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Achtergrond Vanwege de hemodynamische veranderingen die optreden tijdens elektroconvulsietherapie (ECT), bestaat er een theoretisch verhoogd risico op een recidief van cerebrovasculair accident (CVA). Doel De wetenschappelijke evidentie aangaande het risico op een recidief-CVA bij een behandeling met ECT in kaart brengen. Methode Voor dit systematisch literatuuroverzicht werden de PRISMA-richtlijnen toegepast in PubMed en in de Cochrane Library. Artikelen waarin ECT werd beschreven bij patiënten met een voorgeschiedenis van CVA werden geïncludeerd aan de hand van specifieke zoektermen. Resultaten We vonden 19 artikelen: 1 grote en 1 kleine prospectieve studie, 3 kleine retrospectieve studies en 14 gevalsbeschrijvingen. In de grote longitudinale Deense studie was er globaal genomen geen verhoogde prevalentie van recidief- CVA bij de patiënten die behandeld werden met ECT. In de overige artikelen werd er ook geen verhoogd risico op CVA gerapporteerd. Conclusie Ondanks het beperkte aantal prospectieve studies en de methodologische beperkingen kunnen we voorzichtig besluiten dat een behandeling met ECT niet gepaard gaat met verhoogd risico op een recidief-CVA. ECT kan op een veilige wijze toegepast worden bij patiënten met een voorgeschiedenis van CVA, mits men zorgdraagt voor een grondige voorafgaande neurologische en cardiovasculaire diagnostiek en monitoring tijdens de behandeling.

Background Safinamide is a recent multimodal antiparkinsonian drug that inhibits monoamine oxidase B and modulates the glutamatergic system with positive effects on motor and nonmotor symptoms of Parkinson’s disease (PD). This post-hoc analysis of the European SYNAPSES study provides first-time data on the use of safinamide in routine clinical practice in Belgium. Objective To describe the efficacy and safety of safinamide in Belgian PD patients in real-life conditions. Methods Post-hoc analysis of the Belgian cohort from the European SYNAPSES trial, which was an observational, multicenter, retrospective-prospective cohort study. Patients were followed up to 12 months. Analyses were performed in the overall population and according to different criteria such as the age limit (> 75 years), presence or absence of relevant comorbidities, presence or absence of psychiatric conditions such as depression and anxiety, patients on levodopa monotherapy or levodopa in combination with other treatments, patients on rasagiline before inclusion or not. Results Of the 172 patients included, 29.2% were > 75 years, 58.9% had relevant comorbidities and 32.7% had psychiatric conditions. Almost all the patients reported motor (98.8%) or non-motor (86.3%) symptoms. During the study, 36.3% of patients reported drug-related reactions. The adverse drug reactions were those already described in the patients’ information leaflet. The majority were mild or moderate and completely resolved and no differences were detected between the subgroups of patients. Almost 35% of the patients demonstrated a clinically significant improvement in the UPDRS and 50% of the patients with wearing-off at baseline, did not report wearing-off anymore after one year of treatment. Patients under levodopa monotherapy compared to patients receiving levodopa combined with other antiparkinsonian treatments benefit more from safinamide treatment. Patients switched from rasagiline to safinamide seemed also to benefit more from safinamide treatment. Conclusion The study confirms the excellent safety and efficacy profile of safinamide, particularly in more vulnerable groups of patients such as the elderly and patients with significant comorbidities or psychiatric conditions such as depression or anxiety.

ImportanceGiven the rapidly rising dementia incidence, management of modifiable risk factors, such as hearing loss, is vital. Multiple studies have demonstrated an improvement of cognitive functioning in older adults with severe hearing loss after cochlear implantation; however, few of these studies, to the authors’ knowledge, specifically analyzed participants achieving poor cognitive results preoperatively.ObjectiveTo evaluate the cognitive functioning of older adults with severe hearing loss at risk for mild cognitive impairment (MCI) before and after cochlear implantation.Design, Setting, and ParticipantsThis prospective, longitudinal cohort study performed at a single center reports data obtained over a 6-year period (April 2015 to September 2021) of an ongoing prospective, longitudinal cohort study on cochlear implant outcomes in older adults. A consecutive sample of older adults with severe hearing loss eligible for cochlear implantation was included. All participants obtained a Repeatable Battery for the Assessment of Neuropsychological Status for hearing-impaired patients (RBANS-H) total score indicative of MCI preoperatively. Participants were assessed before cochlear implant activation and 12 months after cochlear implant activation.InterventionThe intervention consisted of cochlear implantation.Main Outcome and MeasureThe primary outcome measure was cognition, measured by the RBANS-H.ResultsA total of 21 older adult cochlear implant candidates were included in the analysis (mean [SD] age, 72 [9] years; 13 [62%] men). Cochlear implantation was associated with an improvement of overall cognitive functioning 12 months after activation (median [IQR] percentile, 5 [2-8] vs 12 [7-19]; difference, 7 [95% CI, 2-12]). Eight participants (38%) surpassed the MCI cutoff (16th percentile) postoperatively, while the overall median cognitive score remained under this cutoff. In addition, participants’ speech recognition in noise improved, with a lower score indicating improvement (mean [SD] score, +17.16 [5.45] vs +5.67 [6.3]; difference, −11.49 [95% CI, −14.26 to −8.72]), after cochlear implant activation. Improvement of speech recognition in noise was positively associated with improvement in cognitive functioning (rs, −0.48 [95% CI, −0.69 to −0.19]). Years of education, sex, RBANS-H version, and symptoms of depression and anxiety were not related to the evolution in RBANS-H scores.Conclusions and RelevanceIn this prospective, longitudinal cohort study, cognitive functioning and speech perception in noise showed a clinically meaningful improvement 12 months after cochlear implant activation in older adults with severe hearing loss at risk for MCI, suggesting that cochlear implantation is not contraindicated in cochlear implant candidates with cognitive decline and should be considered after multidisciplinary evaluation.

Background and objectives: Neuromyelitis optica (NMO) is a CNS inflammatory disease that predominantly affects the optic nerves and the spinal cord. It is more frequent in Asian and African populations than in European ones. Data on epidemiology, clinical presentation, additional investigations, and treatment in the African continent are scarce. We aim to (1) collect and analyze published data on neuromyelitis optica spectrum disorder (NMOSD), (2) indicate challenges in the diagnosis and management, and (3) discuss opportunities for future research, education, and policy making, specifically on the African continent. Methods: A systematic review was performed in January 2021 with the search terms "Neuromyelitis optica and Africa," "Devic Disease and Africa," and "NMOSD and Africa." We included all study types except case reports, correspondence, or conference abstracts on NMO or NMOSD. Extracted data included study design, country, study period, demographic and clinical characteristics, results of paraclinical investigations, and outcome. Data analysis was performed with descriptive statistics. Results: We retrieved a total of 79 records, of which 19 were included. Ten of 54 African countries reported a total of 410 cases. Almost half of them were from North African countries. The mean age at diagnosis was 33 years (range 7-88 years), and 75% were female. Transverse myelitis followed by optic neuritis were the most frequent symptoms at the time of presentation. One hundred nineteen patients experienced at least 1 previous relapse, and 106 had a relapsing course after diagnosis. Relapses were treated with IV methylprednisolone. Azathioprine and steroids were used most often as maintenance treatments. Outcomes were rarely described. Discussion: The majority of studies on NMOSD from the African continent are retrospective, and most countries do not report any data. Our systemic review shows that data derived from patients living in Africa correspond well to what has been previously published in meta-analyses on patients of African ancestry with NMOSD who live outside of Africa, except for a younger age at onset and a lower proportion of females. We advocate for systematic data collection to adequately capture and monitor the burden of NMOSD, for expansion of research efforts and facilities to perform fundamental and clinical research, and for improved access to health care including diagnostics, treatments, and rehabilitation services for people affected by NMOSD in the African continent.

