and p.A152T MAPT in 11,572 subjects from Spain (4,327 AD, 563 FTD, 648 Parkinson's disease (PD), 84 progressive supranuclear palsy (PSP), and 5,950 healthy controls). Additionally, we included 101 individuals from 21 families with genetic FTD. MAPT p.A152T was borderline significantly associated with FTD [odds ratio (OR) = 2.03; p = 0.063], but not with AD. MAPT H1 haplotype was associated with AD risk (OR = 1.12; p = 0.0005). Stratification analysis showed that this association was mainly driven by APOE ɛ4 noncarriers (OR = 1.14; p = 0.0025). MAPT H1 was also associated with risk for PD (OR = 1.30; p = 0.0003) and PSP (OR = 3.18; p = 8.59 × 10-8) but not FTD. Our results suggest that the MAPT H1 haplotype increases the risk of PD, PSP, and non-APOE ɛ4 AD.
[Show abstract][Hide abstract] ABSTRACT: Identifying the mutated gene that produces a particular muscle dystrophy is difficult because different genotypes may share a phenotype and vice versa. Muscle MRI is a useful tool to recognize patterns of muscle involvement in patients with muscle dystrophies and to guide the diagnosis process. The radiologic pattern of muscle involvement in patients with mutations in the EMD and LMNA genes has not been completely established. Our objective is to describe the pattern of muscle fatty infiltration in patients with mutations in the EMD and in the LMNA genes and to search for differences between the two genotypes that could be helpful to guide the genetic tests. We conducted a national multicenter study in 42 patients, 10 with mutations in the EMD gene and 32 with mutations in the LMNA gene. MRI or CT was used to study the muscles from trunk to legs. Patients had a similar pattern of fatty infiltration regardless of whether they had the mutation in the EMD or LMNA gene. The main muscles involved were the paravertebral, glutei, quadriceps, biceps, semitendinosus, semimembranosus, adductor major, soleus, and gastrocnemius. Involvement of peroneus muscle, which was more frequently affected in patients with mutations in the EMD gene, was useful to differentiate between the two genotypes. Muscle MRI/CT identifies a similar pattern of muscle fatty infiltration in patients with mutations in the EMD or the LMNA genes. The involvement of peroneus muscles could be useful to conduct genetic analysis in patients with an EDMD phenotype.
[Show abstract][Hide abstract] ABSTRACT: Rare variants in the phospholipase D3 gene (PLD3) were associated with increased risk for late-onset Alzheimer disease (LOAD). We identified a missense mutation in PLD3 in whole genome sequence data of a patient with autopsy confirmed AD and onset age 50 years. Subsequently, we sequenced PLD3 in a Belgian EOAD patient (N = 261) and control (N = 319) cohort, as well as in European EOAD patients (N = 946) and control individuals (N = 1209) ascertained in different European countries. Overall, we identified 22 rare variants with a minor allele frequency <1%, 20 missense and 2 splicing mutations. Burden analysis did not provide significant evidence for an enrichment of rare PLD3 variants in EOAD patients in any of the patient/control cohorts. Also, meta-analysis of the PLD3 data, including a published dataset of a German EOAD cohort, was not significant (p = 0.43; OR = 1.53, 95% CI 0.60 - 3.31). Consequently, our data do not support a role for PLD3 rare variants in the genetic etiology of EOAD in European EOAD patients. Our data corroborate the negative replication data obtained in LOAD studies and therefore a genetic role of PLD3 in AD remains to be demonstrated. This article is protected by copyright. All rights reserved.
Human Mutation 09/2015; DOI:10.1002/humu.22908 · 5.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
The APOE effect on Alzheimer Disease (AD) risk is stronger in women than in men but its mechanisms have not been established. We assessed the APOE-by-sex interaction on core CSF biomarkers, brain metabolism and structure in healthy elderly control individuals (HC).
Cross-sectional study. HC from the Alzheimer's Disease Neuroimaging Initiative with available CSF (n = 274) and/or 3T-MRI (n = 168) and/or a FDG-PET analyses (n = 328) were selected. CSF amyloid-β1-42 (Aβ1-42), total-tau (t-tau) and phospho-tau (p-tau181p) levels were measured by Luminex assays. We analyzed the APOE-by-sex interaction on the CSF biomarkers in an analysis of covariance (ANCOVA). FDG uptake was analyzed by SPM8 and cortical thickness (CTh) was measured by FreeSurfer. FDG and CTh difference maps were derived from interaction and group analyses.
APOE4 carriers had lower CSF Aβ1-42 and higher CSF p-tau181p values than non-carriers, but there was no APOE-by-sex interaction on CSF biomarkers. The APOE-by-sex interaction on brain metabolism and brain structure was significant. Sex stratification showed that female APOE4 carriers presented widespread brain hypometabolism and cortical thinning compared to female non-carriers whereas male APOE4 carriers showed only a small cluster of hypometabolism and regions of cortical thickening compared to male non-carriers.
