Multi-consistency testing during flexible endoscopic evaluation of swallowing (FEES) is clinically necessary, but introduces selection bias: worst scores inflate severity because the number of consistencies tested covaries with disease severity. In this retrospective observational study of hospitalized neurological patients, we derived and validated the FEES Dysphagia Index (FDI) in two temporally independent cohorts (Cohort 1: 2013–2018, N = 1,257; Cohort 2: 2021–2025, N = 1,686) from a single center. FDI-S averages Penetration–Aspiration Scale (PAS) scores across tested consistencies (0–100 scale); FDI-E uses Yale Pharyngeal Residue scores; FDI-C combines both. Selection bias was quantified using sequential branching-tree inverse probability weighting (IPW). Worst PAS overestimated severity by 24

Abstract INTRODUCTION Physical activity is a promising non‐pharmacological approach to support brain health. Although prior studies suggest cognitive benefits, it remains unclear how exercise alters brain structure and connectivity on the Alzheimer's disease (AD) continuum and whether such neural changes translate to functional improvements. This study investigated whether a multicomponent physical‐activity program induced measurable brain changes across the AD continuum. METHODS In the Dementia‐MOVE (Multi‐Objective Validation of Exercise) randomized‐controlled trial, 46 participants with early AD were allocated to either a 6‐month multicomponent physical activity intervention (n = 25) or a psychoeducation program (n = 21). Magnetic resonance imaging (MRI) and clinical assessments were conducted at baseline (T1), after intervention (T3), and 18 months (T4) after T1. Structural MRI was conducted at all timepoints; resting‐state functional MRI was conducted at T1 and T3. Longitudinal analyses evaluated changes in brain volume and functional connectivity and their correlations with cognitive, physical, and fitness profiles. RESULTS Structural analyses revealed long‐term reductions in gray and white matter volumes and ventricular expansion in both groups, with no significant group‐by‐time interaction. There was no significant change on brain structure right after intervention at T3. In contrast, functional connectivity increased after an intervention in the physical activity group, particularly in frontal, limbic, and cerebellar regions. Between‐group comparisons showed higher connectivity in the intervention group at T3 with no difference in connectivity between both groups at T1. Correlation analyses demonstrated stronger and more widespread association patterns between brain metrics, especially on the functional level, and cognitive, fitness, and activity measures in the intervention group at follow‐up. DISCUSSION These findings suggest that structured physical activity induces functional reorganization and strengthens brain–behavior coupling in early AD, while structural differences between groups stabilize first and decline after cessation of the intervention. Multimodal imaging may offer a sensitive approach to detecting early neuroplasticity responses, and sustained engagement may therefore be necessary to maintain effects.

Serine 129 can be phosphorylated in pathological inclusions formed by the intrinsically disordered protein human alpha-synuclein (AS), a key player in Parkinson's disease and other synucleinopathies. Here, molecular simulations provide insight into the structural ensemble of phosphorylated AS. The simulations allow us to suggest that phosphorylation significantly impacts the structural content of the physiological AS conformational ensemble in aqueous solution, as the phosphate group is mostly solvated. The hydrophobic region of AS contains beta-hairpin structures, which may increase the propensity of the protein to undergo amyloid formation, as seen in the nonphysiological (nonacetylated) form of the protein in a recent molecular simulation study. Our findings are consistent with existing experimental data with the caveat of the observed limitations of the force field for the phosphorylated moiety.

Malformations of the brain are common and vary in severity, from negligible to potentially fatal. Their causes have not been fully elucidated. Here, we report pathogenic variants in the core protein-folding machinery TRiC/CCT in individuals with brain malformations, intellectual disability, and seizures. The chaperonin TRiC is an obligate hetero-oligomer, and we identify variants in seven of its eight subunits, all of which impair function or assembly through different mechanisms. Transcriptome and proteome analyses of patient-derived fibroblasts demonstrate the various consequences of TRiC impairment. The results reveal an unexpected and potentially widespread role for protein folding in the development of the central nervous system and define a disease spectrum of “TRiCopathies.”

