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Introduction: Gait initiation is preceded by three anticipatory postural adjustment (APA) phases. In Parkinson's disease (PD) generated force, displacement and timing during APA differ from healthy controls. APA might be influenced by disease status, weight or emotion. It is unknown how motor severity, disease duration or presence of apathy influences APA timing and displacement. Methods: We included 99 people with PD and 50 healthy controls (HC) to perform five gait initiation trials following an auditory cue. Force plates measured timing and center of pressure (CoP) displacement during APA phases. Results: Time to gait initiation (tGI) was higher in the PD group (p

Introduction Untreated hearing loss is the largest potentially modifiable risk factor for dementia. Additionally, vestibular dysfunction has been put forward as a potential risk factor for accelerated cognitive decline. Patients with Deafness Autosomal Dominant 9 (DFNA9) present with progressive sensorineural hearing loss and bilateral vestibulopathy and show significantly worse results in cognitive performance compared with a cognitively healthy control group. This highlights the need for adequate treatment to prevent further cognitive decline. This study aims to determine how hearing and vestibular function evolve in (pre-)symptomatic carriers of the p.Pro51Ser mutation in the COCH gene and how this impacts their cognitive performance and health-related quality of life.Methods and analysis A prospective, longitudinal evaluation of hearing, vestibular function and cognitive performance will be acquired at baseline, 1-year and 2-year follow-up. A total of 40 patients with DFNA9 will be included in the study. The study will be a single-centre study performed at the ORL department at the Antwerp University Hospital (UZA), Belgium. The control group will encompass cognitively healthy subjects, already recruited through the GECkO study. The primary outcome measure will be the Repeatable Battery for the Assessment of Neuropsychological Status adjusted for the Hearing-Impaired total score. Secondary outcome measures include Cortical Auditory-Evoked Potentials, vestibular assessments and health-related quality of life questionnaires. The expected outcomes will aid in the development of gene therapy by providing insight in the optimal time window for the application of gene therapy for the inner ear.Ethics and dissemination The ethical committee of UZA approved the study protocol on 19 December 2022 (protocol number B3002022000170). All participants have to give written initial informed consent in accordance with the Declaration of Helsinki. Results will be disseminated to the public through conference presentations, lectures and peer-reviewed scientific publications.

Abstract 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 (

Abstract 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

Background: Alzheimer’s disease (AD) is the most prevalent cause of dementia which affects a growing number of people worldwide. Early identification of people at risk to develop AD should be prioritized. Hearing loss is considered an independent potentially modifiable risk factor for accelerated cognitive decline and dementia in older adults. The main outcome of interest of this review is the alteration of Cortical Auditory Evoked Potential (CAEP) morphology in an AD or mild cognitive impairment (MCI) population with and without hearing loss.Methods: Two investigators independently and systematically searched publications regarding auditory processing on a cortical level in people with cognitive impairment (MCI or AD) with and without hearing loss. Only articles which mentioned at least one auditory elicited event-related potential (ERP) component and that were written in English or Dutch were included. Animal studies were excluded. No restrictions were imposed regarding publication date. The reference list of potential sources were screened for additional articles.Results: This systematic review found no eligible articles that met all inclusion criteria. Therefore, no results were included, resulting in an empty systematic review.Conclusion: In general, dysfunction – being either from cognitive or auditory origin – reduces CAEP amplitudes and prolongs latencies. Therefore, CAEPs may be a prognostic indicator in the early stages of cognitive decline. However, it remains unclear which CAEP component alteration is due to cognitive impairment, and which is due to hearing loss (or even both). In addition, vestibular dysfunction – associated with hearing loss, cognitive impairment and AD – may also alter CAEP responses. Further CAEP studies are warranted, integrating cognitive, hearing, and vestibular evaluations.

Abstract 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, SD 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.

Abstract 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, 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.

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.

Apathy is a neurobehavioural symptom affecting Parkinson’s disease patients of all disease stages. Apathy seems to be associated with a specific underlying non-motor disease subtype and reflects dysfunction of separate neural networks with distinct neurotransmitter systems. Due to the complicated neuropsychiatric aetiology of apathy, clinical assessment of this invalidating non-motor symptom remains challenging. We aim to summarize the current findings on apathy in Parkinson’s disease and highlight knowledge gaps. We will discuss the prevalence rates across the different disease stages and suggest screening tools for clinically relevant apathetic symptoms. We will approach the fundamental knowledge on the neural networks implicated in apathy in a practical manner and formulate recommendations on patient-tailored treatment. We will discuss the Park apathy phenotype in detail, shedding light on different clinical manifestations and implications for prognosis. With this review, we strive to distil the vast available theoretical knowledge into a clinical and patient-oriented perspective.

