Publications by authors named "Patrick Cras"

159 Publications

REM sleep without atonia and nocturnal body position in prediagnostic Parkinson's disease.

Sleep Med 2021 08 17;84:308-316. Epub 2021 Jun 17.

Department of Neurology, Antwerp University Hospital, Drie Eikenstraat 655, 2650, Edegem, Belgium; Faculty of Medicine and Health Sciences, Translational Neurosciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium; Born-Bunge Institute, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium. Electronic address:

Background: Sleep disturbances are features of Parkinson's disease (PD), that can already occur before PD diagnosis. The most investigated prodromal PD sleep disorder is REM sleep behavior disorder (RBD). The relation between other polysomnographic (PSG) alterations and the prediagnostic stages of PD, however, is less clear.

Methods: We performed a retrospective case-control study to characterize polysomnographic alterations in PD and prediagnostic PD. We included 63 PD subjects (33 subjects that underwent a video-PSG before PD diagnosis [13 with and 20 without RBD] and 30 subjects that underwent a PSG after PD diagnosis) and 30 controls. PSGs were analyzed for sleep stages, different RSWA variables, body position, arousals, periodic limb movements, and REM density.

Results: Higher subscores of all RSWA variables were observed in subjects with PD and prediagnostic PD (with and without RBD). Total RSWA, tonic RSWA and chin RSWA severity were significant predictors for all PD and prediagnostic PD groups. Our study also shows a higher percentage of nocturnal supine body position in all PD and prediagnostic PD groups. Supine body position percentage is the highest in the PD group and has a positive correlation with time since diagnosis.

Conclusions: These findings suggest that increased total, tonic and chin RSWA as well as nocturnal supine body position are already present in prediagnostic PD, independently of RBD status. Prospective longitudinal studies are necessary to confirm the additional value of these PSG abnormalities as prodromal PD biomarkers.
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http://dx.doi.org/10.1016/j.sleep.2021.06.011DOI Listing
August 2021

Safety and immunological proof-of-concept following treatment with tolerance-inducing cell products in patients with autoimmune diseases or receiving organ transplantation: A systematic review and meta-analysis of clinical trials.

Autoimmun Rev 2021 Aug 11;20(8):102873. Epub 2021 Jun 11.

Laboratory of Experimental Hematology, Vaccine & Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium; Center for Cell Therapy and Regenerative Medicine, Antwerp University Hospital, Edegem, Belgium.

In the past years, translational approaches have led to early-stage clinical trials assessing safety and efficacy of tolerance-inducing cell-based treatments in patients. This review aims to determine if tolerance-inducing cell-based therapies, including dendritic cells, regulatory T cells and mesenchymal stem cells, are safe in adult patients who underwent organ transplantation or in those with autoimmune diseases, including multiple sclerosis, diabetes mellitus type 1, Crohn's disease and rheumatoid arthritis. Immunological and clinical outcomes were reviewed, to provide evidence for proof-of-concept and efficacy. To summarize the current knowledge, a systematic review and meta-analysis were conducted. A total of 8906 records were reviewed by 2 independent assessors and 48 records were included in the final quantitative analysis. The overall frequency of serious adverse events was low: 0.018 (95% CI: 0.006-0.051). Immunological outcomes could not be assessed quantitatively because of heterogeneity in outcome assessments and description as well as lack of individual data. Most randomized controlled studies were at a medium risk of bias due to open-label treatment without masking of assessors and/or patients to the intervention. In conclusion, tolerance-inducing cell-based therapies are safe. We advocate for harmonization of study protocols of trials investigating cell-based therapies, adverse event reporting and systematic inclusion of immunological outcome measures in clinical trials evaluating tolerance-inducingcell-basedtreatment. Registration: PROSPERO, registration number CRD42020170557.
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http://dx.doi.org/10.1016/j.autrev.2021.102873DOI Listing
August 2021

Family-based exome sequencing identifies RBM45 as a possible candidate gene for frontotemporal dementia and amyotrophic lateral sclerosis.

Neurobiol Dis 2021 08 9;156:105421. Epub 2021 Jun 9.

Neurodegenerative Brain Diseases, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium; Institute Born-Bunge, Antwerp, Belgium. Electronic address:

Neurodegenerative disorders like frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are pathologically characterized by toxic protein deposition in the cytoplasm or nucleus of affected neurons and glial cells. Many of these aggregated proteins belong to the class of RNA binding proteins (RBP), and, when mutated, account for a significant subset of familial ALS and FTD cases. Here, we present first genetic evidence for the RBP gene RBM45 in the FTD-ALS spectrum. RBM45 shows many parallels with other FTD-ALS associated genes and proteins. Multiple lines of evidence have demonstrated that RBM45 is an RBP that, upon mutation, redistributes to the cytoplasm where it co-aggregates with other RBPs into cytoplasmic stress granules (SG), evolving to persistent toxic TDP-43 immunoreactive inclusions. Exome sequencing in two affected first cousins of a heavily affected early-onset dementia family listed a number of candidate genes. The gene with the highest pathogenicity score was the RBP gene RBM45. In the family, the RBM45 Arg183* nonsense mutation co-segregated in both affected cousins. Validation in an unrelated patient (n = 548) / control (n = 734) cohort identified an additional RBM45 Arg183* carrier with bvFTD on a shared 4 Mb haplotype. Transcript and protein expression analysis demonstrated loss of nuclear RBM45, suggestive of a loss-of-function disease mechanism. Further, two more ultra-rare VUS, one in the nuclear localization signal (NLS, p.Lys456Arg) in an ALS patient and one in the intrinsically disordered homo-oligomer assembly (HOA) domain (p.Arg314Gln) in a patient with nfvPPA were detected. Our findings suggest that the pathomechanisms linking RBM45 with FTD and ALS may be related to its loss of nuclear function as a mediator of mRNA splicing, cytoplasmic retention or its inability to form homo-oligomers, leading to aggregate formation with trapping of other RBPs including TDP-43, which may accumulate into persisted TDP-43 inclusions.
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http://dx.doi.org/10.1016/j.nbd.2021.105421DOI Listing
August 2021

Premature termination codon mutations in ABCA7 contribute to Alzheimer's disease risk in Belgian patients.

