Showing papers by "Rik Vandenberghe published in 2013"

CSF biomarker variability in the Alzheimer's Association quality control program

Abstract: Background The cerebrospinal fluid (CSF) biomarkers amyloid beta 1–42, total tau, and phosphorylated tau are used increasingly for Alzheimer's disease (AD) research and patient management. However, there are large variations in biomarker measurements among and within laboratories. Methods Data from the first nine rounds of the Alzheimer's Association quality control program was used to define the extent and sources of analytical variability. In each round, three CSF samples prepared at the Clinical Neurochemistry Laboratory (Molndal, Sweden) were analyzed by single-analyte enzyme-linked immunosorbent assay (ELISA), a multiplexing xMAP assay, or an immunoassay with electrochemoluminescence detection. Results A total of 84 laboratories participated. Coefficients of variation (CVs) between laboratories were around 20% to 30%; within-run CVs, less than 5% to 10%; and longitudinal within-laboratory CVs, 5% to 19%. Interestingly, longitudinal within-laboratory CV differed between biomarkers at individual laboratories, suggesting that a component of it was assay dependent. Variability between kit lots and between laboratories both had a major influence on amyloid beta 1–42 measurements, but for total tau and phosphorylated tau, between-kit lot effects were much less than between-laboratory effects. Despite the measurement variability, the between-laboratory consistency in classification of samples (using prehoc-derived cutoffs for AD) was high (>90% in 15 of 18 samples for ELISA and in 12 of 18 samples for xMAP). Conclusions The overall variability remains too high to allow assignment of universal biomarker cutoff values for a specific intended use. Each laboratory must ensure longitudinal stability in its measurements and use internally qualified cutoff levels. Further standardization of laboratory procedures and improvement of kit performance will likely increase the usefulness of CSF AD biomarkers for researchers and clinicians.

Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology.

Abstract: Genome-wide association studies (GWAS) have identified a region upstream the BIN1 gene as the most important genetic susceptibility locus in Alzheimer’s disease (AD) after APOE. We report that BIN1 transcript levels were increased in AD brains and identified a novel 3 bp insertion allele ~28 kb upstream of BIN1, which increased (i) transcriptional activity in vitro, (ii) BIN1 expression levels in human brain and (iii) AD risk in three independent case-control cohorts (Meta-analysed Odds ratio of 1.20 (1.14–1.26) (P=3.8 × 10−11)). Interestingly, decreased expression of the Drosophila BIN1 ortholog Amph suppressed Tau-mediated neurotoxicity in three different assays. Accordingly, Tau and BIN1 colocalized and interacted in human neuroblastoma cells and in mouse brain. Finally, the 3 bp insertion was associated with Tau but not Amyloid loads in AD brains. We propose that BIN1 mediates AD risk by modulating Tau pathology.

A Pan‐European Study of the C9orf72 Repeat Associated with FTLD: Geographic Prevalence, Genomic Instability, and Intermediate Repeats

Abstract: We assessed the geographical distribution of C9orf72 G(4) C(2) expansions in a pan-European frontotemporal lobar degeneration (FTLD) cohort (n = 1,205), ascertained by the European Early-Onset Dementia (EOD) consortium. Next, we performed a meta-analysis of our data and that of other European studies, together 2,668 patients from 15 Western European countries. The frequency of the C9orf72 expansions in Western Europe was 9.98% in overall FTLD, with 18.52% in familial, and 6.26% in sporadic FTLD patients. Outliers were Finland and Sweden with overall frequencies of respectively 29.33% and 20.73%, but also Spain with 25.49%. In contrast, prevalence in Germany was limited to 4.82%. In addition, we studied the role of intermediate repeats (7-24 repeat units), which are strongly correlated with the risk haplotype, on disease and C9orf72 expression. In vitro reporter gene expression studies demonstrated significantly decreased transcriptional activity of C9orf72 with increasing number of normal repeat units, indicating that intermediate repeats might act as predisposing alleles and in favor of the loss-of-function disease mechanism. Further, we observed a significantly increased frequency of short indels in the GC-rich low complexity sequence adjacent to the G(4) C(2) repeat in C9orf72 expansion carriers (P < 0.001) with the most common indel creating one long contiguous imperfect G(4) C(2) repeat, which is likely more prone to replication slippage and pathological expansion.

