[Show abstract][Hide abstract] ABSTRACT: Background:
Progranulin is implicated in frontotemporal dementia (FTD), but its role in other neurodegenerative disorders is unknown.
To investigate the levels of progranulin (PGRN) in cerebrospinal fluid (CSF) in different neurodegenerative dementias and their correlation with levels in plasma in cognitively normal subjects.
We measured PGRN in CSF in 229 patients with amnestic mild cognitive impairment, Alzheimer's disease dementia, sporadic FTD, dementia with Lewy bodies, corticobasal syndrome, or progressive supranuclear palsy. We also measured PGRN in CSF and plasma in 74 cognitively normal individuals. We examined the correlation between PGRN levels in CSF and diagnosis, cortical thickness, genetic factors and other CSF biomarkers. We also investigated the correlation between plasma and CSF levels of PGRN in cognitively normal individuals.
CSF levels did not differ across diagnoses or correlate with cortical thickness. Polymorphism rs5848 in GRN influenced CSF PGRN levels, but APOEɛ4 allele did not. Amyloid-β42, t-tau, p-tau, and YKL-40 levels correlated weakly with PGRN in CSF. We found a weak correlation (r = 0.362) between plasma and CSF PGRN levels in cognitively normal individuals.
Our findings do not support a diagnostic value of CSF PGRN in neurodegenerative diseases. Our data confirm that levels of PGRN in plasma do not reflect accurately levels in CSF in cognitively normal controls. These data should be considered in clinical trials aiming to increase PGRN.
Full-text · Article · Dec 2015 · Journal of Alzheimer's disease: JAD
[Show abstract][Hide abstract] ABSTRACT: We report a biomarker and genetic evaluation of four patients with cerebral amyloid angiopathy-related inflammation (CAA-ri) treated with corticosteroids. Patients presented with focal symptomatology and cognitive impairment. MRI revealed cortical microbleeds and asymmetrical hyperintense white matter lesions (WML). Cerebrospinal fluid (CSF) biomarker analyses showed increased anti-Aβ autoantibodies, t-Tau, and p-Tau and decreased Aβ 40 and Aβ 42. After treatment, focal symptomatology disappeared, and WML and anti-Aβ autoantibodies decreased. The APOEɛ4 allele was overrepresented. Florbetapir-PET showed cortical deposition with lower retention in swollen areas. In the case of suspected CAA-ri, both CSF anti-Aβ autoantibodies levels and Florbetapir-PET could provide highly useful data to guide the correct diagnosis, potentially avoiding brain biopsy.
Full-text · Article · Dec 2015 · Journal of Alzheimer's disease: JAD
[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.
Full-text · Article · Nov 2015 · Neurobiology of Aging
[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.
Full-text · Article · Oct 2015 · Journal of Alzheimer's disease: JAD
[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.
No preview · Article · Oct 2015 · Neuromuscular Disorders
[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.
[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.
Full-text · Article · May 2015 · Neurobiology of aging
[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
Full-text · Article · Mar 2015 · Parkinsonism & Related Disorders
[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.
No preview · Article · Mar 2015 · Journal of Cerebral Blood Flow & Metabolism
[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.
Full-text · Article · Dec 2014 · Alzheimer's and Dementia