Neurobiol Aging 2021 10 2;106:307.e1-307.e7. Epub 2021 May 2.

Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, Antwerp, Belgium; Institute Born-Bunge, Antwerp, Belgium; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium. Electronic address:

The ATP-Binding Cassette Subfamily A Member 7 gene (ABCA7) was identified as a risk gene for Alzheimer's disease (AD) in genome-wide association studies of large cohorts of late-onset AD (LOAD) patients. Extended resequencing of the ABCA7 coding regions identified mutations that lead to premature termination codons (PTC) and loss of function of ABCA7. PTC mutations were enriched in LOAD patients and were frequently present in patients with early-onset AD (EOAD). We aimed at assessing the contribution of ABCA7 PTC mutations to AD in the Belgian population by screening the ABCA7 coding region in a Belgian AD cohort of 1376 patients, including LOAD and EOAD patients, and in a Belgian control cohort of 976 individuals. We identified a PTC mutation in 67 AD patients (4.9%) and in 18 control individuals (1.8%) confirming the enrichment of ABCA7 PTC mutations in Belgian AD patients. The patient carriers had a mean onset age of 69.7 ± 9.8 years with a wide onset age range of 42 years (48-90 years). In 77.3% of the families of ABCA7 carriers, there were AD patients present suggestive of a positive family history of disease, but a Mendelian co-segregation of ABCA7 PTC mutations with disease is not clear. Overall, our genetic data predict that PTC mutations in ABCA7 are common in the Belgian population and are present in LOAD and EOAD patients.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.04.023DOI Listing
October 2021

Vestibular Function in Older Adults With Cognitive Impairment: A Systematic Review.

Ear Hear 2021 Apr 22;42(5):1119-1126. Epub 2021 Apr 22.

Department of Translational Neurosciences, University of Antwerp, Antwerp, Belgium.

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.
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http://dx.doi.org/10.1097/AUD.0000000000001040DOI Listing
April 2021

Antigen-Specific Treatment Modalities in MS: The Past, the Present, and the Future.

Front Immunol 2021 19;12:624685. Epub 2021 Feb 19.

Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (VaxInfectio), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.

Antigen-specific therapy for multiple sclerosis may lead to a more effective therapy by induction of tolerance to a wide range of myelin-derived antigens without hampering the normal surveillance and effector function of the immune system. Numerous attempts to restore tolerance toward myelin-derived antigens have been made over the past decades, both in animal models of multiple sclerosis and in clinical trials for multiple sclerosis patients. In this review, we will give an overview of the current approaches for antigen-specific therapy that are in clinical development for multiple sclerosis as well provide an insight into the challenges for future antigen-specific treatment strategies for multiple sclerosis.
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http://dx.doi.org/10.3389/fimmu.2021.624685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933447PMC
September 2021

Contribution of rare homozygous and compound heterozygous VPS13C missense mutations to dementia with Lewy bodies and Parkinson's disease.

Acta Neuropathol Commun 2021 02 12;9(1):25. Epub 2021 Feb 12.

Center for Molecular Neurology, VIB, Antwerp, Belgium.

Dementia with Lewy bodies (DLB) and Parkinson's disease (PD) are clinically, pathologically and etiologically disorders embedded in the Lewy body disease (LBD) continuum, characterized by neuronal α-synuclein pathology. Rare homozygous and compound heterozygous premature termination codon (PTC) mutations in the Vacuolar Protein Sorting 13 homolog C gene (VPS13C) are associated with early-onset recessive PD. We observed in two siblings with early-onset age (< 45) and autopsy confirmed DLB, compound heterozygous missense mutations in VPS13C, p.Trp395Cys and p.Ala444Pro, inherited from their healthy parents in a recessive manner. In lymphoblast cells of the index patient, the missense mutations reduced VPS13C expression by 90% (p = 0.0002). Subsequent, we performed targeted resequencing of VPS13C in 844 LBD patients and 664 control persons. Using the optimized sequence kernel association test, we obtained a significant association (p = 0.0233) of rare VPS13C genetic variants (minor allele frequency ≤ 1%) with LBD. Among the LBD patients, we identified one patient with homozygous missense mutations and three with compound heterozygous missense mutations in trans position, indicative for recessive inheritance. In four patients with compound heterozygous mutations, we were unable to determine trans position. The frequency of LBD patient carriers of proven recessive compound heterozygous missense mutations is 0.59% (5/844). In autopsy brain tissue of two unrelated LBD patients, the recessive compound heterozygous missense mutations reduced VPS13C expression. Overexpressing of wild type or mutant VPS13C in HeLa or SH-SY5Y cells, demonstrated that the mutations p.Trp395Cys or p.Ala444Pro, abolish the endosomal/lysosomal localization of VPS13C. Overall, our data indicate that rare missense mutations in VPS13C are associated with LBD and recessive compound heterozygous missense mutations might have variable effects on the expression and functioning of VPS13C. We conclude that comparable to the recessive inherited PTC mutations in VPS13C, combinations of rare recessive compound heterozygous missense mutations reduce VPS13C expression and contribute to increased risk of LBD.
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http://dx.doi.org/10.1186/s40478-021-01121-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881566PMC
February 2021

HLA Class II Genotype Does Not Affect the Myelin Responsiveness of Multiple Sclerosis Patients.

Cells 2020 12 17;9(12). Epub 2020 Dec 17.

Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (VaxInfectio), Faculty of Medicine and Health Sciences, University of Antwerp, 2610 Antwerp, Belgium.