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.

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).

Abstract 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

Abstract Background We explored the diagnostic performance of cerebrospinal fluid (CSF) biomarkers in allowing differentiation between frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease (AD), as well as between FTLD pathological subtypes. Methods CSF levels of routine AD biomarkers (phosphorylated tau (p-tau181), total tau (t-tau), and amyloid-beta (Aβ)1–42) and neurofilament proteins, as well as progranulin levels in both CSF and serum were quantified in definite FTLD (n = 46), clinical AD (n = 45), and cognitively healthy controls (n = 20). FTLD subgroups were defined by genetic carrier status and/or postmortem neuropathological confirmation (FTLD-TDP: n = 34, including FTLD-C9orf72: n = 19 and FTLD-GRN: n = 9; FTLD-tau: n = 10). Results GRN mutation carriers had significantly lower progranulin levels compared to other FTLD patients, AD, and controls. Both t-tau and p-tau181 were normal in FTLD patients, even in FTLD-tau. Aβ1–42 levels were very variable in FTLD. Neurofilament light chain (Nf-L) was significantly higher in FTLD compared with AD and controls. The reference logistic regression model based on the established AD biomarkers could be improved by the inclusion of CSF Nf-L, which was also important for the differentiation between FTLD and controls. Within the FTLD cohort, no significant differences were found between FTLD-TDP and FTLD-tau, but GRN mutation carriers had higher t-tau and Nf-L levels than C9orf72 mutation carriers and FTLD-tau patients. Conclusions There is an added value for Nf-L in the differential diagnosis of FTLD. Progranulin levels in CSF depend on mutation status, and GRN mutation carriers seem to be affected by more severe neurodegeneration.

Abstract Background In this paper, we describe the clinical and neuropathological findings of nine members of the Belgian progranulin gene (GRN) founder family. In this family, the loss-of-function mutation IVS1 + 5G > C was identified in 2006. In 2007, a clinical description of the mutation carriers was published that revealed the clinical heterogeneity among IVS1 + 5G > C carriers. We report our comparison of our data with the published clinical and neuropathological characteristics of other GRN mutations as well as other frontotemporal lobar degeneration (FTLD) syndromes, and we present a review of the literature. Methods For each case, standardized sampling and staining were performed to identify proteinopathies, cerebrovascular disease, and hippocampal sclerosis. Results The neuropathological substrate in the studied family was compatible in all cases with transactive response DNA-binding protein (TDP) proteinopathy type A, as expected. Additionally, most of the cases presented also with primary age-related tauopathy (PART) or mild Alzheimer’s disease (AD) neuropathological changes, and one case had extensive Lewy body pathology. An additional finding was the presence of cerebral small vessel changes in every patient in this family. Conclusions Our data show not only that the IVS1 + 5G > C mutation has an exclusive association with FTLD-TDP type A proteinopathy but also that other proteinopathies can occur and should be looked for. Because the penetrance rate of the clinical phenotype of carriers of GRN mutations is age-dependent, further research is required to investigate the role of co-occurring age-related pathologies such as AD, PART, and cerebral small vessel disease.

Abstract Background The Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers Aβ1–42, t-tau, and p-tau181 overlap with other diseases. New tau modifications or epitopes, such as the non-phosphorylated tau fraction (p-taurel), may improve differential dementia diagnosis. The goal of this study is to investigate if p-taurel can improve the diagnostic performance of the AD CSF biomarker panel for differential dementia diagnosis. Methods The study population consisted of 45 AD, 45 frontotemporal lobar degeneration (FTLD), 45 dementia with Lewy bodies (DLB), and 21 Creutzfeldt-Jakob disease (CJD) patients, and 20 cognitively healthy controls. A substantial subset of the patients was pathology-confirmed. CSF levels of Aβ1–42, t-tau, p-tau181, and p-taurel were determined with commercially available single-analyte enzyme-linked immunosorbent assay (ELISA) kits. Diagnostic performance was evaluated by receiver operating characteristic (ROC) curve analyses, and area under the curve (AUC) values were compared using DeLong tests. Results The diagnostic performance of single markers as well as biomarker ratios was determined for each pairwise comparison of different dementia groups and controls. The addition of p-taurel to the AD biomarker panel decreased its diagnostic performance when discriminating non-AD, FTLD, and DLB from AD. As a single marker, p-taurel increased the diagnostic performance for CJD. No significant difference was found in AUC values with the addition of p-taurel when differentiating between AD or non-AD dementias and controls. Conclusions The addition of p-taurel to the AD CSF biomarker panel failed to improve differentiation between AD and non-AD dementias.

