Mutated Toll-like receptor 9 increases Alzheimer's disease risk by compromising innate immunity protection.

The development of Alzheimer's disease (AD) involves central and peripheral immune deregulation. Gene identification and studies of AD genetic variants of peripheral immune components may aid understanding of peripheral-central immune crosstalk and facilitate new opportunities for therapeutic intervention. In this study, we have identified in a Flanders-Belgian family a novel variant p.E317D in the Toll-like receptor 9 gene (TLR9), co-segregating with EOAD in an autosomal dominant manner. In human, TLR9 is an essential innate and adaptive immune component predominantly expressed in peripheral immune cells. The p.E317D variant caused 50% reduction in TLR9 activation in the NF-κB luciferase assay suggesting that p.E317D is a loss-of-function mutation. Cytokine profiling of human PBMCs upon TLR9 activation revealed a predominantly anti-inflammatory response in contrast to the inflammatory responses from TLR7/8 activation. The cytokines released upon TLR9 activation suppressed inflammation and promoted phagocytosis of Aß42 oligomers in human iPSC-derived microglia. Transcriptome analysis identified upregulation of AXL, RUBICON and associated signaling pathways, which may underline the effects of TLR9 signaling-induced cytokines in regulating the inflammatory status and phagocytic property of microglia. Our data suggest a protective role of TLR9 signaling in AD pathogenesis, and we propose that TLR9 loss-of-function may disrupt a peripheral-central immune crosstalk that promotes dampening of inflammation and clearance of toxic protein species, leading to the build-up of neuroinflammation and pathogenic protein aggregates in AD development.

The 2022 European postgraduate (residency) programme in neurology in a historical and international perspective.

BACKGROUND AND PURPOSE: Neurology residency programmes, which were first established at the beginning of the 20th century, have become mandatory all over Europe in the last 40-50 years. The first European Training Requirements in Neurology (ETRN) were published in 2005 and first updated in 2016. This paper reports the most recent revisions of the ETRN. METHODS: Members of the EAN board performed an in depth revision of the ETNR 2016-version, which was reviewed by members of the European Board and Section of Neurology of the UEMS, the Education and Scientific Panels, the Resident and Research Fellow Section and the Board of the EAN, as well as the presidents of the 47 European National Societies. RESULTS: The new (2022) ETRN suggest a 5-year training subdivided in three phases: a first phase (2 years) of general neurology training, a second phase (2 years) of training in neurophysiology/neurological subspecialties and a third phase (1 year) to expand clinical training (e.g., in other neurodisciplines) or for research (path for clinical neuroscientist). The necessary theoretical and clinical competences as well as learning objectives in diagnostic tests have been updated, are newly organized in four levels and include 19 neurological subspecialties. Finally, the new ETRN require, in addition to a programme director, a team of clinician-educators who regularly review the resident's progress. The 2022 update of the ETRN reflects emerging requirements for the practice of neurology and contributes to the international standardization of training necessary for the increasing needs of residents and specialists across Europe.

Evidence of Vestibular and Balance Dysfunction in Patients With Mild Cognitive Impairment and Alzheimer's Disease.

OBJECTIVES: Given the expected rise in dementia prevalence, early diagnosis is vital. As a growing body of literature has identified a potential association between vestibular function and cognition, vestibular assessment may aid in early screening. The aim of the study was to better comprehend the proposed association between vestibular function and Alzheimer's disease (AD) by comparing vestibular parameters (vestibular function testing and clinical balance measures) between a group with mild cognitive impairment (MCI), AD, and healthy controls with age-normal cognition. DESIGN: Cross-sectional analysis of the GECkO study, an ongoing prospective single-center longitudinal cohort study. This study included 100 older adults (55 to 84 years). A total of 33 participants with MCI, 17 participants with AD, and 50 participants of age, sex, and hearing-matched healthy controls were included. RESULTS: Participants with AD demonstrated a delayed latency of the p13 component measured by cervical vestibular-evoked myogenic potentials (cVEMP) compared with healthy controls and participants with MCI. Other measures including n23 latency, presence of intact responses, rectified amplitude, mean rectified voltage (measured by cVEMP) and lateral vestibulo-ocular reflex gain (measured by video Head Impulse Test [vHIT]) did not differ between groups. The Timed Up and Go (TUG), Performance-Oriented Mobility Assessment-Balance subscale (POMA-B), and Functional Gait Assessment (FGA) differed significantly between the three groups. Here, more cognitively impaired groups were associated with worse clinical balance scores. CONCLUSIONS: Vestibular and balance deficits were more prevalent in groups with increasing cognitive decline. Regarding vestibular function testing, p13 latency as measured by cVEMP was delayed in participants with AD. Other cVEMP or vHIT measures did not differ between groups. All three clinical balance assessments (TUG, POMA-B, and FGA) resulted in worse scores along the AD continuum. Future research integrating vestibular parameters that add value (including otolith function testing, balance, and spatial navigation) is recommended to validate the association between vestibular function and cognition while avoiding redundant testing.