Background: When aiming to restore myelin tolerance using antigen-specific treatment approaches in MS, the wide variety of myelin-derived antigens towards which immune responses are targeted in multiple sclerosis (MS) patients needs to be taken into account. Uncertainty remains as to whether the myelin reactivity pattern of a specific MS patient can be predicted based upon the human leukocyte antigen (HLA) class II haplotype of the patient.

Methods: In this study, we analyzed the reactivity towards myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP) and proteolipid protein (PLP) peptides using direct interferon (IFN)-γ enzyme-linked immune absorbent spot (ELISPOT). Next, the HLA class II haplotype profile was determined by next-generation sequencing. In doing so, we aimed to evaluate the possible association between the precursor frequency of myelin-reactive T cells and the HLA haplotype.

Results: Reactivity towards any of the analyzed peptides could be demonstrated in 65.0% (13/20) of MS patients and in 60.0% (6/10) of healthy controls. At least one of the MS risk alleles HLA-DRB1*15:01, HLA-DQA1*01:02 and HLA-DQB1*06:02 was found in 70.0% (14/20) of patients and in 20.0% (2/10) of healthy controls. No difference in the presence of a myelin-specific response, nor in the frequency of myelin peptide-reactive precursor cells could be detected among carriers and non-carriers of these risk alleles.

Conclusion: No association between HLA haplotype and myelin reactivity profile was present in our study population. This complicates the development of antigen-specific treatment approaches and implies the need for multi-epitope targeting in an HLA-unrestricted manner to fully address the wide variation in myelin responses and HLA profiles in a heterogeneous group of MS patients.
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http://dx.doi.org/10.3390/cells9122703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766454PMC
December 2020

European white paper: oropharyngeal dysphagia in head and neck cancer.

Eur Arch Otorhinolaryngol 2021 Feb 19;278(2):577-616. Epub 2020 Dec 19.

Head and Neck Oncology Service, Candiolo Cancer Institute, FPO - IRCCS, Candiolo, TO, Italy.

Purpose: To develop a European White Paper document on oropharyngeal dysphagia (OD) in head and neck cancer (HNC). There are wide variations in the management of OD associated with HNC across Europe.

Methods: Experts in the management of specific aspects of OD in HNC across Europe were delegated by their professional medical and multidisciplinary societies to contribute to this document. Evidence is based on systematic reviews, consensus-based position statements, and expert opinion.

Results: Twenty-four sections on HNC-specific OD topics.

Conclusion: This European White Paper summarizes current best practice on management of OD in HNC, providing recommendations to support patients and health professionals. The body of literature and its level of evidence on diagnostics and treatment for OD in HNC remain poor. This is in the context of an expected increase in the prevalence of OD due to HNC in the near future. Contributing factors to increased prevalence include aging of our European population (including HNC patients) and an increase in human papillomavirus (HPV) related cancer, despite the introduction of HPV vaccination in various countries. We recommend timely implementation of OD screening in HNC patients while emphasizing the need for robust scientific research on the treatment of OD in HNC. Meanwhile, its management remains a challenge for European professional associations and policymakers.
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http://dx.doi.org/10.1007/s00405-020-06507-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826315PMC
February 2021

Predictors of 30-day and 90-day mortality among hemorrhagic and ischemic stroke patients in urban Uganda: a prospective hospital-based cohort study.

BMC Cardiovasc Disord 2020 10 8;20(1):442. Epub 2020 Oct 8.

MRC/UVRI and LSHTM Uganda Research Unit, P.O Box 49, Entebbe, Uganda.

Background: We report here on a prospective hospital-based cohort study that investigates predictors of 30-day and 90-day mortality and functional disability among Ugandan stroke patients.

Methods: Between December 2016 and March 2019, we enrolled consecutive hemorrhagic stroke and ischemic stroke patients at St Francis Hospital Nsambya, Kampala, Uganda. The primary outcome measure was mortality at 30 and 90 days. The modified Ranking Scale wasused to assess the level of disability and mortality after stroke. Stroke severity at admission was assessed using the National Institute of Health Stroke Scale (NIHSS) and Glasgow Coma Scale (GCS). Examination included clinical neurological evaluation, laboratory tests and brain computed tomography (CT) scan. Kaplan-Meier curves and multivariate Cox proportional hazard model were used for unadjusted and adjusted analysis to predict mortality.

Results: We enrolled 141 patients; 48 (34%) were male, mean age was 63.2 (+ 15.4) years old; 90 (64%) had ischemic and 51 (36%) had hemorrhagic stroke; 81 (57%) were elderly (≥ 60 years) patients. Overall mortality was 44 (31%); 31 (23%) patients died within the first 30 days post-stroke and, an additional 13 (14%) died within 90 days post-stroke. Mortality for hemorrhagic stroke was 19 (37.3%) and 25 (27.8%) for ischemic stroke. After adjusting for age and sex, a GCS score below < 9 (adjusted hazard ratio [aHR] =3.49, 95% CI: 1.39-8.75) was a significant predictor of 30-day mortality. GCS score < 9 (aHR =4.34 (95% CI: 1.85-10.2), stroke severity (NIHSS ≥21) (aHR = 2.63, 95% CI: (1.68-10.5) and haemorrhagic stroke type (aHR = 2.30, 95% CI: 1.13-4.66) were significant predictors of 90-day mortality. Shorter hospital stay of 7-13 days (aHR = 0.31, 95% CI: 0.11-0.93) and being married (aHR = 0.22 (95% CI: 0.06-0.84) had protective effects for 30 and 90-day mortality respectively.

Conclusion: Mortality is high in the acute and sub-acute phase of stroke. Low levels of consciousness at admission, stroke severity, and hemorrhagic stroke were associated with increased higher mortality in this cohort of Ugandan stroke patients. Being married provided a protective effect for 90-day mortality. Given the high mortality during the acute phase, critically ill stroke patients would benefit from early interventions established as the post-stroke- standard of care in the country.
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http://dx.doi.org/10.1186/s12872-020-01724-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545850PMC
October 2020

Impact of hearing loss and vestibular decline on cognition in Alzheimer's disease: a prospective longitudinal study protocol (Gehoor, Evenwicht en Cognitie, GECkO).