Background: Neuropathic pain is difficult to diagnose and treat. Small fiber neuropathy (SFN) flies under the radar of nerve conduction studies.Objectives: The importance of a structured patient history and physical examination in the context of neuropathic pain is emphasized. Describing SFN as an important cause, the authors consider rare but partially treatable differential diagnoses. They conclude that autonomic symptoms are frequently associated, often presenting with diverse symptoms.Methods: A selective literature research to present SFN symptoms as well as differential diagnostic and therapeutic steps in the context of SFN and rare diseases focusing on the autonomic nervous system.Results: Neuropathic pain significantly reduces quality of life. To shorten the time until diagnosis and to initiate therapy, the authors recommend a structured patient history including sensory plus and minus symptoms and non-specific autonomic signs. If the initial search for the cause is not successful, rare causes such as treatable transthyretin (ATTR) amyloidosis and Fabry's disease or autoimmune causes should be considered, particularly in the case of progressive and/or autonomic symptoms.Conclusion: The diagnosis and therapy of rare SFN requires interdisciplinary collaboration and, in many cases, a referral to specialized centers to achieve the best patient care.

Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders exclusively or predominantly affecting the sensory and autonomic neurons. Due to the rarity of the diseases and findings based mainly on single case reports or small case series, knowledge about these disorders is limited. Here, we describe the molecular workup of a large international cohort of CIP/HSAN patients including patients from normally under-represented countries. We identify 80 previously unreported pathogenic or likely pathogenic variants in a total of 73 families in the >20 known CIP/HSAN-associated genes. The data expand the spectrum of disease-relevant alterations in CIP/HSAN, including novel variants in previously rarely recognized entities such as ATL3-, FLVCR1- and NGF-associated neuropathies and previously under-recognized mutation types such as larger deletions. In silico predictions, heterologous expression studies, segregation analyses and metabolic tests helped to overcome limitations of current variant classification schemes that often fail to categorize a variant as disease-related or benign. The study sheds light on the genetic causes and disease-relevant changes within individual genes in CIP/HSAN. This is becoming increasingly important with emerging clinical trials investigating subtype or gene-specific treatment strategies.

Introduction:Assessment methods for physical activity and fitness are of upmost importance due to the possible beneficial effect of physical conditioning on neurodegenerative diseases. The implementation of these methods can be challenging when examining elderly or cognitively impaired participants. In the presented study, we compared three different assessment methods for physical activity from the Dementia-MOVE trial, a 6-months intervention study on physical activity in Alzheimer's disease. The aim was to determine the comparability of physical activity assessments in elderly participants with cognitive impairment due to Alzheimer's disease.Material or methods:38 participants (mean age 70 ± 7 years) with early-stage Alzheimer's disease (mean MoCA 18.84 ± 4.87) were assessed with (1) fitness trackers for an average of 12 (± 6) days, (2) a written diary on daily activities and (3) a questionnaire on physical activity at three intervention timepoints. For comparison purposes, we present a transformation and harmonization method of the physical assessment output parameters: Metabolic equivalent of task (MET) scores, activity intensity minutes, calorie expenditure and moderate-to-vigorous physical activity (MVPA) scores were derived from all three modalities. The resulting parameters were compared for absolute differences, correlation, and their influence by possible mediating factors such as cognitive state and markers from cerebrospinal fluid.Results:Participants showed high acceptance and compliance to all three assessment methods. MET scores and MVPA from fitness trackers and diaries showed high overlap, whilst results from the questionnaire suggest that participants tended to overestimate their physical activity in the long-term retrospective assessment. All activity parameters were independent of the tested Alzheimer's disease parameters, showing that not only fitness trackers, but also diaries can be successfully applied for physical activity assessment in a sample affected by early-stage Alzheimer's disease.Discussion:Our results show that fitness trackers and physical activity diaries have the highest robustness, leading to a highly comparable estimation of physical activity in people with Alzheimer's disease. As assessed parameters, it is recommendable to focus on MET, MVPA and on accelerometric sensor data such as step count, and less on activity calories and different activity intensities which are dependent on different variables and point to a lower reliability.