A European multicentre PET study of fibrillar amyloid in Alzheimer's disease

Abstract: Purpose Amyloid PET tracers have been developed for in vivo detection of brain fibrillar amyloid deposition in Alzheimer’s disease (AD). To serve as an early biomarker in AD the amyloid PET tracers need to be analysed in multicentre clinical studies.

Reduced expression of hsa-miR-27a-3p in CSF of patients with Alzheimer disease

Abstract: Objective: We evaluated microRNAs (miRNAs) as potential biomarkers for Alzheimer disease (AD) by analyzing the expression level of miRNAs in CSF of patients with AD dementia and nonaffected control subjects. Methods: Using quantitative PCR, we profiled the expression level of 728 miRNAs in CSF of nonaffected control subjects and patients with clinically ascertained AD dementia, and we further compared the expression level of candidate miRNAs in 37 control subjects and 35 patients with AD dementia. Results: The level of hsa-miR-27a-3p in CSF is reduced in patients with dementia due to AD in 2 different cohorts of subjects (cohort 1: p = 0.008; cohort 2: p = 0.015; 2-tailed unpaired Welch t test). Moreover, low levels of hsa-miR-27a-3p were accompanied by high CSF tau levels and low CSF β-amyloid levels. Conclusions: Our pilot study highlights hsa-miR-27a-3p as a candidate biomarker for AD and provides the groundwork for further confirmation studies in larger cohorts and in other hospitals.

Similarity of fMRI activity patterns in left perirhinal cortex reflects semantic similarity between words

Abstract: How verbal and nonverbal visuoperceptual input connects to semantic knowledge is a core question in visual and cognitive neuroscience, with significant clinical ramifications. In an event-related functional magnetic resonance imaging (fMRI) experiment we determined how cosine similarity between fMRI response patterns to concrete words and pictures reflects semantic clustering and semantic distances between the represented entities within a single category. Semantic clustering and semantic distances between 24 animate entities were derived from a concept-feature matrix based on feature generation by >1000 subjects. In the main fMRI study, 19 human subjects performed a property verification task with written words and pictures and a low-level control task. The univariate contrast between the semantic and the control task yielded extensive bilateral occipitotemporal activation from posterior cingulate to anteromedial temporal cortex. Entities belonging to a same semantic cluster elicited more similar fMRI activity patterns in left occipitotemporal cortex. When words and pictures were analyzed separately, the effect reached significance only for words. The semantic similarity effect for words was localized to left perirhinal cortex. According to a representational similarity analysis of left perirhinal responses, semantic distances between entities correlated inversely with cosine similarities between fMRI response patterns to written words. An independent replication study in 16 novel subjects confirmed these novel findings. Semantic similarity is reflected by similarity of functional topography at a fine-grained level in left perirhinal cortex. The word specificity excludes perceptually driven confounds as an explanation and is likely to be task dependent.

Distinct Clinical Characteristics of C9orf72 Expansion Carriers Compared With GRN, MAPT, and Nonmutation Carriers in a Flanders-Belgian FTLD Cohort

Abstract: OBJECTIVE To characterize patients with frontotemporal lobar degeneration (FTLD) with a repeat expansion mutation in the gene C9orf72, and to determine whether there are differences in the clinical presentation compared with FTLD carriers of a mutation in GRN or MAPT or with patients with FTLD without mutation. DESIGN Patient series. SETTING Dementia clinics in Flanders, Belgium. PATIENTS Two hundred seventy-five genetically and phenotypically thoroughly characterized patients with FTLD. MAIN OUTCOME MEASURES Clinical and demographic characteristics of 26 C9orf72 expansion carriers compared with patients with a GRN or MAPT mutation, as well as patients with familial and sporadic FTLD without mutation. RESULTS C9orf72 expansion carriers developed FTLD at an early age (average, 55.3 years; range, 42-69 years), significantly earlier than in GRN mutation carriers or patients with FTLD without mutation. Mean survival (6.2 years; range, 1.5-17.0 years) was similar to other patient groups. Most developed behavioral variant frontotemporal dementia (85%), with disinhibited behavior as the prominent feature. Concomitant amyotrophic lateral sclerosis is a strong distinguishing feature for C9orf72 -associated FTLD. However, in most patients (73%), amyotrophic lateral sclerosis symptoms were absent. Compared with C9orf72 expansion carriers, nonfluent aphasia and limb apraxia were significantly more common in GRN mutation carriers. CONCLUSIONS C9orf72 -associated FTLD most often presents with early-onset behavioral variant frontotemporal dementia with disinhibition as the prominent feature, with or without amyotrophic lateral sclerosis. Based on the observed genotype-phenotype correlations between the different FTLD syndromes and different genetic causes, we propose a decision tree to guide clinical genetic testing in patients clinically diagnosed as having FTLD.