BMJ Open 2020 09 17;10(9):e039601. Epub 2020 Sep 17.

Department of Translational Neurosciences, University of Antwerp, Faculty of Medicine and Health Sciences, Wilrijk, Belgium.

Introduction: Dementia is a prevalent disease affecting a growing number of the ageing population. Alzheimer's disease (AD) is the most common cause of dementia. Previous research investigated the link between hearing loss and cognition, and the effect of vestibular dysfunction on cognition. Hearing loss and, to a lesser extent, vestibular decline both result in a decreasing cognitive function. However, their interaction should not be underestimated. The aim of this study is to assess the effect of hearing loss, vestibular decline and their interaction on cognition in people suffering from mild cognitive impairment (MCI) and dementia due to AD (ADD).

Methods And Analysis: We designed a prospective longitudinal study to assess the effect of hearing loss and vestibular decline on cognition. A total of 100 cognitively impaired elderly (between 55 and 84 years of age), consisting of 60 patients with MCI due to AD and 40 patients with ADD will be included. The control group will consist of individuals with preserved cognition group-matched based on age, hearing level and vestibular function. A comprehensive assessment is performed at baseline, 12-month and 24-month follow-ups. The primary outcome measure is the change in the Repeatable Battery for the Assessment of Neuropsychological Status adjusted for Hearing-impaired individuals total score, a cognitive test battery assessing different cognitive domains. Secondary outcome measures include additional neuropsychological assessments, cortical auditory-evoked potentials, and evaluation of general and disease-specific health-related quality of life. Variables include cognitive, audiological and vestibular evaluation. Variance analyses will assess the effect of hearing loss and vestibular decline on cognition. More precisely, the link between hearing loss and non-spatial cognitive functioning, the effect of vestibular decline on spatial cognition and the impact of both factors on the rate of conversion from MCI due to AD to ADD will be investigated.

Ethics And Dissemination: The study protocol was approved by the ethical committee of the Antwerp University Hospital on 4 February 2019 with protocol number B300201938949. The findings will be disseminated through peer-reviewed publications and conference presentations.

Trial Registration Number: ClinicalTrials.gov Registry (NCT04385225).
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http://dx.doi.org/10.1136/bmjopen-2020-039601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500302PMC
September 2020

No association of CpG SNP rs9357140 with onset age in Belgian C9orf72 repeat expansion carriers.

Neurobiol Aging 2021 01 15;97:145.e1-145.e4. Epub 2020 Aug 15.

Neurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. Electronic address:

We investigated the impact of the recently described chromosome 6 open reading frame 10 (C6orf10)/LOC101929163 locus as age-at-onset modifier in an extended cohort of Belgian chromosome 9 open reading frame 72 (C9orf72) GC repeat expansion carriers. We genotyped the tagging CpG single-nucleotide polymorphism rs9357140 in 224 confirmed C9orf72 repeat expansion carriers, 102 index cases and 122 relatives, and tested association with onset age. The C9orf72 repeat expansion cohort consisted of 131 symptomatic carriers, that is, 78 with dementia only, 13 with frontotemporal dementia (FTD)-amyotrophic lateral sclerosis (ALS), and 40 ALS only, and 93 presymptomatic carriers. Cox proportional hazard regression analysis failed to identify significant association (adjusted hazard ratio = 1.15, p = 0.3). We further extended our analysis to a Belgian cohort of unrelated, mutation-negative FTD index patients (n = 230), but also found no association (adjusted hazard ratio = 0.96, p = 0.3). Overall, our findings suggest that in the Belgian cohort, the C6orf10/LOC101929163 locus cannot explain the marked variability in age at onset, and other genetic or environmental modifiers must drive the clinical heterogeneity observed among C9orf72 repeat expansion carriers.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.07.021DOI Listing
January 2021

Myoclonus and cerebellar ataxia following Coronavirus Disease 2019 (COVID-19).

Mov Disord Clin Pract 2020 Aug 7. Epub 2020 Aug 7.

Department of Neurology Antwerp University Hospital Antwerp Belgium.

The Coronavirus disease 2019 (COVID-19) outbreak has led to a pandemic with an overwhelming impact on daily living and the health care system. Major life-threatening complications may occur [1]. Although most patients suffer from respiratory symptoms, different neurological symptoms have been described, either directly or indirectly caused by COVID-19 [2]. Within the movement disorder spectrum, myoclonus has been observed as a COVID-19-related feature in several patients [3-5].
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http://dx.doi.org/10.1002/mdc3.13049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436437PMC
August 2020

Polysomnographic phenotype of isolated REM sleep without atonia.

Clin Neurophysiol 2020 10 28;131(10):2508-2515. Epub 2020 Jul 28.

Department of Neurology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium; Faculty of Medicine and Health Sciences, Translational Neurosciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium; Institute Born-Bunge, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.

Objective: Isolated REM sleep without atonia (iRSWA) is regarded as a prodromal phase of REM sleep behavior disorder and synucleinopathies. In iRSWA patients, we investigated the polysomnographic characteristics that are known to be altered in (prodromal) Parkinson's disease (PD): periodic limb movements of sleep [PLMS] (increased), REM density (reduced), and heart rate variability ([HRV] (reduced).

Methods: We compared video-polysomnographic studies of 49 iRSWA subjects with 41 controls. RSWA and PLMS were scored visually. REM density (REM/hour) and HRV were calculated automatically.