Importance: Given the rising prevalence of patients with dementia and those at risk for it, early identification is prioritized. As vestibular dysfunction is associated with Alzheimer's disease (AD) and may contribute to its onset, vestibular assessment may yield an opportunity in early dementia screening. Objective: This systematic review structures and compares the different raw outcome measures used to assess vestibular function while comparing older adults with preserved cognition to individuals with cognitive impairment, either suffering from mild cognitive impairment (MCI) or AD. Design: Two investigators independently and systematically searched publications performing objectively measured vestibular testing in a patient population consisting of either MCI or AD, compared with a control group of older adults with preserved cognition. No limitations regarding language or publication date were applied. References of the retrieved articles were hand searched for relevant articles. Results: Seven articles were included for analysis. A total of 235 older adults with impaired cognition (150 AD, 85 MCI) were compared with a control group of 481 older adults with preserved cognition. Evaluation of the peripheral vestibular function included video head impulse test (vHIT), videonystagmography (VNG), electronystagmography (ENG) including bithermal caloric irrigation and vestibular evoked myogenic potentials (VEMP). The VEMP test, assessing otolith function and the elicited vestibulocollic reflex (VCR), was able to differentiate subjects with AD and its prodromal stage from healthy controls, with p13 latency (p < 0.05) and amplitude (p < 0.05) having the most discriminating power. No correlation between cognitive decline and vestibulo-ocular reflex measurements in different frequency ranges of the semicircular canals (using vHIT, rotatory chair testing, and caloric irrigation) was found. Because of the limited number of available studies and the large heterogeneity in outcome measures, these results have to be interpreted with caution. Conclusions: Measurements of the VCR, as evoked by the VEMP test, discriminate between patients with cognitive impairment (MCI and AD) and older adults with preserved cognition, whereas measurements of the vestibulo-ocular reflex do not. More studies are needed to further elaborate on these findings.

Parkinson’s disease (PD) is a progressive neurodegenerative brain disease presenting with a variety of motor and non-motor symptoms, loss of midbrain dopaminergic neurons in the substantia nigra pars compacta and the occurrence of α-synuclein-positive Lewy bodies in surviving neurons. Here, we performed whole exome sequencing in 52 early-onset PD patients and identified 3 carriers of compound heterozygous mutations in the ATP10B P4-type ATPase gene. Genetic screening of a Belgian PD and dementia with Lewy bodies (DLB) cohort identified 4 additional compound heterozygous mutation carriers (6/617 PD patients, 0.97%; 1/226 DLB patients, 0.44%). We established that ATP10B encodes a late endo-lysosomal lipid flippase that translocates the lipids glucosylceramide (GluCer) and phosphatidylcholine (PC) towards the cytosolic membrane leaflet. The PD associated ATP10B mutants are catalytically inactive and fail to provide cellular protection against the environmental PD risk factors rotenone and manganese. In isolated cortical neurons, loss of ATP10B leads to general lysosomal dysfunction and cell death. Impaired lysosomal functionality and integrity is well known to be implicated in PD pathology and linked to multiple causal PD genes and genetic risk factors. Our results indicate that recessive loss of function mutations in ATP10B increase risk for PD by disturbed lysosomal export of GluCer and PC. Both ATP10B and glucocerebrosidase 1, encoded by the PD risk gene GBA1, reduce lysosomal GluCer levels, emerging lysosomal GluCer accumulation as a potential PD driver. Electronic supplementary material The online version of this article (10.1007/s00401-020-02145-7) contains supplementary material, which is available to authorized users.

PURPOSE: Home-time (the number of days spent at home during the first 3 months after stroke) shows a strong association with the modified Rankin scale (mRS). We studied whether Home-time was also a determinant of quality-of-life and medical care costs after ischemic stroke, and assessed factors delaying discharge home. MATERIALS AND METHODS: Five hundred and sixty nine patients participated in a retrospective study when returning for an in-person visit after an ischemic stroke. Home-time, mRS, EQ-5D-3L, inpatient and outpatient resource utilization, use of mobility aids, changes to home and car, comorbidities were recorded. RESULTS: Each additional Home-time day was significantly associated with an increase in utility of 0.0056 (p

Emerging evidence suggested a converging mechanism in neurodegenerative brain diseases (NBD) involving early neuronal network dysfunctions and alterations in the homeostasis of neuronal firing as culprits of neurodegeneration. In this study, we used paired-end short-read and direct long-read whole genome sequencing to investigate an unresolved autosomal dominant dementia family significantly linked to 7q36. We identified and validated a chromosomal inversion of ca. 4 Mb, segregating on the disease haplotype and disrupting the coding sequence of dipeptidyl-peptidase 6 gene (DPP6). DPP6 resequencing identified significantly more rare variants—nonsense, frameshift, and missense—in early-onset Alzheimer’s disease (EOAD, p value = 0.03, OR = 2.21 95% CI 1.05–4.82) and frontotemporal dementia (FTD, p = 0.006, OR = 2.59, 95% CI 1.28–5.49) patient cohorts. DPP6 is a type II transmembrane protein with a highly structured extracellular domain and is mainly expressed in brain, where it binds to the potassium channel Kv4.2 enhancing its expression, regulating its gating properties and controlling the dendritic excitability of hippocampal neurons. Using in vitro modeling, we showed that the missense variants found in patients destabilize DPP6 and reduce its membrane expression (p

This position document has been developed by the Dysphagia Working Group, a committee of members from the European Society for Swallowing Disorders and the European Union Geriatric Medicine Society, and invited experts. It consists of 12 sections that cover all aspects of clinical management of oropharyngeal dysphagia (OD) related to geriatric medicine and discusses prevalence, quality of life, and legal and ethical issues, as well as health economics and social burden. OD constitutes impaired or uncomfortable transit of food or liquids from the oral cavity to the esophagus, and it is included in the World Health Organization's classification of diseases. It can cause severe complications such as malnutrition, dehydration, respiratory infections, aspiration pneumonia, and increased readmissions, institutionalization, and morbimortality. OD is a prevalent and serious problem among all phenotypes of older patients as oropharyngeal swallow response is impaired in older people and can cause aspiration. Despite its prevalence and severity, OD is still underdiagnosed and untreated in many medical centers. There are several validated clinical and instrumental methods (videofluoroscopy and fiberoptic endoscopic evaluation of swallowing) to diagnose OD, and treatment is mainly based on compensatory measures, although new treatments to stimulate the oropharyngeal swallow response are under research. OD matches the definition of a geriatric syndrome as it is highly prevalent among older people, is caused by multiple factors, is associated with several comorbidities and poor prognosis, and needs a multidimensional approach to be treated. OD should be given more importance and attention and thus be included in all standard screening protocols, treated, and regularly monitored to prevent its main complications. More research is needed to develop and standardize new treatments and management protocols for older patients with OD, which is a challenging mission for our societies.