The Growing Role of Telerehabilitation and Teleassessment in the Management of Movement Disorders in Rare Neurological Diseases: A Scoping Review.

Background: People with rare neurological diseases (RNDs) often experience symptoms related to movement disorders, requiring a multidisciplinary approach, including rehabilitation. Telemedicine applied to rehabilitation and symptom monitoring may be suitable to ensure treatment consistency and personalized intervention. The objective of this scoping review aimed to emphasize the potential role of telerehabilitation and teleassessment in managing movement disorders within RNDs. By providing a systematic overview of the available literature, we sought to highlight potential interventions, outcomes, and critical issues. Methods: A literature search was conducted on PubMed, Google Scholar, IEEE, and Scopus up to March 2024. Two inclusion criteria were followed: (1) papers focusing on telerehabilitation and teleassessment and (2) papers dealing with movement disorders in RNDs. Results: Eighteen papers fulfilled the inclusion criteria. The main interventions were home-based software and training programs, exergames, wearable sensors, smartphone applications, virtual reality and digital music players for telerehabilitation; wearable sensors, mobile applications, and patient home video for teleassessment. Key findings revealed positive outcomes in gait, balance, limb disability, and in remote monitoring. Limitations include small sample sizes, short intervention durations, and the lack of standardized protocols. Conclusion: This review highlighted the potential of telerehabilitation and teleassessment in addressing movement disorders within RNDs. Data indicate that these modalities may play a major role in supporting conventional programs. Addressing limitations through multicenter studies, longer-term follow-ups, and standardized protocols is essential. These measures are essential for improving remote rehabilitation and assessment, contributing to an improved quality of life for people with RNDs.

50 Years of terrorism in Belgium: a review of 121 incidents in the global terrorism database.

OBJECTIVES: Belgium is not only prone to inland terrorism but also attracts terrorist factions aiming at various political, diplomatic, military, and/or religious targets. This study aimed to identify and characterize all documented terrorist attacks in Belgium reported to the Global Terrorism Database (GTD) over a period of 50 years. METHODS: The GTD was searched for all terrorist attacks in Belgium between 1970 and 2019. Analyses were performed on temporal factors, location, target type, attack and weapon type, attacker type, and number of casualties or hostages. RESULTS: In 50 years, 121 incidents accounted for 80 confirmed fatalities and 498 injured people. Bombings and explosions were the most frequently identified attack type (46.3%), followed by assassination (16.5%), infrastructure damage (15.7%) and armed or unarmed assaults (14.0%). Governmental and diplomatic institutions were the most frequent target (24.0%). For those perpetrators the GTD did have enough information we saw a timely change from far left and separatist dominating the early decades to Jihadi groups in the last decade, while anti-semitic factions were active in every decade. CONCLUSION: In contrast to other studies, this study did not show an increase over time. Left-wing perpetrators dominated the eighties. In 50 years of terrorist activity in Belgium, the health care system was spared. Devastating mass casualty attacks challenging the health care system are rare in Belgium.

Comparing the top 100 attacks in the Global Terrorism Database: high injury rate versus high fatality rate attacks.