Results: We found a higher median total (15.90 vs 7.20; p = 0.001), REM (21.80 vs 11.0; p < 0.001) and non-REM (11.75 vs 5.72; p = 0.027) PLMS index, and a higher mean REM density (342.45 vs 275.96; p = 0.010) in the iRSWA group, with a significant positive correlation between RSWA severity and these variables (r = 0.39; p < 0.00, r = 0.48; p < 0.001, r = 0.24; p = 0.021, r = 0.28; p = 0.012). We found no significant difference in HRV between groups.

Conclusions: Our results suggest an association between RWSA and REM density and PLMS, but not HRV. The positive correlation between these variabilities may imply overlapping pathophysiological processes.

Significance: The evidence of higher REM density and normal HRV weakens the hypothesis that iRWSA is a prodromal PD stage. An alternative interpretation is, however, that REM density and HRV change during caudal-rostral neurodegeneration.
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http://dx.doi.org/10.1016/j.clinph.2020.07.005DOI Listing
October 2020

Practices and opinions about disclosure of the diagnosis of Alzheimer's disease to patients with MCI or dementia: a survey among Belgian medical experts in the field of dementia.

Acta Neurol Belg 2020 Oct 26;120(5):1157-1163. Epub 2020 Jul 26.

Institute of NeuroScience, UCLouvain, 1200, Brussels, Belgium.

Previous surveys revealed that only a minority of clinicians routinely disclosed the diagnosis of Alzheimer's disease (AD) to their patients. Many health professionals fear that the disclosure could be harmful to the patient. Recent advances in the development of biomarkers and new diagnostic criteria allow for an earlier diagnosis of AD at the mild cognitive impairment (MCI) stage. The Belgian Dementia Council, a group of Belgian experts in the field of dementia, performed a survey among its 44 members about their opinions and practices regarding disclosure of the diagnosis of AD, including MCI due to AD, and its consequences. Twenty-six respondents declared that they often or always disclose the diagnosis of AD to patients with dementia and to patients with MCI when AD CSF biomarkers are abnormal. The majority observed that the disclosure of AD is rarely or never harmful to the patients. Their patients and their caregivers rarely or never demonstrated animosity towards the clinicians following disclosure of the diagnosis of AD. These results should reassure clinicians about the safety of AD diagnosis disclosure in most cases whether the patient is at the MCI or the dementia stage.
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http://dx.doi.org/10.1007/s13760-020-01448-6DOI Listing
October 2020

Does Motor Cortex Engagement During Movement Preparation Differentially Inhibit Nociceptive Processing in Patients with Chronic Whiplash Associated Disorders, Chronic Fatigue Syndrome and Healthy Controls? An Experimental Study.

J Clin Med 2020 May 18;9(5). Epub 2020 May 18.

Pain in Motion International Research Group, www.paininmotion.be, Brussels, Belgium.

Background: Patients with chronic fatigue syndrome (CFS) and chronic whiplash associated disorders (cWAD) present a reduced ability to activate central descending nociceptive inhibition after exercise, compared to measurements before exercise. It was hypothesised that a dysfunctional motor-induced inhibition of nociception partly explains this dysfunctional exercise-induced hypoalgesia. This study investigates if engagement of the motor system during movement preparation inhibits nociception-evoked brain responses in these patients as compared to healthy controls (HC).

Methods: The experiment used laser-evoked potentials (LEPs) during three conditions (no task, mental task, movement preparation) while recording brain activity with a 32-channel electroencephalogram in 21 patients with cWAD, 20 patients with CFS and 18 HC. Two-factor mixed design Analysis of variance were used to evaluate differences in LEP amplitudes and latencies.

Results: No differences in N1, N2, N2P2, and P2 LEP amplitudes were found between the HC, CFS, and cWAD groups. After nociceptive stimulation, N1, N2 (only at hand location), N2P2, and P2 LEP amplitudes significantly decreased during movement preparation compared to no task (within group differences).

Conclusion: Movement preparation induces a similar attenuation of LEPs in patients with CFS, patients with cWAD and HC. These findings do not support reduced motor-induced nociceptive inhibition in these patients.
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http://dx.doi.org/10.3390/jcm9051520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290436PMC
May 2020

Processing of Laser-Evoked Potentials in Patients with Chronic Whiplash-Associated Disorders, Chronic Fatigue Syndrome, and Healthy Controls: A Case-Control Study.

Pain Med 2020 10;21(10):2553-2563

Pain in Motion International Research Group.

Objective: Laser-evoked potentials (LEPs) are among the reliable neurophysiological tools to investigate patients with neuropathic pain, as they can provide an objective account of the functional status of thermo-nociceptive pathways. The goal of this study was to explore the functioning of the nociceptive afferent pathways by examining LEPs in patients with chronic whiplash-associated disorders (cWAD), patients with chronic fatigue syndrome (CFS), and healthy controls (HCs).

Design: Case-control study.

Setting: A single medical center in Belgium.

Subjects: The LEPs of 21 patients with cWAD, 19 patients with CFS, and 18 HCs were analyzed in this study.

Methods: All participants received brief nociceptive CO2 laser stimuli applied to the dorsum of the left hand and left foot while brain activity was recorded with a 32-channel electroencephalogram (EEG). LEP signals and transient power modulations were compared between patient groups and HCs.

Results: No between-group differences were found for stimulus intensity, which was supraliminal for Aδ fibers. The amplitudes and latencies of LEP wave components N1, N2, and P2 in patients with cWAD and CFS were statistically similar to those of HCs. There were no significant differences between the time-frequency maps of EEG oscillation amplitude between HCs and both patient populations.

Conclusions: EEG responses of heat-sensitive Aδ fibers in patients with cWAD and CFS revealed no significant differences from the responses of HCs. These findings thus do not support a state of generalized central nervous system hyperexcitability in those patients.
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http://dx.doi.org/10.1093/pm/pnaa068DOI Listing
October 2020

Mutated ATP10B increases Parkinson's disease risk by compromising lysosomal glucosylceramide export.

Acta Neuropathol 2020 06 14;139(6):1001-1024. Epub 2020 Mar 14.