Mutations leading to premature termination codons in ATP-Binding Cassette Subfamily A Member 7 (ABCA7) are high penetrant risk factors of Alzheimer’s disease (AD). The influence of other genetic variants in ABCA7 and downstream functional mechanisms, however, is poorly understood. To address this knowledge gap, we investigated tandem repetitive regions in ABCA7 in a Belgian cohort of 1529 AD patients and control individuals and identified an intronic variable number tandem repeat (VNTR). We observed strong association between VNTR length and a genome-wide associated signal for AD in the ABCA7 locus. Expanded VNTR alleles were highly enriched in AD patients [odds ratio = 4.5 (1.3–24.2)], and VNTR length inversely correlated with amyloid β1–42 in cerebrospinal fluid and ABCA7 expression. In addition, we identified three novel ABCA7 alternative splicing events. One isoform in particular—which is formed through exon 19 skipping—lacks the first nucleotide binding domain of ABCA7 and is abundant in brain tissue. We observed a tight correlation between exon 19 skipping and VNTR length. Our findings underline the importance of studying repetitive DNA in complex disorders and expand the contribution of genetic and transcript variation in ABCA7 to AD. Electronic supplementary material The online version of this article (10.1007/s00401-018-1841-z) contains supplementary material, which is available to authorized users.

© 2015 The Authors. ∗∗ Human Mutation published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes., 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 Alzheimer disease (AD) and onset age of 50 years. Subsequently, we sequenced PLD3 in a Belgian early-onset Alzheimer disease (EOAD) patient (N = 261) and control (N = 319) cohort, as well as in European EOAD patients (N = 946) and control individuals (N = 1,209) ascertained in different European countries. Overall, we identified 22 rare variants with a minor allele frequency, MetLife Foundation for Medical Research Award (USA); the U.S. Army Medical Research and Material Command (USAMRMC) Research Award; the Janssen Pharmaceutical Stellar Research Project; the Belgian Science Policy Office Interuniversity Attraction Poles program; the Alzheimer Research Foundation (SAO-FRA); the Flemish Government initiated Flanders Impulse Program on Networks for Dementia Research (VIND); the Flemish Government initiated Methusalem Excellence Program; the Research Foundation Flanders (FWO); the University of Antwerp Research Fund; ISCIII, Cofinancia Fondo Europeo de Desarrollo Regional (FEDER), Unión Europea, Otra manera de hacer Europa (PI11/00234); Instituto de Salud Carlos III (PI12/01311); Grant Agency of Ministry of Health and Charles University Project PRVOUK P26/1/4 (IGA NT12094-5); the Fundação para a Ciência e a Tecnologia (SFRH/BPD/29354/2006); the Ricerca Corrente, Italian Ministry of Health; the Cassa di Risparmio di Pistoia e Pescia (2014.0365); the Cassa di Risparmio di Firenze (2014.0310); Ministry of Health (RF-2010-2319722); Swedish Brain Power, Swedish Research Council (521-2010-3134, A031340); the King Gustaf V and Queen Victoria's Foundation of Freemasons; the Foundations of Marianne and Marcus Wallenberg, Knut and Alice Wallenberg, Gun and Bertil Stohne, Gamla tjänarinnor, Demensfonden Swedish Alzheimer Foundation (462081); StratNeuro at Karolinska Institute (KI).

Real-time quaking-induced conversion (RT-QuIC) has been proposed as a sensitive diagnostic test for sporadic Creutzfeldt-Jakob disease; however, before this assay can be introduced into clinical practice, its reliability and reproducibility need to be demonstrated. Two international ring trials were undertaken in which a set of 25 cerebrospinal fluid samples were analyzed by a total of 11 different centers using a range of recombinant prion protein substrates and instrumentation. The results show almost complete concordance between the centers and demonstrate that RT-QuIC is a suitably reliable and robust technique for clinical practice. Ann Neurol 2016;80:160-165. peerReviewed

Purpose: Detection of, and alarming for epileptic seizures is increasingly demanded and researched. Our previous review article provided an overview of non-invasive, non-EEG (electro-encephalography) body signals that can be measured, along with corresponding methods, state of the art research, and commercially available systems. Three years later, many more studies and devices have emerged. Moreover, the boom of smart phones and tablets created a new market for seizure detection applications. Method: We performed a thorough literature review and had contact with manufacturers of commercially available devices. Results: This review article gives an updated overview of body signals and methods for seizure detection, international research and (commercially) available systems and applications. Reported results of non EEG based detection devices vary between 2.2% and 100% sensitivity and between 0 and 3.23 false detections per hour compared to the gold standard video-EEG, for seizures ranging from generalized to convulsive or non-convulsive focal seizures with or without loss of consciousness. It is particularly interesting to include monitoring of autonomic dysfunction, as this may be an important pathophysiological mechanism of SUDEP (sudden unexpected death in epilepsy), and of movement, as many seizures have a motor component. Conclusion: Comparison of research results is difficult as studies focus on different seizure types, timing (night versus day) and patients (adult versus pediatric patients). Nevertheless, we are convinced that the most effective seizure detection systems are multimodal, combining for example detection methods for movement and heart rate, and that devices should especially take into account the user's seizure types and personal preferences. (C) 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

achtergrondPsychogene bewegingsstoornissen zijn bewegingsstoornissen die het gevolg zijn van een psychiatrische eerder dan een primaire neurologische aandoening. Sommige auteurs verkiezen de term functionele bewegingsstoornis. doelBeschrijven van de classificatie, kliniek, diagnosestelling en behandeling van psychogene bewegingsstoornissen. methodeBespreken van recente, geselecteerde literatuur. resultatenEr is een grote onvervulde therapeutische nood bij deze patiënten met invaliderende symptomen die leiden tot langdurige arbeidsongeschiktheid. Vaak wordt bij patiënten een conversiestoornis gediagnosticeerd. Er zijn aanwijzingen dat stress de motoriek kan beïnvloeden door een invloed op centra die zorgen voor planning en actiemonitoring. Deze patiënten hebben een gestructureerde en multidisciplinaire behandeling nodig met neurologische en psychiatrische follow-up. Cognitieve gedragstherapie en laagfrequente transcraniële magnetische stimulatie hebben een beperkt effect. conclusiePsychogene bewegingsstoornissen hebben kenmerken gemeenschappelijk met conversiestoornissen. Er zijn aanwijzingen dat cognitieve gedragstherapie gunstige effecten heeft, maar de prognose blijft zorgelijk.