ABSTRACTBackgroundSpinal cord damage is a hallmark of Friedreich's ataxia (FRDA), but its progression and clinical correlates remain unclear.ObjectiveThe objective of this study was to perform a characterization of cervical spinal cord structural damage in a large multisite FRDA cohort.MethodsWe performed a cross‐sectional analysis of cervical spinal cord (C1–C4) cross‐sectional area (CSA) and eccentricity using magnetic resonance imaging data from eight sites within the ENIGMA‐Ataxia initiative, including 256 individuals with FRDA and 223 age‐ and sex‐matched control subjects. Correlations and subgroup analyses within the FRDA cohort were undertaken based on disease duration, ataxia severity, and onset age.ResultsIndividuals with FRDA, relative to control subjects, had significantly reduced CSA at all examined levels, with large effect sizes (d > 2.1) and significant correlations with disease severity (r < −0.4). Similarly, we found significantly increased eccentricity (d > 1.2), but without significant clinical correlations. Subgroup analyses showed that CSA and eccentricity are abnormal at all disease stages. However, although CSA appears to decrease progressively, eccentricity remains stable over time.ConclusionsPrevious research has shown that increased eccentricity reflects dorsal column (DC) damage, while decreased CSA reflects either DC or corticospinal tract (CST) damage, or both. Hence our data support the hypothesis that damage to the DC and damage to CST follow distinct courses in FRDA: developmental abnormalities likely define the DC, while CST alterations may be both developmental and degenerative. These results provide new insights about FRDA pathogenesis and indicate that CSA of the cervical spinal cord should be investigated further as a potential biomarker of disease progression. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Many homodimeric enzymes tune their functions by exploiting either negative or positive cooperativity between subunits. In the SARS-CoV-2 Main protease (Mpro) homodimer, the latter has been suggested by symmetry in most of the 500 reported protease/ligand complex structures solved by macromolecular crystallography (MX). Here we apply the latter to both covalent and noncovalent ligands in complex with Mpro. Strikingly, our experiments show that the occupation of both active sites of the dimer originates from an excess of ligands. Indeed, cocrystals obtained using a 1:1 ligand/protomer stoichiometry lead to single occupation only. The empty binding site exhibits a catalytically inactive geometry in solution, as suggested by molecular dynamics simulations. Thus, Mpro operates through negative cooperativity with the asymmetric activity of the catalytic sites. This allows it to function with a wide range of substrate concentrations, making it resistant to saturation and potentially difficult to shut down, all properties advantageous for the virus' adaptability and resistance.

INTRODUCTION:Friedreich ataxia (FA) is the most common hereditary ataxia in Europe, characterised by progressively worsening movement and speech impairments with a typical onset before the age of 25 years. The symptoms affect the patients' health-related quality of life (HRQoL) and psychosocial health. FA leads to an increasing need for care, associated with an economic burden. Little is known about the impact of FA on daily lives and HRQoL. To fill that gap, we will assess patient-reported, psychosocial and economic outcomes using momentary data assessment via a mobile health application (app).METHODS AND ANALYSIS:The PROFA Study is a prospective observational study. Patients with FA (n=200) will be recruited at six European study centres (Germany, France and Austria). We will interview patients at baseline in the study centre and subsequently assess the patients' health at home via mobile health app. Patients will self-report ataxia severity, HRQoL, speech and hearing disabilities, coping strategies and well-being, health services usage, adverse health events and productivity losses due to informal care on a daily to monthly basis on the app for 6 months. Our study aims to (1) validate measurements of HRQoL and psychosocial health, (2) assess the usability of the mobile health app, and (3) use descriptive and multivariate statistics to analyse patient-reported and economic outcomes and the interaction effects between these outcomes. Insights into the app's usability could be used for future studies using momentary data assessments to measure outcomes of patients with FA.ETHICS AND DISSEMINATION:Ethical approval has been obtained from the Ethics Committee of the University Medicine of Greifswald, (BB096/22a, 26 October 2022) and from all local ethics committees of the participating study sites. Findings of the study will be published in peer-reviewed journals, presented at relevant international/national congresses and disseminated to German and French Patient Advocacy Organizations.TRIAL REGISTRATION NUMBER:ClinicalTrials.gov Registry (NCT05943002); Pre-results.

Background and purpose: A primary admission of patients with suspected acute ischemic stroke and large vessel occlusion (LVO) to centers capable of providing endovascular stroke therapy (EVT) may induce shorter time to treatment and better functional outcomes. One of the limitations in this strategy is the need for accurately identifying LVO patients in the prehospital setting. We aimed to study the feasibility and diagnostic performance of point-of-care ultrasound (POCUS) for the detection of LVO in patients with acute stroke. Methods: We conducted a proof-of-concept study and selected 15 acute ischemic stroke patients with angiographically confirmed LVO and 15 patients without LVO. Duplex ultrasonography (DUS) of the common carotid arteries was performed, and flow profiles compatible with LVO were scored independently by one experienced and one junior neurologist. Results: Among the 15 patients with LVO, 6 patients presented with an occlusion of the carotid-T and 9 patients presented with an M1 occlusion. Interobserver agreement between the junior and the experienced neurologist was excellent (kappa = 0.813, p < 0.001). Flow profiles of the CAA allowed the detection of LVO with a sensitivity of 73%, a positive predictive value of 92 and 100%, and a c-statistics of 0.83 (95%CI = 0.65-0.94) and 0.87 (95%CI = 0.69-0.94) (experienced neurologist and junior neurologist, respectively). In comparison with clinical stroke scales, DUS was associated with better trade-off between sensitivity and specificity. Conclusion: POCUS in acute stroke setting is feasible, it may serve as a complementary tool for the detection of LVO and is potentially applicable in the prehospital phase.