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.

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.

Mindfulness was introduced in the Western world by Jon Kabat-Zinn in 1979. He defined it as “awareness that arises through paying attention, on purpose, in the present moment, non-judgmentally.” Since then, research on mindfulness-based interventions (MBIs) has increased exponentially both in health and disease, including in patients with neurodegenerative diseases such as dementia and Parkinson's disease. Research on the effect of mindfulness and multiple sclerosis (MS) only recently gained interest. Several studies completed since 2010 provided evidence that mindfulness improves quality of life (QoL), depression and fatigue in MS patients. In addition to patient-reported outcome measures, potential effects on cognitive function have been investigated only to a very limited extent. However, research on laboratory biomarkers and neuroimaging, capable to deliver proof-of-concept of this behavioral treatment in MS, is mainly lacking. In this perspective, we illustrate possible neurobiological mechanisms, including the tripartite interaction between the brain, the immune system and neuroendocrine regulation, through which this treatment might affect multiple sclerosis symptoms. We propose to (1) include immunological and/or neuroimaging biomarkers as standard outcome measures in future research dedicated to mindfulness and MS to help explain the clinical improvements seen in fatigue and depression; (2) to investigate effects on enhancing cognitive reserve and cognitive function; and (3) to investigate the effects of mindfulness on the disease course in MS.

Classical or M1 activity of microglia/macrophages has been described in several neurodegenerative and brain inflammatory conditions and has also been linked to expansion of ischemic injury in post-stroke brain. While different pathways of M1 polarization have been suggested to occur in the post-stroke brain, the precise underlying mechanisms remain undefined. Using a transient middle cerebral artery occlusion (MCAO) rat model, we showed a progressive M2 to M1 polarization in the perilesional brain region with M1 cells becoming one of the dominant subsets by day 4 post-stroke. Comparing key receptors involved in M1 polarization (CD8, IFNγR, Clec4, FcγR, TLR3 and TLR4) and their signal transducers (Syk, Stat1, Irf3, and Traf6) at the day 4 time point, we showed a strong upregulation of CD8 along with SYK transducer in dissected perilesional brain tissue. We further showed that CD8 expression in the post-stroke brain was associated with activated (CD68+) macrophages and that progressive accumulation of CD8+CD68+ cells in the post-stroke brain coincided with increased iNOS (M1 marker) and reduced Arg1 (M2 marker) expression on these cells. In vitro ligand-based stimulation of the CD8 receptor caused increased iNOS expression and an enhanced capacity to phagocytose E. coli particles; and interestingly, CD8 stimulation was also able to repolarize IL4-treated M2 cells to an M1 phenotype. Our data suggest that increased CD8 signaling in the post-stroke brain is primarily associated with microglia/macrophages and can independently drive M1 polarization, and that modulation of CD8 signaling could be a potential target to limit secondary post-stroke brain damage.

Introduction. In sub-Saharan Africa (SSA), there is a significant burden of ischemic stroke (IS) and hemorrhagic stroke (HS), although data on risk factors for each type are sparse. In this systematic review we attempt to characterize the risk factors. Methods. We systematically reviewed (PubMed, EMBASE, WHOLIS, Google Scholar, Wiley online, and the Cochrane Central Register of Controlled Trials (CENTRAL)) case-control studies and case series from 1980 to 2016 that reported risk factors for IS and/or HS in SSA. For each risk factor we calculated random-effects pooled odds ratios (ORs) for case-control studies and pooled prevalence estimates for case series. Results. We identified 12 studies, including 4,387 stroke patients. Pooled analysis showed that patients who had diabetes (OR = 2.39; 95% CI: 1.14–5.03) and HIV (OR = 2.46 (95% CI: 1.59–3.81) were at a significantly greater risk of suffering from all stroke types. There were insufficient data to examine these factors by stroke type. Among case series, the pooled prevalence of hypertension was higher for HS than for IS (73.5% versus 62.8%), while diabetes mellitus (DM) and atrial fibrillation (AF) were more prevalent among IS compared to HS (15.9% versus 10.6% and 9.6% versus 2.3%, respectively). Conclusions. There remain too few data from SSA to reliably estimate the effect of various factors on the risk of IS and HS. Furthermore, the vast majority of cases were identified in hospital and so are unlikely to be representative of the totality of stroke cases in the community.

