[Show abstract][Hide abstract] ABSTRACT: Biobanks are important resources for biomarker discovery and assay development. Biomarkers for Alzheimer's and Parkinson's disease (BIOMARKAPD) is a European multicenter study, funded by the EU Joint Programme-Neurodegenerative Disease Research, which aims to improve the clinical use of body fluid markers for the diagnosis and prognosis of Alzheimer's disease (AD) and Parkinson's disease (PD). The objective was to standardize the assessment of existing assays and to validate novel fluid biomarkers for AD and PD. To support the validation of novel biomarkers and assays, a central and a virtual biobank for body fluids and associated data from subjects with neurodegenerative diseases have been established. In the central biobank, cerebrospinal fluid (CSF) and blood samples were collected according to the BIOMARKAPD standardized pre-analytical procedures and stored at Integrated BioBank of Luxembourg. The virtual biobank provides an overview of available CSF, plasma, serum, and DNA samples at each site. Currently, at the central biobank of BIOMARKAPD samples are available from over 400 subjects with normal cognition, mild cognitive impairment (MCI), AD, frontotemporal dementia (FTD), vascular dementia, multiple system atrophy, progressive supranuclear palsy, PD, PD with dementia, and dementia with Lewy bodies. The virtual biobank contains information on over 8,600 subjects with varying diagnoses from 21 local biobanks. A website has been launched to enable sample requests from the central biobank and virtual biobank.
Full-text · Article · Oct 2015 · Frontiers in Neurology
[Show abstract][Hide abstract] ABSTRACT: Prospective memory (PM) is a fundamental requirement for independent living which might be prematurely compromised in the neurodegenerative process, namely in mild cognitive impairment (MCI), a typical prodromal Alzheimer's disease (AD) phase. Most encoding manipulations that typically enhance learning in healthy adults are of minimal benefit to AD patients. However, there is some indication that these can display a recall advantage when encoding is accompanied by the physical enactment of the material. The aim of this study was to explore the potential benefits of enactment at encoding and cue-action relatedness on memory for intentions in MCI patients and healthy controls using a behavioral PM experimental paradigm.
We report findings examining the influence of enactment at encoding for PM performance in MCI patients and age- and education-matched controls using a laboratory-based PM task with a factorial independent design.
PM performance was consistently superior when physical enactment was used at encoding and when target-action pairs were strongly associated. Importantly, these beneficial effects were cumulative and observable across both a healthy and a cognitively impaired lifespan as well as evident in the perceived subjective difficulty in performing the task.
The identified beneficial effects of enacted encoding and semantic relatedness have unveiled the potential contribution of this encoding technique to optimize attentional demands through an adaptive allocation of strategic resources. We discuss our findings with respect to their potential impact on developing strategies to improve PM in AD sufferers.
Full-text · Article · Oct 2015 · Journal of Clinical and Experimental Neuropsychology
[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: Introduction:
Lumbar puncture (LP) is increasingly performed in memory clinics. We investigated patient-acceptance of LP, incidence of and risk factors for post-LP complications in memory clinic populations.
We prospectively enrolled 3868 patients (50% women, age 66 ± 11 years, mini mental state examination 25 ± 5) at 23 memory clinics. We used logistic regression analysis using generalized estimated equations to investigate risk factors for post-LP complications, such as typical postlumbar puncture headache (PLPH) and back pain.
A total of 1065 patients (31%) reported post-LP complaints; 589 patients (17%) reported back pain, 649 (19%) headache, of which 296 (9%) reported typical PLPH. Only few patients needed medical intervention: 11 (0.3%) received a blood patch, 23 (0.7%) were hospitalized. The most important risk factor for PLPH was medical history of headache. An atraumatic needle and age >65 years were preventive. Gender, rest after LP, or volume of cerebrospinal fluid had no effect.
The overall risk of complications is relatively low. If risk factors shown in this study are taken into account, LPs can be safely performed in memory clinics.
No preview · Article · Sep 2015 · Alzheimer's & dementia: the journal of the Alzheimer's Association
[Show abstract][Hide abstract] ABSTRACT: Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies.
To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI).
Relevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators.
Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity.
Individual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies.
Prevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations.
The prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-ε4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and 95 years for ε2ε3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality.