BACKGROUND: Terrorist attacks have the potential to be mass casualty events, causing multiple injuries and deaths. High injury rate attacks will particularly place a high burden on emergency medical systems. This study aimed to assess if there is a difference between attacks with high injury rates and high fatality rates. METHODS: The top 100 terrorist events causing the highest number of fatalities versus the highest number of injuries were selected from the Global Terrorism Database. Analyses were performed on temporal factors, location, target type, attack and weapon type, and perpetrator type. RESULTS: The 9/11 attacks caused the highest number of both fatalities and injuries. With regards to injury rates, the sarin attacks in Tokyo, Japan ranked second. Events with high fatality rates were overrepresented in Sub-Saharan Africa, whereas events with high injury rates were predominant in the Middle East & North Africa. High fatality rates were most often associated with armed assaults and hostage takings. Bombings were responsible for the highest number of injuries. CBRN attacks were overrepresented in the top 100 injuries, and accounted for 11% of the incidents. CONCLUSION: High injury rate incidents place a heavy burden on the health care system as the number of injuries is nearly ten times as high as the number of injuries in high fatality rate incidents. Epidemiological analysis of high impact terrorist events may contribute to counter-terrorism preparedness, to an increased focus on dealing with CBRN-events, and thus to a proper medical response to future terrorist events.

Accelerated Cognitive Decline Associated With Hearing Loss and Bilateral Vestibulopathy: Insights From a Prospective Cross-Sectional Study Using the Repeatable Battery for the Assessment of Neuropsychological Status Adjusted for the Hearing Impaired in the DFNA9 Population.

BACKGROUND: DeaFNess Autosomal dominant 9 (DFNA9) is a hereditary disorder known to affect both hearing and vestibular function in its carriers. Its phenotype is characterized by progressive sensorineural hearing loss (SNHL) and vestibular dysfunction evolving towards bilateral vestibulopathy (BV) by the 3rd to 5th life decade. Recent studies have identified the impact of hearing loss and vestibular dysfunction on cognitive functioning. OBJECTIVE: The main objective of this study was to investigate how the cognitive functioning of carriers of the p.Pro51Ser variant in the COCH gene is affected by the disease and compare these results with a matched healthy control group. STUDY DESIGN: Forty-six carriers of the pathogenic p.Pro51Ser variant in the COCH gene were included in this study, of which 38 met the Bárány Society criteria and were thus diagnosed with BV. All subjects were between the age of 22 and 72 years old. Each control was individually matched based on age, gender, and education level. A cognitive, vestibular, and hearing assessment was performed in all subjects. All participants completed the Repeatable Battery for the Assessment of Neuropsychological Status, adjusted for the Hearing Impaired (RBANS-H), a cognitive test battery that includes subtests probing Immediate and Delayed Memory, Visuospatial/Constructional, Language, and Attention. RESULTS: Overall, the DFNA9 patients demonstrated significantly lower scores on the Immediate Memory subscale and lower Total Scale scores than their healthy matched controls. The total sample was divided into two groups: age <55 years old and age ≥55 years old. The DFNA9 group aged ≥55 years old obtained significantly lower scores on the Attention subscale and lower Total Scale scores than their matched controls. Cognition of DFNA9 patients aged <55 years old no longer differed significantly from their matched controls. CONCLUSION: This cross-sectional study found that DFNA9 patients demonstrated cognitive deficits in comparison with their healthy matched controls. The DFNA9 group aged ≥ 55 years old obtained significantly lower scores on the Total Scale and Attention subscale. This finding; however, was not observed for the age group younger than 55 years old. Further research is needed on the individual trajectory of SNHL and vestibular function, and how hearing rehabilitation affects cognitive functioning.

Concordance of cerebrospinal fluid real-time quaking-induced conversion across the European Creutzfeldt-Jakob Disease Surveillance Network.

BACKGROUND AND PURPOSE: Cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) has a high degree of sensitivity and specificity for the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) and this has led to its being included in revised European CJD Surveillance Network diagnostic criteria for sCJD. As CSF RT-QuIC becomes more widely established, it is crucial that the analytical performance of individual laboratories is consistent. The aim of this ring-trial was to ascertain the degree of concordance between European countries undertaking CSF RT-QuIC. METHODS: Ten identical CSF samples, seven from probable or neuropathologically confirmed sCJD and three from non-CJD cases, were sent to 13 laboratories from 11 countries for RT-QuIC analysis. A range of instrumentation and different recombinant prion protein substrates were used. Each laboratory analysed the CSF samples blinded to the diagnosis and reported the results as positive or negative. RESULTS: All 13 laboratories correctly identified five of the seven sCJD cases and the remaining two sCJD cases were identified by 92% of laboratories. Of the two sCJD cases that were not identified by all laboratories, one had a disease duration >26 months with a negative 14-3-3, whilst the remaining case had a 4-month disease duration and a positive 14-3-3. A single false positive CSF RT-QuIC result was observed in this study. CONCLUSIONS: This study shows that CSF RT-QuIC demonstrates an excellent concordance between centres, even when using a variety of instrumentation, recombinant prion protein substrates and CSF volumes. The adoption of CSF RT-QuIC by all CJD surveillance centres is recommended.