Center for Molecular Neurology, VIB, University of Antwerp, Universiteitsplein 1, 2610, Antwerpen, Belgium.

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.
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http://dx.doi.org/10.1007/s00401-020-02145-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244618PMC
June 2020

Caring for a stroke patient: The burden and experiences of primary caregivers in Uganda - A qualitative study.

Nurs Open 2019 Oct 4;6(4):1551-1558. Epub 2019 Aug 4.

MRC/UVRI and LSHTM Uganda Research Unit Entebbe Uganda.

Aim: We assessed the burden and experiences of caregivers looking after stroke patients in Kampala, Uganda.

Design: We conducted a qualitative cross-sectional study between May 2018-July 2018 among primary caregivers of stroke patients.

Methods: The primary caregiver was defined as the person spending most of the time providing daily care for the stroke patient for at least four months. Purposive sampling was used to consecutively recruit the primary caregivers. In-depth interviews were conducted, and audiotape recorded, and observations were also made. Data were managed using NVIVO 12.0 following thematic approach.

Results: Twenty-five caregivers were included in the analysis with a mean age of 39.3, 10.7. Four themes were identified from the qualitative analysis on caregivers' experiences of looking after stroke patients: taking on new responsibilities, factors that protected caregivers from breaking down, limited resources and experiences with patient outcomes. Our findings highlight the need for interventions to support stroke patients and their caregivers.
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http://dx.doi.org/10.1002/nop2.356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805272PMC
October 2019

Tolerogenic dendritic cell-based treatment for multiple sclerosis (MS): a harmonised study protocol for two phase I clinical trials comparing intradermal and intranodal cell administration.

BMJ Open 2019 09 9;9(9):e030309. Epub 2019 Sep 9.

Interuniversity Institute for Biostatistics and statistical Bioinformatics (I-BioStat), Universiteit Hasselt, Hasselt, Belgium.

Introduction: Based on the advances in the treatment of multiple sclerosis (MS), currently available disease-modifying treatments (DMT) have positively influenced the disease course of MS. However, the efficacy of DMT is highly variable and increasing treatment efficacy comes with a more severe risk profile. Hence, the unmet need for safer and more selective treatments remains. Specifically restoring immune tolerance towards myelin antigens may provide an attractive alternative. In this respect, antigen-specific tolerisation with autologous tolerogenic dendritic cells (tolDC) is a promising approach.

Methods And Analysis: Here, we will evaluate the clinical use of tolDC in a well-defined population of MS patients in two phase I clinical trials. In doing so, we aim to compare two ways of tolDC administration, namely intradermal and intranodal. The cells will be injected at consecutive intervals in three cohorts receiving incremental doses of tolDC, according to a best-of-five design. The primary objective is to assess the safety and feasibility of tolDC administration. For safety, the number of adverse events including MRI and clinical outcomes will be assessed. For feasibility, successful production of tolDC will be determined. Secondary endpoints include clinical and MRI outcome measures. The patients' immune profile will be assessed to find presumptive evidence for a tolerogenic effect in vivo.

Ethics And Dissemination: Ethics approval was obtained for the two phase I clinical trials. The results of the trials will be disseminated in a peer-reviewed journal, at scientific conferences and to patient associations.

Trial Registration Numbers: NCT02618902 and NCT02903537; EudraCT numbers: 2015-002975-16 and 2015-003541-26.
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http://dx.doi.org/10.1136/bmjopen-2019-030309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738722PMC
September 2019

Clinical and immunological control of experimental autoimmune encephalomyelitis by tolerogenic dendritic cells loaded with MOG-encoding mRNA.

J Neuroinflammation 2019 Aug 15;16(1):167. Epub 2019 Aug 15.

Laboratory of Experimental Hematology, Faculty of Medicine and Health Sciences, Vaccine and Infectious Disease Institute (VaxInfectio), University of Antwerp, Antwerp University Hospital (UZA), Wilrijkstraat 10, 2650, Edegem, Belgium.

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 MS-associated 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, MOG-immunized C57BL/6 mice were injected intravenously at days 13, 17, and 21 post-disease induction with 1α,25-dihydroxyvitamin D-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 MOG-immunized C57BL/6 mice with MOG mRNA-electroporated or MOG-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, MOG-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.
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http://dx.doi.org/10.1186/s12974-019-1541-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6696692PMC
August 2019

Frequency and characteristic features of REM sleep without atonia.

Clin Neurophysiol 2019 10 27;130(10):1825-1832. Epub 2019 Jul 27.

Faculty of Medicine and Health Sciences, Translational Neurosciences, University of Antwerp, Antwerp, Belgium; Department of Neurology, Antwerp University Hospital, Edegem, Belgium; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.

Objectives: Isolated REM sleep without atonia (iRSWA) is regarded as prodromal phase of REM sleep behavior disorder (RBD) and synucleinopathies. Other factors, however, have also been described to cause RSWA, including sleep apnea, antidepressants use and narcolepsy. We investigated the frequency of RSWA and its different etiologies.

Methods: We investigated RSWA in patients that underwent a clinical video polysomnography. In iRSWA subjects, we examined polysomnography indication and two markers of prodromal Parkinson's disease: excessive daytime sleepiness and depressive symptoms, with a case-control design.

Results: Of the 864 included polysomnographies, 188 were positive for RSWA (21.8%), 17 for RBD (2.0%) and 48 for iRSWA (5.6%). Mean Epworth Sleepiness Scale scores were 9.8 ± 4.8 (iRSWA subjects) and 7.5 ± 4.9 (controls), p = 0.014. Mean Beck Depression Inventory-II scores were 11.3 ± 7.9 (iRSWA subjects) and 9.5 ± 8.4 (controls), p = 0.229. Excessive daytime sleepiness was more often the polysomnography indication in the iRSWA group (p = 0.006).