BACKGROUND: Background The leucine-rich repeat kinase 2 gene (LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinson's disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility. METHODS: LRRK2 was genotyped in patients with PD and controls from three series (white, Asian, and Arab-Berber) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Genotyping was done for exonic variants of LRRK2 that were identified through searches of literature and the personal communications of consortium members. Associations with PD were assessed by use of logistic regression models. For variants that had a minor allele frequency of 0.5% or greater, single variant associations were assessed, whereas for rarer variants information was collapsed across variants. FINDINGS: 121 exonic LRRK2 variants were assessed in 15 540 individuals: 6995 white patients with PD and 5595 controls, 1376 Asian patients and 962 controls, and 240 Arab-Berber patients and 372 controls. After exclusion of carriers of known pathogenic mutations, new independent risk associations were identified for polymorphic variants in white individuals (M1646T, odds ratio 1.43, 95% CI 1.15-1.78; p=0.0012) and Asian individuals (A419V, 2.27, 1.35-3.83; p=0.0011). A protective haplotype (N551K-R1398H-K1423K) was noted at a frequency greater than 5% in the white and Asian series, with a similar finding in the Arab-Berber series (combined odds ratio 0.82, 0.72-0.94; p=0.0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1.73, 1.20-2.49; p=0.0026), but no association was noted for R1628P (0.62, 0.36-1.07; p=0.087). In the Arab-Berber series, Y2189C showed potential evidence of risk association with PD (4.48, 1.33-15.09; p=0.012). INTERPRETATION: The results for LRRK2 show that several rare and common genetic variants in the same gene can have independent effects on disease risk. LRRK2, and the pathway in which it functions, is important in the cause and pathogenesis of PD in a greater proportion of patients with this disease than previously believed. These results will help discriminate those patients who will benefit most from therapies targeted at LRRK2 pathogenic activity. FUNDING: Michael J Fox Foundation and National Institutes of Health. Lancet Neurol

Objectives: The objective of this study is to clarify the role of (G 4 C 2 ) n expansions in the etiology of Parkinson disease (PD) in the worldwide multicenter Genetic Epidemiology of Parkinson9s Disease (GEO-PD) cohort. Methods: C9orf72 (G 4 C 2 ) n repeats were assessed in a GEO-PD cohort of 7,494 patients diagnosed with PD and 5,886 neurologically healthy control individuals ascertained in Europe, Asia, North America, and Australia. Results: A pathogenic (G 4 C 2 ) n>60 expansion was detected in only 4 patients with PD (4/7,232; 0.055%), all with a positive family history of neurodegenerative dementia, amyotrophic lateral sclerosis, or atypical parkinsonism, while no carriers were detected with typical sporadic or familial PD. Meta-analysis revealed a small increase in risk of PD with an increasing number of (G 4 C 2 ) n repeats; however, we could not detect a robust association between the C9orf72 (G 4 C 2 ) n repeat and PD, and the population attributable risk was low. Conclusions: Together, these findings indicate that expansions in C9orf72 do not have a major role in the pathogenesis of PD. Testing for C9orf72 repeat expansions should only be considered in patients with PD who have overt symptoms of frontotemporal lobar degeneration/amyotrophic lateral sclerosis or apparent family history of neurodegenerative dementia or motor neuron disease.

De ziektegeschiedenis van een 33-jarige man met een juveniel ischemisch cerebrovasculair accident (CVA) wordt beschreven. De patiënt meldde zich aan met acute hoofdpijn, amnesie en dysgrafie. Cerebrale beeldvorming met een MRI toonde op de diffusiegewogen beelden een hyperintense infarctzone in de pariëtale cortex rechts ter hoogte van de gyrus postcentralis en een kleiner ischemisch letsel ter hoogte van de subinsulaire cortex. Een uitgebreide etiologische oppuntstelling bracht geen duidelijke oorzaak aan het licht, er was dus sprake van een zogenaamd cryptogeen ischemisch CVA. Wegens de stijgende prevalentie van cardiovasculaire risicofactoren bij jongvolwassenen is de nadruk op secundaire preventie bij jonge patiënten met een CVA een belangrijk aandachtspunt. Voor patiënten met een cryptogeen CVA bij wie er een patent foramen ovale (PFO) wordt aangetroffen, zijn er nieuwe richtlijnen in de maak. Enkele recent gepubliceerde studies besloten dat er geen voordeel was van het systematisch sluiten van het PFO in vergelijking met een medicamenteuze behandeling onder de vorm van anti-aggregantia en/of anticoagulantia. Met uitzondering van individuele gevallen waarbij er belangrijke argumenten zijn voor een paradoxaal embool, lijkt, gezien de hoge prevalentie van een PFO en de lage incidentie van een recidief CVA, het routinematig sluiten van PFOs bij juveniele cryptogene CVAs niet aangewezen. In de toekomst zullen deze beslissingen genomen worden op basis van modellen die het individuele recidiefrisico kunnen voorspellen.

Objective The aim of the current study is to investigate structural changes on brain MRI using voxel based morphometry (VBM) related to an eight-week mindfulness based intervention (MBI) in Parkinson's Disease (PD). Methods A total of 27 out of 30 PD patients completed a randomized controlled longitudinal trial. Fourteen patients participated in a structured eight-week program of MBI. Thirteen patients received usual care (UC) alone. MRI data sets of the brain were obtained at baseline and after eight weeks follow-up. VBM analysis was performed using DARTEL from the SPM8 software. The resulting difference maps were statistically compared to examine gray matter density (GMD) differences. Results were reported at p < 0.001, uncorrected for multiple comparisons. Results Increased GMD was found in the MBI compared to the UC group in the region of interest (ROI) analysis in the right amygdala, and bilaterally in the hippocampus. Whole brain analysis showed increased GMD in the left and right caudate nucleus, the left occipital lobe at the lingual gyrus and cuneus, the left thalamus, and bilaterally in the temporo-parietal junction. In contrast, GMD differences were found in the UC group in the left anterior lobe and dentate nucleus of the cerebellum. Conclusions To the best of our knowledge this is the first quantitative analysis of neurobiological effects of MBI in PD. Increased GMD was found in the MBI group in the neural networks that have been postulated to play an important role in PD. These areas have also been implicated in the functional networks mediating the benefits of meditation.

In dit artikel wordt aan de hand van 2 casus geïllustreerd dat donderslaghoofdpijn (‘thunderclap headache’) in zeldzame gevallen kan optreden als prominentste symptoom bij een acute ischemische beroerte. Deze casus worden vergeleken met eerder verschenen artikelen. De valkuilen bij diagnostiek van donderslaghoofdpijn en de noodzaak tot aanvullende onderzoeken na uitsluiting van een subarachnoïdale bloeding worden in dit artikel benadrukt.

Background: Autosomal dominant dopa-responsive dystonia (AD-DRD) is caused by a biochemical defect primarily resulting from guanosine triphosphate cyclohydrolase 1 gene (GCH1) mutations. Few families have been reported without mutations in GCH1. Methods: Genome-wide linkage analysis and positional cloning to identify the genetic defect in a Belgian AD-DRD family was carried out. Results and Conclusion: In this study, we report on the identification and characterization of a novel 24-kb deletion spanning exon 1 and the 5′ regulatory region of GCH1 causing a wide spectrum of motor and nonmotor symptoms in a large Belgian AD-DRD family. This large-scale deletion of regulatory sequences leads to decreased GCH1 activity in all carriers, most probably resulting from allelic loss of transcription. We mapped the breakpoints of this deletion to the nucleotide level, allowing the development of a straightforward polymerase chain reaction assay for fast, efficient detection of this large deletion, which will prove valuable for preimplantation genetic diagnosis.