The in vivo cutaneous nerve regeneration model using capsaicin is applied extensively to study the regenerative mechanisms and therapeutic efficacy of disease modifying molecules for small fiber neuropathy (SFN). Since mismatches between functional and morphological nerve fiber recovery are described for this model, we aimed at determining the capability of the capsaicin model to truly mimic the morphological manifestations of SFN in diabetes. As nerve and blood vessel growth and regenerative capacities are defective in diabetes, we focused on studying the key regulator of these processes, the neuropilin-1 (NRP-1)/semaphorin pathway. This led us to the evaluation of NRP-1 receptor expression in epidermis and dermis of subjects presenting experimentally induced small fiber neuropathy, diabetic polyneuropathy and of diabetic subjects without clinical signs of small fiber neuropathy. The NRP-1 receptor was co-stained with CD31 vessel-marker using immunofluorescence and analyzed with Definiens® technology. This study indicates that capsaicin application results in significant loss of epidermal NRP-1 receptor expression, whereas diabetic subjects presenting small fiber neuropathy show full epidermal NRP-1 expression in contrast to the basal expression pattern seen in healthy controls. Capsaicin induced a decrease in dermal non-vascular NRP-1 receptor expression which did not appear in diabetic polyneuropathy. We can conclude that the capsaicin model does not mimic diabetic neuropathy related changes for cutaneous NRP-1 receptor expression. In addition, our data suggest that NRP-1 might play an important role in epidermal nerve fiber loss and/or defective regeneration and that NRP-1 receptor could change the epidermal environment to a nerve fiber repellant bed possibly through Sem3A in diabetes.

While emerging evidence indicates that dendritic cells (DC) play a central role in the pathogenesis of multiple sclerosis (MS), their modulation with immunoregulatory agents provides prospect as disease-modifying therapy. Our observations reveal that 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) treatment of monocyte-derived DC results in a semimature phenotype and anti-inflammatory cytokine profile as compared to conventional DC, in both healthy controls and MS patients. Importantly, 1,25(OH)2D3-treated DC induce T cell hyporesponsiveness, as demonstrated in an allogeneic mixed leukocyte reaction. Next, following a freeze-thaw cycle, 1,25(OH)2D3-treated immature DC could be recovered with a 78% yield and 75% viability. Cryopreservation did not affect the expression of membrane markers by 1,25(OH)2D3-treated DC nor their capacity to induce T cell hyporesponsiveness. In addition, the T cell hyporesponsiveness induced by 1,25(OH)2D3-treated DC is antigen-specific and robust since T cells retain their capacity to respond to an unrelated antigen and do not reactivate upon rechallenge with fully mature conventional DC, respectively. These observations underline the clinical potential of tolerogenic DC (tolDC) to correct the immunological imbalance in MS. Furthermore, the feasibility to cryopreserve highly potent tolDC will, ultimately, contribute to the large-scale production and the widely applicable use of tolDC.

An in situ approach was used to identify the oxidized RNA nucleoside 8-hydroxyguanosine (8OHG) in the frontal cortex of familial Alzheimer's disease (FAD) with a mutation in presenilin-1 (PS-1) or amyloid β protein precursor (AβPP) gene (n = 13, age 47–81 years). Neurons with marked 8OHG immunoreaction in the cytoplasm were widely distributed in the superior/middle frontal gyrus of FAD. Relative intensity measurements of neuronal 8OHG immunoreactivity showed that there was a significant increase in FAD compared with controls (n = 15, age 59–81 years), while there was no difference in relative 8OHG between the PS-1 and the AβPP FAD. Interestingly, a presymptomatic case carrying a PS-1 mutation showed a considerable level of relative 8OHG, and the increased levels of neuronal 8OHG in FAD were more prominent in cases with a lower percentage area of Aβ42 burden. These results suggest that oxidative stress is an early event involved in the pathological cascade of FAD.