Conclusions: RSWA is a frequent finding in the context of antidepressant use or synucleinopathies. iRSWA subjects reported increased excessive daytime sleepiness and more often had excessive daytime sleepiness as polysomnography indication.

Significance: Our study provides evidence for high frequency of RSWA, underscoring the need for longitudinal studies in iRSWA patients, with interest for conversion to synucleinopathies.
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http://dx.doi.org/10.1016/j.clinph.2019.07.018DOI Listing
October 2019

REM sleep without atonia and the relation with Lewy body disease.

Parkinsonism Relat Disord 2019 10 7;67:90-98. Epub 2019 Jul 7.

Department of Neurology, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Belgium; Faculty of Medicine and Health Sciences, Translational Neurosciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium; Institute Born-Bunge, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium. Electronic address:

REM sleep without atonia (RSWA) is the polysomnographic finding of persistent muscle tone during REM sleep, resulting in paroxysmal phasic or tonic EMG activity. RSWA is essential for the diagnosis of REM sleep behavior disorder (RBD), but can also occur without dream-enacting behavior. Loss of atonia during REM sleep is considered as a biomarker for synucleinopathies. We will give an overview of the pathophysiology of RSWA and will highlight the diagnostic methods for RSWA. We will describe the different etiologies of RSWA and finally we will focus on the role of RSWA as biomarker for Lewy body disease. RSWA severity in isolated RBD patients is a potential predictor for early conversion to Parkinson's disease (PD) or dementia with Lewy bodies. In PD patients, RSWA severity is associated with more severe motor symptoms and disease progression. Future studies are needed to delineate the importance of isolated RSWA as prodromal marker of Lewy body disease.
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http://dx.doi.org/10.1016/j.parkreldis.2019.07.007DOI Listing
October 2019

Diagnosing solvent-induced chronic toxic encephalopathy: the effect of underperformance in neuropsychological testing.

Int J Psychiatry Clin Pract 2019 Sep 13;23(3):171-177. Epub 2019 May 13.

University Department of Psychiatry, Campus Antwerp University Hospital (UZA) , Antwerp , Belgium.

The diagnoses of solvent-induced chronic toxic encephalopathy (CSE) can be supported by neuropsychological tests. However, since results not only reflect cognitive functioning but also the patient's effort to perform well, this study examines to what extent underperformance impacts neuropsychological outcomes in individuals referred for suspected CSE. : A retrospective study of 48 suspected CSE patients having completed ten neuropsychological tests assessing different domains of cognition. Underperformance was identified using the Amsterdam Short-Term Memory Test and the Rey 15-item Memory Test (FIT). Multiple linear regression was applied to examine the effect of insufficient effort on test performance. A total of 54.1% of the patients were identified as having underperformed on one or both performance validity tests. Analyses showed a significant effect of underperformance on most tests barring letter-number sequencing. Most of the neuropsychological tests evaluated showed significant effects of underperformance. Performance on letter-number sequencing was not affected. In case of underperformance, the results of the neuropsychological assessment should be disregarded when weighing the final multi-disciplinary diagnosis, with the exception of letter-number sequencing. Key points A total of 54.1% of patients with suspected CSE referred for neuropsychological assessment was identified as having underperformed on one or both PVTs. Underperformance has a significant effect on most neuropsychological tests with the exception of letter-number sequencing assessing attention and working memory. In case of underperformance, the results of the neuropsychological assessment should be disregarded when weighing the final multi-disciplinary diagnosis, with the exception of letter-number sequencing.
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http://dx.doi.org/10.1080/13651501.2019.1571210DOI Listing
September 2019

Impulsive-Compulsive Behaviours in Belgian-Flemish Parkinson's Disease Patients: A Questionnaire-Based Study.

Parkinsons Dis 2019 18;2019:7832487. Epub 2019 Mar 18.

Department of Neurology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium.

Background: Impulsive-compulsive behaviours (ICB) are a potentially harmful group of behavioural symptoms among the nonmotor aspects of Parkinson's disease (PD).

Objective: To develop and perform partial validation of a Belgian-Flemish version of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP) as a screening instrument for ICB in PD patients.

Methods: Using a translation-backtranslation method, we developed a Belgian-Flemish version of the QUIP, which was subsequently completed by 88 PD patients. QUIP-positive patients were invited for a semistructured diagnostic interview.

Results: A positive QUIP score for one or more ICB was observed in 37 patients (41%). In 15 patients (17%), a positive QUIP score for one or more impulse control disorders (ICD) was noted: pathological gambling in 1, hypersexuality in 8, compulsive shopping in 5, and compulsive eating in 8 patients. A positive QUIP score for punding, hobbyism, and/or walkabout was observed in 30 patients. The semistructured diagnostic interview was performed in 22 QUIP-positive patients. The diagnosis of ICB was confirmed in 6 patients, suggesting a positive predictive value of 27% for the Belgian-Flemish version of the QUIP.

Conclusions: We have developed a Belgian-Flemish version of the QUIP, which can be used as a screening questionnaire for ICB in PD patients. Our data suggest that sensitivity is high, specificity is low, and validity of the questionnaire is similar to the original version. We confirm the necessity of additional clinical assessment of QUIP-positive patients to ascertain a diagnosis of ICB.
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http://dx.doi.org/10.1155/2019/7832487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442308PMC
March 2019

Training volume is associated with pain sensitivity, but not with endogenous pain modulation, in competitive swimmers.

Phys Ther Sport 2019 May 5;37:150-156. Epub 2019 Apr 5.

Rehabilitation Sciences and Physiotherapy, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium. Electronic address:

Objectives: To investigate the association of pain sensitivity and endogenous analgesia capacity, and training volume in a group of competitive swimmers.

Design: An observational multi-center study.

Setting: Multiple competitive swimming clubs.

Participants: 102 healthy competitive swimmers.