Parkinsons disease is known to present and mostly persist as an asymmetrical movement disorder in most cases. The asymmetry is mainly described in motor features such as bradykinesia, rigidity and tremor in upper and lower limbs. Unilateral hypomimia however, has only been reported in 14 patients, all of whom showed right-sided hemihypomimia. In this case report we describe the symptoms of a 51-year-old man with predominant left-sided Parkinsons disease in whom we discovered a left-sided hemihypomimia. We also briefly review the literature concerning hemihypomimia in Parkinsons disease. We conclude that a larger case series needs to be studied to further elucidate the pathophysiology and clinical implications of this observation.

We present the case of an elderly woman chronically treated with valproate as migraine prophylaxis. She developed acute chorea secondary to valproate dose increase. Choreiform movements ceased following valproate discontinuation. Chorea is a rare and dose dependent side effect of valproate.

Naast motorische symptomen wordt de ziekte van Parkinson gekenmerkt door talrijke nietmotorische symptomen die een negatieve impact hebben op de kwaliteit van leven van de patiënt. Er bestaat reeds een korte Engelstalige vragenlijst die de patiënt zelf kan invullen, om deze niet-motorische symptomen te detecteren. Deze vragenlijst (NMSQuest) werd door ons vertaald naar het Nederlands en vervolgens in een populatie van 47 patiënten met de ziekte van Parkinson getest. De vragenlijst was begrijpbaar voor alle patiënten. De meest voorkomende niet-motorische symptomen waren nycturie (61,7%), urinaire urgency (55,3%) en slaapstoornissen (51,1%). Het aantal niet-motorische symptomen vertoonde een positieve correlatie met ziekteduur en met merkers van motorische ziekte-ernst (motorische UPDRS score en Hoehn-en-Yahr-stadium). We menen dat de Nederlandstalige versie van de NMSQuest een bruikbaar screeningsinstrument is om niet-motorische symptomen te detecteren in de klinische praktijk bij patiënten met de ziekte van Parkinson.

Baron Dr. Ludo van Bogaert (18971989) authored more than 700 publications, gave countless lectures at Belgian and foreign universities and at international congresses, and trained more than 300 specialists from all over the world in the Bunge Institute. He filmed many of his patients suffering from movement disorders. Hallervorden-Spatz disease (HSD) was first described in 1922. The recognition of this well-defined syndrome was followed by several case reports published and in 1936, a new case was reported by Ludo van Bogaert and Clovis Vincent. To the best of our knowledge, this case report can be considered as the first filmed case of HSD.

Background: Epidemiological data concerning the prevalence of major depression in PD patients in Belgium is very scarce. Methods: A total of 1086 patients with idiopathic Parkinsons disease were included in the analysis. The neurological evaluation of the patients was made by the Hoehn and Yahr Staging of Parkinsons disease, the Unified Parkinson Disease Rating Scale (UPDRS), and the Schwab and England Activities of Daily Living. The psychiatric evaluation was based on the Mini-International Neuropsychiatric Interview (MINI) and the Montgomery Asberg Depression Rating Scale (MADRS). Results: Based on the MINI questionnaire, the overall proportion of PD patients presenting a current major depressive episode was 15.6%. Interestingly, 30% of all patients included had a history of mood disorder and 46% received either an anxiolytic, an antidepressant or an atypical neuroleptic or a combination of them. The characterisation of the profile of depressed parkinsonian patients shows very few patient's parameters (demographics or motor symptoms) to be associated with a higher risk for major depression. Conclusions: The PARKIDEP survey confirms a high prevalence of major depression in PD patients in Belgium. A careful follow up of PD patients with a poor functionality, a history of mood disorder or with a complaint of depression or anxiety during the "off" state would help towards a better treatment of the Parkinson's disease associated depression and should improve the quality of life of PD patients.

The anatomical localization of 5-HT4 receptor mRNA and 5-HT4 receptor protein was examined in sections of post-mortem human brain by in situ hybridization histochemistry and radioligand receptor autoradiography. In the in situ hybridization study, the highest levels of 5-HT4 receptor mRNA were found in caudate nucleus, putamen, nucleus accumbens, and in the hippocampal formation. No 5-HT4 receptor mRNA was detected in globus pallidus and substantia nigra. For receptor autoradiography, two new and highly selective radioligands were compared: [H-3]prucalopride, which preferentially labels the G-protein coupled fraction of receptors, and [H-3]R116712, which labels the entire receptor population at subnanomolar concentrations. [H-3]Prucalopride and [H-3]R116712 binding was performed on human brain hemisphere sections. The highest densities for both radioligands were found in the basal ganglia (caudate nucleus, putamen, nucleus accumbens, globus pallidus, substantia nigra). Moderate to low densities were detected in the hippocampal formation and in the cortical mantle. Mismatches between 5-HT4 receptor mRNA and binding sites in the globus pallidus and the substantia nigra suggested that the binding sites may be localized on axonal projections originating from the striatum. To compare densities of binding sites, concentration binding curves with [H-3]prucalopride, [H-3]R116712 and [H-3]GR113808 were performed on membranes from homogenates of several human brain regions. Comparison of B-max-values obtained with [H-3]prucalopride and [H-3]R116712 indicated that the G-protein coupled fraction of 5-HT4 receptors in the substantia nigra was exceptionally high (54%) in comparison with percentages (16-27%) found in the frontal cortex, the striatum and the hippocampus. Such a high percentage (40%) of [H-3]prucalopride vs. [H-3]R116712 binding was also observed in the substantia nigra in the receptor autoradiography experiments. The [H-3]prucalopride binding was GppNHp-sensitive, whereas [H-3]R116712 and [H-3]GR113808 was not. These data indicate that in the substantia nigra 5-HT4 receptors are more strongly coupled to their signal transduction pathway than in other brain regions. (C) 2000 Wiley-Liss, Inc.

Dementia is characterised by progressive memory loss, associated with agnosia, aphasia, dyscalculia, apraxia, and deficits in executive functioning. Alzheimer disease is the most frequent cause of dementia, with vascular dementia, diffuse Lewy body disease, and other etiologies being important differential diagnoses. A strategy and diagnostic hierarchy for diagnosis in dementia is proposed. Diagnostic criteria for Alzheimer disease, diffuse Lewy body disease, and vascular dementia are discussed.

[H-3]alniditan, a new potent non-indole serotonin 5-HT1B/1D agonist, was used as a radioligand to characterize 5-HT1B and 5-HT1D receptor (previously termed 5-HT1D beta and 5-HT1D alpha) in various regions of the human brain. Quantitative receptor autoradiography was applied for high anatomical resolution and sensitivity. Highest densities of 5-HT1B/1D receptors were found in the substantia nigra and in the globus pallidus. High to moderate densities were measured in the caudate nucleus, putamen, nucleus accumbens, central gray and hippocampal formation. Very low densities were detected in various cortical regions. In the cerebellum no [H-3]alniditan binding was detected. Selective 5-HT1B receptor labeling was achieved using [3H]alniditan in the presence of 300 nM of ketanserin (sufficient to block 5-HT1D receptor labeling). The identity of the 5-HT1B binding sites under these conditions was corroborated by the pIC(50) of sumatriptan, which corresponded to its affinity for cloned human 5-HT1B receptors expressed in cells. Surprisingly, the distribution of selective 5-HT1B receptor labeling was completely identical to the distribution of labeling of 5-HT1B + 5-HT1D receptors. The present data indicate that [H-3]alniditan is a suitable radioligand for measuring 5-HT1B/1D receptor in the human brain and that the 5-HT1B binding sites are predominant in the presently investigated regions of the human brain.