Amyloid positron emission tomography with 18F-flutemetamol and structural magnetic resonance imaging in the classification of mild cognitive impairment and Alzheimer’s disease

Abstract: Objective To evaluate the contributions of amyloid-positive (Am+) and medial temporal atrophy–positive (MTA+) scans to the diagnostic classification of prodromal and probable Alzheimer's disease (AD). Methods 18 F-flutemetamol-labeled amyloid positron emission tomography (PET) and magnetic resonance imaging (MRI) were used to classify 10 young normal, 15 elderly normal, 20 amnestic mild cognitive impairment (aMCI), and 27 AD subjects. MTA+ status was determined using a cut point derived from a previous study, and Am+ status was determined using a conservative and liberal cut point. Results The rates of MRI scans with positive results among young normal, elderly normal, aMCI, and AD subjects were 0%, 20%, 75%, and 82%, respectively. Using conservative cut points, the rates of Am+ scans for these same groups of subjects were 0%, 7%, 50%, and 93%, respectively, with the aMCI group showing the largest discrepancy between Am+ and MTA+ scans. Among aMCI cases, 80% of Am+ subjects were also MTA+, and 70% of amyloid-negative (Am−) subjects were MTA+. The combination of amyloid PET and MTA data was additive, with an overall correct classification rate for aMCI of 86%, when a liberal cut point (standard uptake value ratio=1.4) was used for amyloid positivity. Interpretation 18 F-flutemetamol PET and structural MRI provided additive information in the diagnostic classification of aMCI subjects, suggesting an amyloid-independent neurodegenerative component among aMCI subjects in this sample.

APP Processing in Human Pluripotent Stem Cell-Derived Neurons Is Resistant to NSAID-Based γ-Secretase Modulation

Abstract: Increasing evidence suggests that elevated Aβ42 fractions in the brain cause Alzheimer’s disease (AD). Although γ-secretase modulators (GSMs), including a set of nonsteroidal anti-inflammatory drugs (NSAIDs), were found to lower Aβ42 in various model systems, NSAID-based GSMs proved to be surprisingly inefficient in human clinical trials. Reasoning that the nonhuman and nonneuronal cells typically used in pharmaceutical compound validation might not adequately reflect the drug responses of human neurons, we used human pluripotent stem cell-derived neurons from AD patients and unaffected donors to explore the efficacy of NSAID-based γ-secretase modulation. We found that pharmaceutically relevant concentrations of these GSMs that are clearly efficacious in conventional nonneuronal cell models fail to elicit any effect on Aβ42/As40 ratios in human neurons. Our work reveals resistance of human neurons to NSAID-based γ-secretase modulation, highlighting the need to validate compound efficacy directly in the human cell type affected by the respective disease.

BACE1 levels correlate with phospho-tau levels in human cerebrospinal fluid.

Abstract: Previous studies have investigated the activity and protein levels of BACE1, the β-secretase, in the brain and cerebrospinal fluid (CSF) of Alzheimer’s disease (AD) patients, however, results remain contradictory. We present here a highly specific and sensitive BACE1 ELISA, which allows measuring accurately BACE1 levels in human samples. We find that BACE1 levels in CSF of AD patients and other neurological disorder (OND) patients are slightly increased when compared to those of a non-neurological disorder control group (NND). BACE1 levels in CSF were well correlated with total-tau and hyperphosphorylated tau levels in the CSF, suggesting that the recorded alterations in BACE1 levels correlate with cell death and neurodegeneration.

Glucose metabolism in nine patients with probable sporadic Creutzfeldt–Jakob disease: FDG-PET study using SPM and individual patient analysis