Objective. To investigate possible neurobehavioral changes secondary to a mindfulness based intervention (MBI) training for individuals living with Parkinson’s disease (PD). Background. In the context of complementary medicine, MBIs are increasingly being used for stress reduction and in patient populations coping with chronic illness. The use of alternative and complementary medicine may be higher in patients with chronic conditions such as PD. However, behavioral effects of mindfulness training in PD have not yet been reported in the literature and this points to an unmet need and warrants further examination. Methods. A total of 27 out of 30 PD patients completed a randomized controlled longitudinal trial. Questionnaires and the UPDRS I–IV were obtained at baseline and 8-week follow-up. Results. Significant changes after the MBI were found including a 5.5 point decrease on the UPDRS motor score, an increase of 0.79 points on Parkinson’s disease questionnaire (PDQ-39) pain item, and a 3.15 point increase in the Five Facet Mindfulness Questionnaire observe facet. Conclusions. To the best of our knowledge, this is the first quantitative analysis of neurobehavioral effects of MBI in PD.

The contribution of mutations in the amyloid precursor protein (APP) gene known as Flemish (APP/A692G) and Dutch (APP/E693Q) to the pathogenesis of Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis of the Dutch type, respectively, was studied in transgenic mice that overexpress the mutant APP in brain. These transgenic mice showed the same early behavioral disturbances and defects and increased premature death as the APP/London (APP V717I), APP/Swedish (K670N, M671L), and other APP transgenic mice described previously. Pathological changes included intense glial reaction, extensive microspongiosis in the white matter, and apoptotic neurons in select areas of the brain, while amyloid deposits were absent, even in mice over 18 months of age. This contrasts with extensive amyloid deposition in APP/London transgenic mice and less pronounced amyloid deposition in APP/Swedish transgenic mice generated identically. It demonstrated, however, that the behavioral deficiencies and the pathological changes in brain resulting from an impaired neuronal function are caused directly by APP or its proteolytic derivative(s). These accelerate or impinge on the normal process of aging and amyloid deposits per se are not essential for this phenotype.

Mutations in the presenilin 1 (PSEN1) gene are an important cause of autosomal dominant Alzheimer's disease (AD). Both in vitro and in vivo experiments showed that PSEN1 mutations increase secretion of amyloid β42 (Aβ42), the longer and more fibrillogenic isoform of Aβ. We measured secreted Aβ42 in plasma of patients, presymptomatic mutation carriers, and escapees of two extended Belgian early-onset AD families, AD/A and AD/B, with a similar severe phenotype in terms of onset age (mean 35 years), duration of the disease (mean 6.5 years), and pathology. Both families segregate a different missense mutation in PSEN1 located in different parts of the protein: I143T in family AD/A and G384A in family AD/B. A significant increase in Aβ42 concentrations was observed in plasma of mutation carriers in family AD/B, but not in family AD/A. A differential effect of the two PSEN1 mutations on Aβ42 secretion was also detected in conditioned medium of stably transfected HEK293 cells. Both mutations increased Aβ42 secretion significantly; however, the increase was highest for G384A (5.5-fold over wild-type PSEN1), the largest effect observed for missense PSEN1 mutations to date. Although the Aβ42 concentrations measured in vivo and in vitro did not correlate with onset age, a positive correlation was obtained with age in the presymptomatic mutation carriers and a negative correlation with duration of disease in the patients. Our data obtained for PSEN1 mutation carriers suggest that measuring Aβ42 concentrations in plasma will be informative as a diagnostic marker in a limited number of cases.

OBJECTIVES: to determine the concurrent validity of a physical activity diary for measuring physical activity level and total energy expenditure in hospitalized stroke patients. METHOD: Sixteen stroke patients kept coded activity diaries and wore SenseWear Pro2 multi-sensor activity monitors during daytime hours for one day. A researcher observed the patients and completed a diary. Data from the patients' diaries were compared with observed and measured data to determine total activity (METs*minutes), activity level and total energy expenditure. RESULTS: Spearman correlations between the patients' and researchers' diaries revealed a high correlation for total METs*minutes (rs = 0.75, p

This study examines the impact of Parkinson's disease (PD) on communicative efficiency conveyed through prosody. A new assessment method for evaluating productive prosodic skills in Dutch speaking dysarthric patients was devised and tested on 36 individuals (18 controls, 18 PD patients). Three professional listeners judged the intended meanings in four communicative functions of Dutch prosody: Boundary Marking, Focus, Sentence Typing, and Emotional Prosody. Each function was tested through reading and imitation. Interrater agreement was calculated. Results indicated that healthy speakers, compared to PD patients, performed significantly better on imitation of Boundary Marking, Focus, and Sentence Typing. PD patients with a moderate or severe dysarthria performed significantly worse on imitation of Focus than on reading of Focus. No significant differences were found for Emotional Prosody. Judges agreed well on all tasks except Emotional Prosody. Future research will focus on elaborating the assessment and on developing a therapy programme paralleling the assessment.