Polysomnographic Predictors of Sleep, Motor, and Cognitive Dysfunction Progression in Parkinson's Disease.

PURPOSE OF REVIEW: Sleep disturbances are an important nonmotor feature of Parkinson's disease (PD) that can cause polysomnographic (PSG) alterations. These alterations are already present in early PD and may be associated with a specific disease course. This systematic review describes the role of PSG variables as predictors of sleep dysfunction, motor and cognitive dysfunction progression in PD. RECENT FINDINGS: Nineteen longitudinal cohort studies were included. Their main findings were that (1) REM sleep behavioral events, REM sleep without atonia (RSWA), and electroencephalography (EEG) changes (mainly microsleep instability) are predictors of the development of REM sleep behavior disorder (RBD); (2) RBD, RSWA, and lower slow-wave sleep energy predict motor progression; (3) RBD, EEG slowing, and sleep spindles changes are predictors of cognitive deterioration; and (4) OSA is associated with severe motor and cognitive symptoms at baseline, with inconsistent findings on the effect of continuous positive airway pressure (CPAP) therapy for these symptoms. The results of our systematic review support a role of the video-PSG in disease progression prediction in PD and its usefulness as a biomarker. However, future studies are needed to investigate whether treatment of these PSG abnormalities and sleep disturbances may have a neuroprotective effect on disease progression.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

Emerging evidence suggested a converging mechanism in neurodegenerative brain diseases (NBD) involving early neuronal network dysfunctions and alterations in the homeostasis of neuronal firing as culprits of neurodegeneration. In this study, we used paired-end short-read and direct long-read whole genome sequencing to investigate an unresolved autosomal dominant dementia family significantly linked to 7q36. We identified and validated a chromosomal inversion of ca. 4 Mb, segregating on the disease haplotype and disrupting the coding sequence of dipeptidyl-peptidase 6 gene (DPP6). DPP6 resequencing identified significantly more rare variants-nonsense, frameshift, and missense-in early-onset Alzheimer's disease (EOAD, p value = 0.03, OR = 2.21 95% CI 1.05-4.82) and frontotemporal dementia (FTD, p = 0.006, OR = 2.59, 95% CI 1.28-5.49) patient cohorts. DPP6 is a type II transmembrane protein with a highly structured extracellular domain and is mainly expressed in brain, where it binds to the potassium channel Kv4.2 enhancing its expression, regulating its gating properties and controlling the dendritic excitability of hippocampal neurons. Using in vitro modeling, we showed that the missense variants found in patients destabilize DPP6 and reduce its membrane expression (p < 0.001 and p < 0.0001) leading to a loss of protein. Reduced DPP6 and/or Kv4.2 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.

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

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.

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

Objective: 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. Methods: 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. Results: 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. Conclusions: 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.

An intronic VNTR affects splicing of ABCA7 and increases risk of Alzheimer's disease.

Mutations leading to premature termination codons in ATP-Binding Cassette Subfamily A Member 7 (ABCA7) are high penetrant risk factors of Alzheimer's disease (AD). The influence of other genetic variants in ABCA7 and downstream functional mechanisms, however, is poorly understood. To address this knowledge gap, we investigated tandem repetitive regions in ABCA7 in a Belgian cohort of 1529 AD patients and control individuals and identified an intronic variable number tandem repeat (VNTR). We observed strong association between VNTR length and a genome-wide associated signal for AD in the ABCA7 locus. Expanded VNTR alleles were highly enriched in AD patients [odds ratio = 4.5 (1.3-24.2)], and VNTR length inversely correlated with amyloid ß1-42 in cerebrospinal fluid and ABCA7 expression. In addition, we identified three novel ABCA7 alternative splicing events. One isoform in particular-which is formed through exon 19 skipping-lacks the first nucleotide binding domain of ABCA7 and is abundant in brain tissue. We observed a tight correlation between exon 19 skipping and VNTR length. Our findings underline the importance of studying repetitive DNA in complex disorders and expand the contribution of genetic and transcript variation in ABCA7 to AD.