Abstract: Only one large series using statistical parametric mapping (SPM) reports on FDG-PET in sporadic (Heidenhain and non-Heidenhain variant) Creutzfeldt-Jakob disease (sCJD), describing hypometabolism in bilateral parietal, frontal, and occipital cortices. Our aim was to study FDG-PET in non-Heidenhain probable sCJD patients in order to assess the most pertinent FDG-PET pattern, and to compare FDG-PET and MRI data. We used both SPM and NeuroGam(®) software analysis, compared with healthy controls, to describe the FDG-PET abnormalities. Individual FDG-PET and MRI-DWI data were compared. SPM group analysis showed lateralized hypometabolism in the medial parietal cortex, the lateral and medial frontal (sparing Brodmann's area 4 and 6 and the anterior cingulate cortex), and lateral parietal cortex, in the absence of basal ganglia or cerebellar hypometabolism. The most severe hypometabolism was seen in Brodmann's area 31, and to a lesser degree area 23 (both areas correspond to the posterior cingulate cortex) and the precuneus. On individual analysis using NeuroGam(®) software, additional variable temporal cortex and frequent basal ganglia (with caudate nucleus as the most frequently involved structure) hypometabolism was seen, in the absence of cerebellar hypometabolism. The cerebral lobe cortex was more frequently and more severely hypometabolic than basal ganglia structures. Concordance between FDG-PET and MRI abnormalities was most often present for both the cerebral lobe cortex and the basal ganglia. In the case of discordance, FDG-PET was more sensitive than MRI for the cortex, whereas MRI was more sensitive than FDG-PET for the basal ganglia. When pathological, both cortical lobe cortex and basal ganglia involvement were slightly more often lateralized on FDG-PET than on MRI. Despite the presence of overlapping features with other diseases presenting with rapidly progressive dementia, the FDG-PET pattern we found in our non-Heidenhain sCJD patients may help in the differential diagnosis of rapidly progressive dementia.

The interest of amyloid PET imaging in the diagnosis of Alzheimer's disease.

Abstract: Purpose of reviewThis review evaluates the potential clinical utility of amyloid imaging.Recent findingsAmyloid PET is a valid in-vivo marker of neuritic plaque load and correlates with amyloid plaque surface area. Abundant diffuse plaques, however, with scant neuritic plaques can also give rise to

Dissociations between spatial-attentional processes within parietal cortex: insights from hybrid spatial cueing and change detection paradigms.

Abstract: Spatial cueing has been used by many different groups under multiple forms to study spatial attention processes. We will present evidence obtained in brain-damaged patients and healthy volunteers using a variant of this paradigm, the hybrid spatial cueing paradigm, which, besides single-target trials with valid and invalid cues, also contains trials where a target is accompanied by a contralateral competing stimulus (competition trials). This allows one to study invalidity-related processes and selection between competing stimuli within the same paradigm. In brain-damaged patients, lesions confined to the intraparietal sulcus result in contralesional attentional deficits, both during competition and invalid trials, according to a pattern that does not differ from that observed following inferior parietal lesions. In healthy volunteers, however, selection between competing stimuli and invalidity-related processes are partially dissociable, the former relying mainly on cytoarchitectonic areas hIP1-3 in the intraparietal sulcus, the latter on cytoarchitectonic area PF in the right inferior parietal lobule. The activity profile in more posterior inferior parietal areas PFm and PGa, does not distinguish between both types of trials. The functional account for right PF and adjacent areas is further constrained by the activity profile observed during other experimental paradigms. In a change detection task with variable target and distracter set size, for example, these inferior parietal areas show highest activity when the stimulus array consists of only one single target, while the intraparietal sulcus show increased activity as the array contains more targets and distracters. Together, these findings lead us to the hypothesis that right PF functions as a target singleton detector, which is activated when a target stands out from the background, referring both to the temporal background (expectancy) and the momentaneous background (stimulus-driven saliency).

Spatial Stimulus Configuration and Attentional Selection: Extrastriate and Superior Parietal Interactions

Abstract: The intraparietal sulcus (IPS) is critical for resolving stimulus competition. Its activity is modulated depending on how competing stimuli are spatially configured. Lesions extending into IPS lead to selection deficits when stimuli are configured along a horizontal relative to a vertical or diagonal axis. Using functional magnetic resonance imaging, we examined whether the effect of configuration axis originates at the level of the sensory map in early visual cortex or at the level of the attentional priority map in IPS. In each trial, we presented 1 or 2 peripheral gratings in the upper right visual field and a central letter stream. Subjects performed either a peripheral orientation discrimination task or a central letter detection task. Left IPS activity was higher when peripheral stimuli were configured along the horizontal relative to the vertical axis, but only in peripheral attention conditions. The portions of extrastriate cortex that responded to the peripheral stimuli showed a similar interaction. Connectivity from superior parietal to extrastriate cortex was enhanced by adding a competing distracter during the peripheral attention task. The effect of the spatial configuration between competing stimuli originates at the level of the attentional priority map in IPS rather than the visual sensory map.