The impact of APOE4 on brain metabolism and structure is modified by sex. Female APOE4 carriers show greater hypometabolism and atrophy than male carriers. This APOE-by-sex interaction should be considered in clinical trials in preclinical AD where APOE4 status is a selection criterion.
[Show abstract][Hide abstract] ABSTRACT: Meta-analysis of existing genome-wide association studies on Alzheimer’s Disease (AD) showed sub-genome wide association of an intronic variant in the Sequestosome 1 gene (SQSTM1) 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 non-affected individuals (n=872) to investigate the role of both common and rare SQSTM1 variants. Results were extended to the European Early-Onset Dementia (EU EOD) cohorts (926 EOAD patients and 1,476 non-affected individuals).
Of the 61 detected exonic variants in SQSTM1, the majority was rare (n=57). Rare variant (MAF<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 (ORp.D292==1.11[95%C.I.1-1.22];p-value 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.
Neurobiology of aging 05/2015; 36(5). DOI:10.1016/j.neurobiolaging.2015.02.014 · 5.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction:
Essential tremor (ET) is the most frequent movement disorder in adults. Its pathophysi-
ology is not clearly understood, however there is growing evidence showing common etiologic factors
with other neurodegenerative disorders such as Alzheimer's and Parkinson's diseases (AD, PD). Recently,
a rare p.R47H substitution (rs75932628) in the TREM2 protein (triggering receptor expressed on myeloid
cells 2; OMIM: *605086) has been proposed as a risk factor for AD, PD and amyotrophic lateral sclerosis
(ALS). The objective of the study was to determine whether TREM2 p.R47H allele is also a risk factor for
Parkinsonism & Related Disorders 03/2015; DOI:10.1016/j.parkreldis.2014.12.010 · 3.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Atraumatic convexal subarachnoid hemorrhage (cSAH) in elderly patients is a rare entity that has been associated with cerebral amyloid angiopathy (CAA) and intracerebral hematomas (ICH). To characterize this entity and to study these associations, 22 patients over 60 with cSAH were included in a multicenter ambispective cohort study. Clinical data, magnetic resonance imaging (MRI) studies, APOE genotyping, and cerebrospinal fluid (CSF) biomarkers were evaluated. Results were compared with data from healthy controls (HC), non-cSAH CAA patients (CAAo), and Alzheimer disease patients. Convexal subarachnoid hemorrhage presented with transient sensory or motor symptoms. At follow-up (median 30.7 months), 5 patients had died, 6 survivors showed functional disability (modified Rankins Scale (mRS)>2), and 12 cognitive impairment. Four patients had prior ICH and six had an ICH during follow-up. CSF-Aß40 and Aß42 levels were lower in cSAH and CAAo compared with HC. Convexal subarachnoid hemorrhage presented an APOE-ɛ2 overrepresentation and CAAo had an APOE-ɛ4 overrepresentation. On MRI, all patients fulfilled CAA-modified Boston criteria and 9 showed cortical ischemia in the surrounding cortex or the vicinity of superficial siderosis. The neuropathologic study, available in one patient, showed severe CAA and advanced Alzheimer-type pathology. Convexal subarachnoid hemorrhage in the elderly is associated with cognitive impairment and lobar ICH occurrence. Our findings support the existence of an underlying CAA pathology.Journal of Cerebral Blood Flow & Metabolism advance online publication, 4 March 2015; doi:10.1038/jcbfm.2015.25.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND:
Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis.
The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain.
ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 × 10-12 after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 × 10-11), cholesterol transport (P = 2.96 × 10-9), and proteasome-ubiquitin activity (P = 1.34 × 10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05).
The immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.
Alzheimer's and Dementia 12/2014; 11(6). DOI:10.1016/j.jalz.2014.05.1757 · 12.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous disorder. Rare TREM2 variants have been recently identified in families affected by FTD-like phenotype. However, genetic studies of the role of rare TREM2 variants in FTD have generated conflicting results possibly because of difficulties on diagnostic accuracy. The aim of the present study was to investigate associations between rare TREM2 variants and specific FTD subtypes (FTD-S). The entire coding sequence of TREM2 was sequenced in FTD-S patients of Spanish (n = 539) and German (n = 63) origin. Genetic association was calculated using Fisher exact test. The minor allele frequency for controls was derived from in-house genotyping data and publicly available databases. Seven previously reported rare coding variants (p.A28V, p.W44X, p.R47H, p.R62H, p.T66M, p.T96K, and p.L211P) and 1 novel missense variant (p.A105T) were identified. The p.R47H variant was found in 4 patients with FTD-S. Two of these patients showed cerebrospinal fluid pattern of amyloid beta, tau, and phosphorylated-tau suggesting underlying Alzheimer's disease (AD) pathology. No association was found between p.R47H and FTD-S. A genetic association was found between p.T96K and FTD-S (p = 0.013, odds ratio = 4.23, 95% Confidence Interval [1.17-14.77]). All 6 p.T96K patients also carried the TREM2 variant p.L211P, suggesting linkage disequilibrium. The remaining TREM2 variants were found in 1 patient, respectively, and were absent in controls. The present findings provide evidence that p.T96K is associated with FTD-S and that p.L211P may contribute to its pathogenic effect. The data also suggest that p.R47H is associated with an FTD phenotype that is characterized by the presence of underlying AD pathology.