Eosinophilia-myalgia syndrome is an idiopathic disorder characterized by myalgia, especially of the extremities and peripheral eosinophilia. It is found in some patients as a result of tryptophan ingestion. We examined four patients showing clinical features and muscle biopsy changes consistent with eosinophilia-myalgia syndrome. The results of conventional histology were compared with immunohistochemical studies using monoclonal antibodies to human T lymphocytes, macrophages, HLA-DR antigen. Our findings confirm the potential importance of lymphocytes and macrophages in this syndrome. In particular, new observations are presented concerning the immunoreactivity of HLA-DR antigen.

Objective: Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown. Methods: Investigators from the Genetic Epidemiology of Parkinson9s Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry. Results: In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78–0.87 ( LAMP3 , BST1 , and MAPT ) and susceptibility per-allele odds ratios of 1.14–1.43 ( STK39 , GAK , SNCA , LRRK2 , SYT11 , and HIP1R ). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes ( I 2 estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA , LRRK2 , LAMP3 , HIP1R , and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD. Conclusion: Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity. Neurology ® 2012;79:659–667

Frontotemporal lobar degeneration (FTLD) represents a group of neurodegenerative disorders characterized by relatively localized degeneration of the frontal and temporal lobes. The most important clinical entity caused by FTLD is frontotemporal dementia (FTD), which is a rare disorder accounting for about 3% of all dementias. In patients under 65 years, however, FTD is the second most common dementia subtype, after Alzheimer’s disease, accounting for approximately 10% of cases. FTD commonly presents with a behavioral variant (bvFTD) subtype, where changes in behavior such as disinhibition, apathy and hyperorality stand out, as well as cognitive impairment such as executive dysfunction. Language variants of the disease (primary progressive aphasia, PPA) may also occur and are characterized by word finding difficulties, impaired motor speech or impaired language understanding. Due to the progressive nature of FTD, with ever-increasing disability in often young patients, the burden of disease is considerable, even more so because an effective cure has yet to be found. FTD is a disorder characterized by tremendous heterogeneity, not only when it comes to the clinical picture. Neuropathologically, different types of protein inclusions are known to cause the neuronal degradation (FTLD-tau, FTLD-TDP, FTLD-UPS, …). Genetically, multiple different pathogenic mutations have been shown to be associated with FTD. The most common FTD-related genes so far are MAPT, GRN and C9orf72. Though some correlations between underlying pathogenic mutations and associated clinical phenotypes have been reported in previous studies, these associations remain largely unexplained and pointed out an interesting knowledge gap. The aim of this PhD project was to elucidate genotype-phenotype correlations in Belgian FTD patients carrying pathogenic mutations in genes associated with FTD. We aimed to perform deep-phenotyping of these factors and analyze their role in the heterogenous spectrum of FTD. We also aimed to uncover genetic modifiers that could further explain this wide variability. Within the scope of this PhD, we were able to provide in-depth phenotypic data on a known pathogenic missense variant, p.R406W, in the MAPT gene encoding the tau protein. Previous reports had shown an unusual, Alzheimer’s disease (AD)-like phenotype in carriers of this variant. In our cohort of 38 Belgian carriers, which is the largest so far, to our knowledge, we uncovered a remarkable clinical phenotype. Mutation carriers presented with an intriguing spectrum of disease, ranging from typical bvFTD on one side to pure clinical AD on the other. In between these extremes, overlap syndromes with characteristics of both diseases occurred. Our findings provide a novel presentation of this known pathogenic mutation and shed more light on the clinical variability with this familial FTLD-tau syndrome. In this PhD thesis, we also present an interesting new pedigree carrying a novel, highly likely pathogenic variant in GRN. Functional mRNA analysis, suggestive clinical features and inheritance pattern, and serum progranulin measurement all provided evidence that helped shed light on the role and pathomechanism of this novel mutation. We have also sought to reproduce findings that were reported by a different group, suggesting a modifying role for locus C6orf10/LOC101929163 in patients with C9orf72 repeat expansion mutations. In our Belgian carrier cohort, we were not able to confirm these previous results. More research will be required to determine the true effect of this potential modifier. More extensive knowledge on genotype-phenotype correlations is relevant in clinical practice, as it may provide the clinician with more tools to suspect a genetic cause of FTD. This will help guide the diagnostic workup in patients as well as in their family members. These findings may also guide research into new disease-modifying therapies and disease-specific biomarkers. Genotype-phenotype correlations linking a set of clinical characteristics to an underlying genetic mutation and pathology can help identify patients most likely to benefit from novel therapies, ensuring more reliable and accurate results in future clinical trials.

Neurological disorders are a complex of symptoms and signs related to the nervous system that may be due to a wide variety of etiologies. Most causative conditions can be severe if left untreated and contribute to the major global mortality and morbidity of this syndrome. In sub-Saharan Africa, the burden is even more considerable because of a wider spectrum of infections, substantial delays in management and lack of diagnostic facilities and specialized care. The main purpose of this PhD dissertation is to improve the diagnostic workup of neurological disorders in rural areas of the Democratic Republic of the Congo (DRC). A large prospective etiological and diagnostic study was conducted from 2012 to 2016 in 351 children > 5 years and adults presenting with a pre-defined set of neurological complaints at the “Hôpital Général de Réference” of Mosango, Kwilu province, DRC. This study on NDs in DRC was part of a larger multicentric research project, conducted by the NIDIAG (Neglected Infections DIAGnosis; htpps://nidiag.eu) consortium, that aimed at improving the diagnosis of Neglected Tropical/Infectious Diseases in challenging syndromes. Considering its main study purpose, this PhD thesis had three specific objectives: •Firstly, to investigate the clinical spectrum, etiologies, and outcome of neurological disorders observed in the rural hospital of Mosango, DRC •Then to assess the diagnostic performance and contribution of clinical symptoms, first-line laboratory results and novel point-of-care RDTs for the diagnosis of HAT and other priority NTDs/IDs in patients with neurological disorders in the rural hospital of Mosango •Finally, to support the elaboration of an innovative integrated syndromic diagnostic tool (multi-disease approach) for neurological disorders, designed to first-line clinicians in rural DRC Reference diagnostic methods were systematically used for the diagnosis of a set of severe and treatable neuro-infections considered as priority conditions and for the field evaluation of new rapid diagnostic tests (RDTs). Pre-established clinical case definitions and post-hoc expert consensus were used for diagnostic ascertainment of the remaining etiologies. No neuroimaging was available in the study hospital. The core prospective study revealed that (i) the patterns of clinical presentation were very diverse; (ii) both infectious and noncommunicable etiologies had varied presentations; and (iii) the frequency of seven priority neuro-infections (Second-stage HAT, cerebral malaria, bacterial meningitis, CNS tuberculosis, neurosyphilis, HIV-related neurological disorders, cryptococcal meningitis in HIV-positive individuals) were respectively low (between 1 and 5% for each of these diagnoses). Death occurred in 8% of the patients and was more frequent in cases diagnosed with neuro-infection. An additional post-hoc analysis showed that about 13% of the patients enrolled with NDs had serological evidence of circulating Taenia solium antigen. This suggests, for the first time, that active neurocysticercosis might be endemic in this part of DRC and supports the need for additional neuroimaging studies. We demonstrated that lumbar puncture (LP), a key procedure to diagnose neuro-infections, but with which most first-line clinicians feel uncomfortable, was safe in the absence of neuroimaging, provided that the locally elaborated protocol was strictly adhered to. In particular, no major procedure-attributable adverse event was observed. Several predictors of cerebrospinal (CSF) pleocytosis (> 5 white blood cell/µL), a surrogate marker for infectious meningo-encephalitis, were identified, such as fever, altered consciousness, HIV infection and positive screening serology for human African trypanosomiasis (HAT). The study findings may assist in the selection of a subgroup of patients who would benefit most a diagnostic LP, and to withhold this procedure when it might be too risky. An additional diagnostic study demonstrated that a novel Human African trypanosomiasis (HAT)- Sero K-SeT rapid diagnostic test (RDT) was highly sensitive 100% (95% confidence interval: 67.6 to 100.0%) and specific 97% (95% confidence interval: 94.2% to 98.5%), with similar performance to that of the card agglutination test for trypanosomiasis (CATT), the currently routinely used screening assay. The high sensitivity and ease of use of this new RDT allows its current deployment in the most remote heath centers as screening tool for both clinical care and control activities. A post-hoc analysis evaluated the potential value of two bacterial biomarkers (C-reactive protein, CRP and procalcitonin, PCT) for the diagnosis of invasive bacterial infection (defined as bacterial meningitis or bacteremia or severe pneumonia; n=19 in the study population). Areas under the curve were 94.3% and 91.7% for CRP and PCT, respectively. More importantly, no single case of invasive bacterial infection was observed when the CRP value was normal (