Objective: Understanding the lateralization factors, including the anatomic and hemodynamic mechanisms, is essential for diagnosing cardio-embolic stroke. This study aims to investigate the elements, for the first time together, that could affect the laterality of stroke.Methods: We performed a monocentric retrospective case-control study based on prospective registries of acute ischemic stroke patients in the comprehensive stroke center of the RWTH University hospital of Aachen for three years (June 2018-June 2021). We enrolled 222 patients with cardioembolic stroke (136 left stroke and 86 right stroke) admitted for first-ever acute ischemic stroke with unilateral large vessel occlusion of the anterior circulation. The peak systolic velocity (PSV) asymmetry of middle cerebral artery (MCA) was assessed by doppler as well as internal carotid artery (ICA) angle, aortic arch (AA) branching pattern and anatomy were assessed by CT-Angiography.Results: We found that the increasing left ICA angle (p = 0.047), presence of bovine type AA anatomy (p = 0.041) as well as slow PSV of the right MCA with a value of >15% than left (p = 0.005) were the predictors for left stroke lateralization, while the latter was an independent predictor for the left stroke (OR=3.341 [1.415-7.887]). Inter-Rater Reliability ranged from moderate to perfect agreement.Conclusion: The predictors for left stroke lateralization include the higher values of left ICA angle, presence of the bovine type AA and the slow right MCA PSV.

ABSTRACTBackgroundFriedreich's ataxia (FA) is a rare multisystemic disorder which can cause premature death.ObjectivesTo investigate predictors of survival in FA.MethodsWithin a prospective registry established by the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS; ClinicalTrials.gov identifier NCT02069509) we enrolled genetically confirmed FA patients at 11 tertiary centers and followed them in yearly intervals. We investigated overall survival applying the Kaplan–Meier method, life tables, and log‐rank test. We explored prognostic factors applying Cox proportional hazards regression and subsequently built a risk score which was assessed for discrimination and calibration performance.ResultsBetween September 2010 and March 2017, we enrolled 631 FA patients. Median age at inclusion was 31 (range, 6–76) years. Until December 2022, 44 patients died and 119 terminated the study for other reasons. The 10‐year cumulative survival rate was 87%. In a multivariable analysis, the disability stage (hazard ratio [HR] 1.51, 95% CI 1.08–2.12, P = 0.02), history of arrhythmic disorder (HR 2.93, 95% CI 1.34–6.39, P = 0.007), and diabetes mellitus (HR 2.31, 95% CI 1.05–5.10, P = 0.04) were independent predictors of survival. GAA repeat lengths did not improve the survival model. A risk score built on the previously described factors plus the presence of left ventricular systolic dysfunction at echocardiography enabled identification of four trajectories to prognosticate up to 10‐year survival (log‐rank test P < 0.001).ConclusionsArrhythmias, progressive neurological disability, and diabetes mellitus influence the overall survival in FA. We built a survival prognostic score which identifies patients meriting closer surveillance and who may benefit from early invasive cardiac monitoring and therapy. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

IntroductionDrug development for neurodegenerative diseases such as Friedreich's ataxia (FRDA) is limited by a lack of validated, sensitive biomarkers of pharmacodynamic response in affected tissue and disease progression. Studies employing neuroimaging measures to track FRDA have thus far been limited by their small sample sizes and limited follow up. TRACK-FA, a longitudinal, multi-site, and multi-modal neuroimaging natural history study, aims to address these shortcomings by enabling better understanding of underlying pathology and identifying sensitive, clinical trial ready, neuroimaging biomarkers for FRDA.Methods200 individuals with FRDA and 104 control participants will be recruited across seven international study sites. Inclusion criteria for participants with genetically confirmed FRDA involves, age of disease onset ≤ 25 years, Friedreich's Ataxia Rating Scale (FARS) functional staging score of ≤ 5, and a total modified FARS (mFARS) score of ≤ 65 upon enrolment. The control cohort is matched to the FRDA cohort for age, sex, handedness, and years of education. Participants will be evaluated at three study visits over two years. Each visit comprises of a harmonized multimodal Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS) scan of the brain and spinal cord; clinical, cognitive, mood and speech assessments and collection of a blood sample. Primary outcome measures, informed by previous neuroimaging studies, include measures of: spinal cord and brain morphometry, spinal cord and brain microstructure (measured using diffusion MRI), brain iron accumulation (using Quantitative Susceptibility Mapping) and spinal cord biochemistry (using MRS). Secondary and exploratory outcome measures include clinical, cognitive assessments and blood biomarkers.DiscussionPrioritising immediate areas of need, TRACK-FA aims to deliver a set of sensitive, clinical trial-ready neuroimaging biomarkers to accelerate drug discovery efforts and better understand disease trajectory. Once validated, these potential pharmacodynamic biomarkers can be used to measure the efficacy of new therapeutics in forestalling disease progression.Clinical trial registrationClinicalTrails.gov Identifier: NCT04349514.