Among persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia.
Full-text · Article · May 2015 · JAMA The Journal of the American Medical Association
[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: Our objective was to test whether data mining techniques, through an unsupervised learning approach, support the three-group diagnostic model of primary progressive aphasia (PPA) versus the existence of two main/classic groups. A series of 155 PPA patients observed in a clinical setting and subjected to at least one neuropsychological/language assessment was studied. Several demographic, clinical and neuropsychological attributes, grouped in distinct sets, were introduced in unsupervised learning methods (Expectation Maximization, K-Means, X-Means, Hierarchical Clustering and Consensus Clustering). Results demonstrated that unsupervised learning methods revealed two main groups consistently obtained throughout all the analyses (with different algorithms and different set of attributes). One group included most of the agrammatic/non-fluent and some logopenic cases while the other was mainly composed of semantic and logopenic cases. Clustering the patients in a larger number of groups (k > 2) revealed some clusters composed mostly of non-fluent or of semantic cases. However, we could not evidence any group chiefly composed of logopenic cases. In conclusion, unsupervised data mining approaches do not support a clear distinction of logopenic PPA as a separate variant.
[Show abstract][Hide abstract] ABSTRACT: We investigated the use of Alzheimer's disease (AD) biomarkers in European Alzheimer's Disease Consortium centers and assessed their perceived usefulness for the etiologic diagnosis of mild cognitive impairment (MCI). We surveyed availability, frequency of use, and confidence in diagnostic usefulness of markers of brain amyloidosis (amyloid positron emission tomography [PET], cerebrospinal fluid [CSF] Aβ42) and neurodegeneration (medial temporal atrophy [MTA] on MR, fluorodeoxyglucose positron emission tomography [FDG-PET], CSF tau). The most frequently used biomarker is visually rated MTA (75% of the 37 responders reported using it “always/frequently”) followed by CSF markers (22%), FDG-PET (16%), and amyloid-PET (3%). Only 45% of responders perceive MTA as contributing to diagnostic confidence, where the contribution was rated as “moderate”. Seventy-nine percent of responders felt “very/extremely” comfortable delivering a diagnosis of MCI due to AD when both amyloid and neuronal injury biomarkers were abnormal (P < .02 versus any individual biomarker). Responders largely agreed that a combination of amyloidosis and neuronal injury biomarkers was a strongly indicative AD signature.
Full-text · Article · Aug 2014 · Alzheimer's and Dementia
[Show abstract][Hide abstract] ABSTRACT: Mutations in the gene coding for Sequestosome 1 (SQSTM1) have been genetically associated with amyotrophic lateral sclerosis (ALS) and Paget disease of bone. In the present study, we analyzed the SQSTM1 coding sequence for mutations in an extended cohort of 1,808 patients with frontotemporal lobar degeneration (FTLD), ascertained within the European Early-Onset Dementia consortium. As control dataset, we sequenced 1,625 European control individuals and analyzed whole-exome sequence data of 2,274 German individuals (total n = 3,899). Association of rare SQSTM1 mutations was calculated in a meta-analysis of 4,332 FTLD and 10,240 control alleles. We identified 25 coding variants in FTLD patients of which 10 have not been described. Fifteen mutations were absent in the control individuals (carrier frequency <0.00026) whilst the others were rare in both patients and control individuals. When pooling all variants with a minor allele frequency <0.01, an overall frequency of 3.2 % was calculated in patients. Rare variant association analysis between patients and controls showed no difference over the whole protein, but suggested that rare mutations clustering in the UBA domain of SQSTM1 may influence disease susceptibility by doubling the risk for FTLD (RR = 2.18 [95 % CI 1.24–3.85]; corrected p value = 0.042). Detailed histopathology demonstrated that mutations in SQSTM1 associate with widespread neuronal and glial phospho-TDP-43 pathology. With this study, we provide further evidence for a putative role of rare mutations in SQSTM1 in the genetic etiology of FTLD and showed that, comparable to other FTLD/ALS genes, SQSTM1 mutations are associated with TDP-43 pathology.
Electronic supplementary material
The online version of this article (doi:10.1007/s00401-014-1298-7) contains supplementary material, which is available to authorized users.
Full-text · Article · Jun 2014 · Acta Neuropathologica