Background: Although effective in reducing relapse rate and delaying progression, current therapies for multiple sclerosis (MS) do not completely halt disease progression. T cell autoimmunity to myelin antigens is considered one of the main mechanisms driving MS. It is characterized by autoreactivity to disease-initiating myelin antigen epitope(s), followed by a cascade of epitope spreading, which are both strongly patient-dependent. Targeting a variety of MSassociated antigens by myelin antigen-presenting tolerogenic dendritic cells (tolDC) is a promising treatment strategy to re-establish tolerance in MS. Electroporation with mRNA encoding myelin proteins is an innovative technique to load tolDC with the full spectrum of naturally processed myelin-derived epitopes. Methods: In this study, we generated murine tolDC presenting myelin oligodendrocyte glycoprotein (MOG) using mRNA electroporation and we assessed the efficacy of MOG mRNA-electroporated tolDC to dampen pathogenic T cell responses in experimental autoimmune encephalomyelitis (EAE). For this, MOG35–55- immunized C57BL/6 mice were injected intravenously at days 13, 17, and 21 post-disease induction with 1α, 25-dihydroxyvitamin D3-treated tolDC electroporated with MOG-encoding mRNA. Mice were scored daily for signs of paralysis. At day 25, myelin reactivity was evaluated following restimulation of splenocytes with myelin-derived epitopes. Ex vivo magnetic resonance imaging (MRI) was performed to assess spinal cord inflammatory lesion load.Results: Treatment of MOG35–55-immunized C57BL/6 mice with MOG mRNA-electroporated or MOG35–55- pulsed tolDC led to a stabilization of the EAE clinical score from the first administration onwards, whereas it worsened in mice treated with non-antigen-loaded tolDC or with vehicle only. In addition, MOG35–55-specific pro-inflammatory pathogenic T cell responses and myelin antigen epitope spreading were inhibited in the peripheral immune system of tolDC-treated mice. Finally, magnetic resonance imaging analysis of hyperintense spots along the spinal cord was in line with the clinical score. Conclusions: Electroporation with mRNA is an efficient and versatile tool to generate myelin-presenting tolDC that are capable to stabilize the clinical score in EAE. These results pave the way for further research into mRNA-electroporated tolDC treatment as a patient-tailored therapy for MS. This work was supported by the Methusalem Funding Program from the University of Antwerp, by an applied biomedical research project of the Institute for the Promotion of Innovation by Science and Technology in Flanders (IWTTBM 140191), and by the Belgian Charcot Foundation. Furthermore, the authors received research funding from Roche Belgium. Judith Derdelinckx holds a PhD fellowship from the Research Foundation Flanders (FWO)

We previously reported a granulin (GRN) null mutation, originating from a common founder, in multiple Belgian families with frontotemporal dementia. Here, we used data of a 10-year follow-up study to describe in detail the clinical heterogeneity observed in this extended founder pedigree. We identified 85 patients and 40 unaffected mutation carriers, belonging to 29 branches of the founder pedigree. Most patients (74.4%) were diagnosed with frontotemporal dementia, while others had a clinical diagnosis of unspecified dementia, Alzheimer's dementia or Parkinson's disease. The observed clinical heterogeneity can guide clinical diagnosis, genetic testing, and counseling of mutation carriers. Onset of initial symptomatology is highly variable, ranging from age 45 to 80 years. Analysis of known modifiers, suggested effects of GRN rs5848, microtubule-associated protein tau H-1/H-2, and chromosome 9 open reading frame 72 G(4)C(2) repeat length on onset age but explained only a minor fraction of the variability. Contrary, the extended GRN founder family is a valuable source for identifying other onset age modifiers based on exome or genome sequences. These modifiers might be interesting targets for developing disease-modifying therapies. (C) 2018 The Authors. Published by Elsevier Inc. Belgian Science Policy Office Interuniversity Attraction Poles program; Flemish government initiated Methusalem excellence program; Flemish government initiated Impulse Program on Networks for Dementia Research; Queen Elisabeth Medical Foundation; Alzheimer Research Foundation; Research Foundation Flanders (FWO); Agency for Innovation by Science and Technology Flanders (IWT); University of Antwerp Research Fund; Belgium; IWT; FWO

Objectives: ACST-2 is currently the largest trial ever conducted to compare carotid artery stenting (CAS) with carotid endarterectomy (CEA) in patients with severe asymptomatic carotid stenosis requiring revascularization. Methods: Patients are entered into ACST-2 when revascularization is felt to be clearly indicated, when CEA and CAS are both possible, but where there is substantial uncertainty as to which is most appropriate. Trial surgeons and interventionalists are expected to use their usual techniques and CE-approved devices. We report baseline characteristics and blinded combined interim results for 30-day mortality and major morbidity for 986 patients in the ongoing trial up to September 2012. Results: A total of 986 patients (687 men, 299 women), mean age 68.7 years (SD ± 8.1) were randomized equally to CEA or CAS. Most (96%) had ipsilateral stenosis of 70-99% (median 80%) with contralateral stenoses of 50-99% in 30% and contralateral occlusion in 8%. Patients were on appropriate medical treatment. For 691 patients undergoing intervention with at least 1-month follow-up and Rankin scoring at 6 months for any stroke, the overall serious cardiovascular event rate of periprocedural (within 30 days) disabling stroke, fatal myocardial infarction, and death at 30 days was 1.0%. Conclusions: Early ACST-2 results suggest contemporary carotid intervention for asymptomatic stenosis has a low risk of serious morbidity and mortality, on par with other recent trials. The trial continues to recruit, to monitor periprocedural events and all types of stroke, aiming to randomize up to 5,000 patients to determine any differential outcomes between interventions. Clinical trial: ISRCTN21144362. © 2013 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