Main Outcome Measures: Training volume was estimated using self-reported information. Static and dynamic measures of pain were assessed using pressure pain thresholds (PPTs) and conditioned pain modulation (CPM), the latter as a measure of endogenous pain inhibition. Selected demographic and psychosocial measures were considered as possible confounding factors.

Results: Moderate positive correlations (0.38 < r < 0.44; p < 0.01) exist between self-reported training volume and PPTs at widespread body areas in competitive swimmers. These results were maintained during linear regression analysis while addressing possible confounding factors such as age and selected psychosocial factors. No associations were found between self-reported training volume and conditioned pain modulation (-0.08 < r < 0.06; p > 0.05).

Conclusions: Self-reported swim training volume is associated with pain sensitivity in competitive swimmers. Swimmers who train more show higher pressure pain thresholds, indicating lower pain sensitivity. Swim training volume is not associated with endogenous nociceptive inhibitory capacity as determined using CPM.
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http://dx.doi.org/10.1016/j.ptsp.2019.04.001DOI Listing
May 2019

Loss of DPP6 in neurodegenerative dementia: a genetic player in the dysfunction of neuronal excitability.

Acta Neuropathol 2019 06 14;137(6):901-918. Epub 2019 Mar 14.

Center for Molecular Neurology, VIB, Antwerp, Belgium.

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 K4.2 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 < 0.001 and p < 0.0001) leading to a loss of protein. Reduced DPP6 and/or K4.2 expression was also detected in brain tissue of missense variant carriers. Loss of DPP6 is known to cause neuronal hyperexcitability and behavioral alterations in Dpp6-KO mice. Taken together, the results of our genomic, genetic, expression and modeling analyses, provided direct evidence supporting the involvement of DPP6 loss in dementia. We propose that loss of function variants have a higher penetrance and disease impact, whereas the missense variants have a variable risk contribution to disease that can vary from high to low penetrance. Our findings of DPP6, as novel gene in dementia, strengthen the involvement of neuronal hyperexcitability and alteration in the homeostasis of neuronal firing as a disease mechanism to further investigate.
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http://dx.doi.org/10.1007/s00401-019-01976-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531610PMC
June 2019

The combined impact of dependency on caregivers, disability, and coping strategy on quality of life after ischemic stroke.

Health Qual Life Outcomes 2019 Feb 7;17(1):31. Epub 2019 Feb 7.

Stroke Division, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia.

Background: To estimate the additional impact of coping and of being dependent on caregivers, over and above the large effects of disability on utility after ischemic stroke.

Methods: A total of 539 patients were recruited into an observational, retrospective study when returning for a check-up between 3 and 36 months after an ischemic stroke. Patients' modified Rankin Scale (mRS), dependency on caregivers, the Brandtstädter and Renner Coping questionnaire (with summary scores: Tenacity of Goal Pursuit (TGP) and Flexible Goal Adjustment (FGA) coping styles), EQ-5D-3 L and co-morbidities were evaluated.

Results: In multivariable regression, greater disability (mRS) resulted in large utility losses, between 0.06 for mRS 1 to 0.65 for mRS 5 (p < 0.0001). Dependency on caregivers caused an additional dis-utility of 0.104 (p = 0.0006) which varied by mRS (0.044, 0.060, 0.083, 0.115, 0.150 and 0.173 for mRS 0-5). The effect of coping on utility varied by coping style, by the disability level of the patient and by his or her dependency on caregivers. FGA coping was associated with additional increases in utility (p < 0.0001) over and above the effect of disability and dependency, whereas TGA had no significant impact. FGA coping was associated with larger utility changes among more disabled patients (0.018 to 0.105 additional utility, for mRS 0 to mRS 5 respectively). Dependent patients had more to gain from FGA coping than patients who function independently of caregivers: utility gains were between 0.049 and 0.072 for moderate to high levels of FGA coping. In contrast, the same positive evolution in FGA coping resulted in 0.039 and 0.057 utility gain among independent patients. Finally, we found that important stroke risk factors and co-morbidities, such as diabetes and atrial fibrillation, were not predictors of EQ-5D utility in a multivariable setting.

Conclusions: This study suggests that treatment strategies targeting flexible coping styles and decreasing dependency on caregivers may lead to significant gains in quality of life above and beyond treatment strategies that solely target disability.
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http://dx.doi.org/10.1186/s12955-018-1069-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367764PMC
February 2019

The relationship between Home-time, quality of life and costs after ischemic stroke: the impact of the need for mobility aids, home and car modifications on Home-time.

Disabil Rehabil 2020 02 2;42(3):419-425. Epub 2018 Oct 2.

Stroke Division, Florey Institute of Neuroscience and Mental Health, University of Melbourne and Austin Health, Victoria, Australia.

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. 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. Each additional Home-time day was significantly associated with an increase in utility of 0.0056 ( < 0.0001) and an in- and outpatient cost saving of $99 ( = 0.0158). Requiring extra material support significantly decreased Home-time by 76 days (including: requiring home changes: -68 days, car alterations: -49 days, needing a wheelchair: -80 days or walker: -71 days, needing bed or bath rails: -79 days). This univariable effect was confirmed in multivariable analysis when comparing with patients having the same disability level without requiring material support. Home-time is a stroke outcome associated with disease severity, healthcare costs and patient wellbeing. Streamlining the discharge process for those requiring extra material support may lead to cost savings and higher quality-of-life.Implications for rehabilitationDelays in discharge from the acute hospital or rehabilitation facility are incurred when patients need extra material support in order to return home.Staff from the discharging facility should assist families by giving timely information on the availability and the cost of wheel chairs and walkers; and explaining and planning the need of a stair lift, bed and bath rails as well as car modifications.Planning the discharge process with the families will lead to a more rapid return home and will result in reduced overall health care costs and higher quality of life for the patients.
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http://dx.doi.org/10.1080/09638288.2018.1501438DOI Listing
February 2020
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