Recombinant human erythropoietin (rhEPO) has been shown to exert anti-apoptotic and anti-inflammatory effects after cerebral ischemia. Inflammatory cytokines interleukin-1β and -18 (IL-1β and IL-18) are crucial mediators of apoptosis and are maturated by multiprotein complexes termed inflammasomes. Microglia are the first responders to post-ischemic brain damage and are a main source of inflammasomes. However, the impact of rhEPO on microglial activation and the subsequent induction of inflammasomes after ischemia remains elusive. To address this, we subjected human microglial clone 3 (HMC-3) cells to various durations of oxygen-glucose-deprivation/reperfusion (OGD/R) to assess the impact of rhEPO on cell viability, metabolic activity, oxidative stress, phagocytosis, migration, as well as on the regulation and activation of the NLRP1, NLRP3, NLRC4, and AIM2 inflammasomes. Administration of rhEPO mitigated OGD/R-induced oxidative stress and cell death. Additionally, it enhanced metabolic activity, migration and phagocytosis of HMC-3. Moreover, rhEPO attenuated post-ischemic activation and regulation of the NLRP1, NLRP3, NLRC4, and AIM2 inflammasomes as well as their downstream effectors CASPASE1 and IL-1β. Pharmacological inhibition of NLRP3 via MCC950 had no effect on the activation of CASPASE1 and maturation of IL-1β after OGD/R, but increased protein levels of NLRP1, NLRC4, and AIM2, suggesting compensatory activities among inflammasomes. We provide evidence that EPO-conveyed anti-inflammatory actions might be mediated via the regulation of the inflammasomes.

Missense mutations in the pore-forming α1-subunits of voltage-gated calcium channels (Cav) have been linked to a range of neurodevelopmental and neurodegenerative disorders such as autism, epilepsy, developmental delay and ataxia. Here we prove the pathogenicity of heterozygous variants in L-type Cav1.3 (CACNA1D) and P/Q-type Cav2.1 (CACNA1A) channels identified in patients with neurological pathologies using the whole-cell patch-clamp technique with heterologously expressed channel complexes. Previously, we demonstrated that pathogenic de novo missense mutations in the Cav1.3 channel gating machinery induce typical gating changes compatible with a gain-of-function phenotype. Here we report a novel α1-subunit variant, S652L, detected in two patients with a severe global developmental delay. S652L also revealed aberrant gain-of-function gating evident from a negative shift (≈-16mV) of the voltage-dependences of activation and steady-state inactivation, enhanced window-current and slower deactivation kinetics. Interestingly, variant S652W in the same position, which is reported in neurologically healthy individuals, induced gating changes opposite to the effects of S652L (significant shift of voltage-dependent gating to more positive voltages), consistent with a loss-of-function phenotype. These results demonstrate that Cav1.3 gain- but not loss-of-function mutations confer a high risk for neurodevelopmental disorders. In contrast, our studies on the Cav2.1 α1-subunit variant C256F, identified in a patient diagnosed with spinocerebellar ataxia type-6 (SCA6), confirmed its pathogenicity by demonstrating a loss of channel function. This was evident from significantly faster channel inactivation and an ≈45% reduction of the maximal Ca2+-current density which could not be explained by a lower protein expression level of the mutant channel. This case of SCA6 is of particular interest since, unlike in typical SCA6 cases, it is caused by a missense mutation rather than a diagnostic C-terminal poly-glutamine expansion. Funding: Austrian Science Fund (FWFP27809, CavX-DOC 30, Erika-Cremer-fellowship University Innsbruck)