SummaryBackgroundIf carotid artery narrowing remains asymptomatic (ie, has caused no recent stroke or other neurological symptoms), successful carotid endarterectomy (CEA) reduces stroke incidence for some years. We assessed the long-term effects of successful CEA.MethodsBetween 1993 and 2003, 3120 asymptomatic patients from 126 centres in 30 countries were allocated equally, by blinded minimised randomisation, to immediate CEA (median delay 1 month, IQR 0·3–2·5) or to indefinite deferral of any carotid procedure, and were followed up until death or for a median among survivors of 9 years (IQR 6–11). The primary outcomes were perioperative mortality and morbidity (death or stroke within 30 days) and non-perioperative stroke. Kaplan-Meier percentages and logrank p values are from intention-to-treat analyses. This study is registered, number ISRCTN26156392.Findings1560 patients were allocated immediate CEA versus 1560 allocated deferral of any carotid procedure. The proportions operated on while still asymptomatic were 89·7% versus 4·8% at 1 year (and 92·1% vs 16·5% at 5 years). Perioperative risk of stroke or death within 30 days was 3·0% (95% CI 2·4–3·9; 26 non-disabling strokes plus 34 disabling or fatal perioperative events in 1979 CEAs). Excluding perioperative events and non-stroke mortality, stroke risks (immediate vs deferred CEA) were 4·1% versus 10·0% at 5 years (gain 5·9%, 95% CI 4·0–7·8) and 10·8% versus 16·9% at 10 years (gain 6·1%, 2·7–9·4); ratio of stroke incidence rates 0·54, 95% CI 0·43–0·68, p

Item does not contain fulltext BACKGROUND: Findings from randomised trials have shown a higher early risk of stroke after carotid artery stenting than after carotid endarterectomy. We assessed whether white-matter lesions affect the perioperative risk of stroke in patients treated with carotid artery stenting versus carotid endarterectomy. METHODS: Patients with symptomatic carotid artery stenosis included in the International Carotid Stenting Study (ICSS) were randomly allocated to receive carotid artery stenting or carotid endarterectomy. Copies of baseline brain imaging were analysed by two investigators, who were masked to treatment, for the severity of white-matter lesions using the age-related white-matter changes (ARWMC) score. Randomisation was done with a computer-generated sequence (1:1). Patients were divided into two groups using the median ARWMC. We analysed the risk of stroke within 30 days of revascularisation using a per-protocol analysis. ICSS is registered with controlled-trials.com, number ISRCTN 25337470. FINDINGS: 1036 patients (536 randomly allocated to carotid artery stenting, 500 to carotid endarterectomy) had baseline imaging available. Median ARWMC score was 7, and patients were dichotomised into those with a score of 7 or more and those with a score of less than 7. In patients treated with carotid artery stenting, those with an ARWMC score of 7 or more had an increased risk of stroke compared with those with a score of less than 7 (HR for any stroke 2.76, 95% CI 1.17-6.51; p=0.021; HR for non-disabling stroke 3.00, 1.10-8.36; p=0.031), but we did not see a similar association in patients treated with carotid endarterectomy (HR for any stroke 1.18, 0.40-3.55; p=0.76; HR for disabling or fatal stroke 1.41, 0.38-5.26; p=0.607). Carotid artery stenting was associated with a higher risk of stroke compared with carotid endarterectomy in patients with an ARWMC score of 7 or more (HR for any stroke 2.98, 1.29-6.93; p=0.011; HR for non-disabling stroke 6.34, 1.45-27.71; p=0.014), but there was no risk difference in patients with an ARWMC score of less than 7. INTERPRETATION: The presence of white-matter lesions on brain imaging should be taken into account when selecting patients for carotid revascularisation. Carotid artery stenting should be avoided in patients with more extensive white-matter lesions, but might be an acceptable alternative to carotid endarterectomy in patients with less extensive lesions. FUNDING: Medical Research Council, the Stroke Association, Sanofi-Synthelabo, the European Union Research Framework Programme 5.

Early genome-wide association (GWA) studies on Parkinson's disease (PD) have not been able to yield conclusive, replicable signals of association, perhaps due to limited sample size. We aimed to investigate whether association signals derived from the meta-analysis of the first two GWA investigations might be replicable in different populations. We examined six single-nucleotide polymorphisms (SNPs) (rs1000291, rs1865997, rs2241743, rs2282048, rs2313982, and rs3018626) that had reached nominal significance with at least two of three different strategies proposed in a previous analysis of the original GWA studies. Investigators from the "Genetic Epidemiology of Parkinson's Disease" (GEOPD) consortium were invited to join in this study. Ten teams contributed replication data from 3,458 PD cases and 3,719 controls. The data from the two previously published GWAs (599 PD cases, 592 controls and 443 sibling pairs) were considered as well. All data were synthesized using both fixed and random effects models. The summary allelic odds ratios were ranging from 0.97 to 1.09 by random effects, when all data were included. The summary estimates of the replication data sets (excluding the original GWA data) were very close to 1.00 (range 0.98-1.09) and none of the effects were nominally statistically significant. The replication data sets had significantly different results than the GWA data. Our data do not support evidence that any of these six SNPs reflect susceptibility markers for PD. Much stronger signals of statistical significance in GWA platforms are needed to have substantial chances of replication. Specifically in PD genetics, this would require much larger GWA studies and perhaps novel analytical techniques. (C) 2009 Wiley-Liss, Inc. American Journal of Medical Genetics Part B-Neuropsychiatric Genetics

Background: Ischemic stroke is the leading cause of mortality worldwide and a major contributor to neurological disability and dementia. Terutroban is a specific TP receptor antagonist with antithrombotic, antivasoconstrictive, and antiatherosclerotic properties, which may be of interest for the secondary prevention of ischemic stroke. This article describes the rationale and design of the Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic Attack (PERFORM) Study, which aims to demonstrate the superiority of the efficacy of terutroban versus aspirin in secondary prevention of cerebrovascular and cardiovascular events. Methods and Results: The PERFORM Study is a multicenter, randomized, double-blind, parallel-group study being carried out in 802 centers in 46 countries. The study population includes patients aged ≥55 years, having suffered an ischemic stroke (≤3 months) or a transient ischemic attack (≤8 days). Participants are randomly allocated to terutroban (30 mg/day) or aspirin (100 mg/day). The primary efficacy endpoint is a composite of ischemic stroke (fatal or nonfatal), myocardial infarction (fatal or nonfatal), or other vascular death (excluding hemorrhagic death of any origin). Safety is being evaluated by assessing hemorrhagic events. Follow-up is expected to last for 2–4 years. Assuming a relative risk reduction of 13%, the expected number of primary events is 2,340. To obtain statistical power of 90%, this requires inclusion of at least 18,000 patients in this event-driven trial. The first patient was randomized in February 2006. Conclusions: The PERFORM Study will explore the benefits and safety of terutroban in secondary cardiovascular prevention after a cerebral ischemic event.