Neurobiology of Aging 12/2014; 35(11). DOI:10.1016/j.neurobiolaging.2014.06.018. · 5.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose
Benign epilepsy with centrotemporal spikes (BECTS) is considered to be the most common childhood epileptic syndrome. Different mutations in genes that control the excitability of neurons have been described. Recent reports on the involvement of the BDNF and ELP4 genes in cell motility, migration, and adhesion raise the possibility that these genes are involved in pathogenesis of BECTS.
Materials and methods
we conducted a case-control association study on 60 patients with BECTS and 60 control participants to assess the influence of the BDNF and ELP4 polymorphisms on BECTS. The polymorphisms were detected with a PCR-RFLP method. Moreover, we explored the possible association of these polymorphisms with clinical and electroencephalographic parameters of patients with BECTS.
Our results show no difference in BDNF and ELP4 genotype frequencies between patients and controls. Haplotype analysis also revealed no statistical difference.
the role of BDNF and ELP4 polymorphisms remains controversial.
Epilepsy Research 09/2014; DOI:10.1016/j.eplepsyres.2014.09.005 · 2.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this study we found that patients with C9orf72 repeat expansion showed cerebellar and posterior brain hypometabolism as compared to bvFTD non-carriers. Our results suggest that impairment in cerebellar and parietal glucose metabolism may be a feature of some cases with the C9orf72 repeat expansion. Importantly, the two carriers of the C9orf72 repeat expansion were in the early stages of bvFTD and the symptoms were mild at the time of brain scanning. This suggests that changes in glucose metabolism may be an early feature that may precede dementia.
Although the structural imaging patterns associated to the C9orf72 expansion have been widely described, functional imaging studies are limited. To date, Boeve et al.3 reported the 18F-FDG PET findings in 5 patients carrying the C9orf72 expansion. Four of them showed predominantly anterior cingulate hypometabolism, while the other had parietal hypometabolism, with sparing of frontal cortical regions. Savica et al.4 described a family carrying the C9orf72 expansion, and 18F-FDG PET showed mild hypometabolism in frontotemporal regions, but normal in parietal cortices. Recently, Devenney et al.9 reported 6 patients with bvFTD carrying the C9orf72 expansion. Most had a typical frontal and temporal hypometabolism, but two also showed parietal hypometabolism and one had cerebellar hypometabolism. Additionally, Cistaro et al.6 found that ALS cases with the C9orf72 expansion had cerebellar hypermetabolism compared to healthy controls but not compared to sporadic ALS cases. Hypometabolism in posterior brain regions has also been described in SLE patients with neuropsychiatric symptoms.10 Therefore, we cannot completely exclude that SLE contributed to some of the findings in brain metabolism observed in case 2.
MRI findings in the two C9orf72 expansion carriers presented herein are in agreement with previous studies,3–5 showing a pattern of parietal and cerebellar atrophy that differentiate them from sporadic bvFTD patients or from those carrying a MAPT or GRN mutation.5 The presence of cerebellar atrophy on MRI or hypometabolism in 18F-FDG PET (described herein) is an intriguing finding since cerebellar symptoms are not usually present in C9orf72 mutation carriers. Only one patient with cerebellar symptoms has been reported in the literature in a family with genetic linkage within the chromosome 9p region.11 None of our two cases had either cerebellar symptoms or signs on neurological examination.
Interestingly, the neuropathology of patients carrying the C9orf72 expansion typically includes cerebellar atrophy with ubiquitinated p62-positive TDP-43 negative inclusions.12 Whether these pathological findings have any relationship with 18F-FDG PET hypometabolism reported here remains to be established.
The imaging findings reported herein were found in two patients from a highly selected population and they need to be confirmed in larger series of patients with bvFTD with the C9orf72 expansion. Whether cerebellar hypometabolism is present in most subjects with bvFTD and C9orf72 or only in a subset of them also needs to be determined. If confirmed, the presence of cerebellar abnormalities in 18F-FDG PET in a patient with bvFTD might be a sign of suspicion of a C9orf72 expansion.