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Spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease (MJD) is a heritable proteinopathy disorder, whose causative gene, ATXN3, undergoes alternative splicing. Ataxin-3 protein isoforms differ in their toxicity, suggesting that certain ATXN3 splice variants may be crucial in driving the selective toxicity in SCA3. Using RNA-seq datasets we identified and determined the abundance of annotated ATXN3 transcripts in blood (n = 60) and cerebellum (n = 12) of SCA3 subjects and controls. The reference transcript (ATXN3–251), translating into an ataxin-3 isoform harbouring three ubiquitin-interacting motifs (UIMs), showed the highest abundance in blood, while the most abundant transcript in the cerebellum (ATXN3–208) was of unclear function. Noteworthy, two of the four transcripts that encode full-length ataxin-3 isoforms but differ in the C-terminus were strongly related with tissue expression specificity: ATXN3–251 (3UIM) was expressed in blood 50-fold more than in the cerebellum, whereas ATXN3–214 (2UIM) was expressed in the cerebellum 20-fold more than in the blood. These findings shed light on ATXN3 alternative splicing, aiding in the comprehension of SCA3 pathogenesis and providing guidance in the design of future ATXN3 mRNA-lowering therapies.

Abstract Background The Scale for Assessment and Rating of Ataxia (SARA) is widely used in different types of ataxias and has been chosen as the primary outcome measure in the European natural history study for Friedreich ataxia (FA). Methods To assess distribution and longitudinal changes of SARA scores and its single items, we analyzed SARA scores of 502 patients with typical‐onset FA (

Abstract Objective Our aim was to study the evolution of ataxia and neurological symptoms before and after ataxia onset in the most common spinocerebellar ataxias (SCAs), SCA1, SCA2, SCA3 and SCA6. We therefore jointly analysed the data of the EUROSCA and RISCA studies, which recruited ataxic and non‐ataxic mutation carriers. Methods We used mixed effect models to analyse the evolution of Scale for the Rating and Assessment of Ataxia (SARA) scores, SCA Functional Index (SCAFI) and Inventory of Non‐Ataxia Signs (INAS) counts. We applied multivariable modelling to identify factors associated with SARA progression. In the time interval 5 years prior to and after ataxia onset, we calculated sensitivity to change ratios (SCS) of SARA, SCAFI and INAS. Results 2740 visits of 677 participants were analysed. All measures showed non‐linear progression that was best fitted by linear mixed models with linear, quadratic and cubic time effects. R2 values indicating quality of the fit ranged from 0.70 to 0.97. CAG repeat was associated with faster progression in SCA1, SCA2 and SCA3, but not SCA6. 5 years prior to and after ataxia onset, SARA had the highest SCS of all measures with a mean of 1.21 (95% CI: 1.20, 1.21) in SCA1, 0.94 (0.93, 0.94) in SCA2 and 1.23 (1.22, 1.23) in SCA3. Interpretation Our data have important implications for the understanding of disease progression in SCA1, SCA2, SCA3 and SCA6 across the lifespan. Furthermore, our study provides information for the design of interventional trials, especially in pre‐ataxic mutation carriers close to ataxia onset and patients in early disease stages.

Abstract We explored whether disease severity of Friedreich ataxia can be predicted using data from clinical examinations. From the database of the European Friedreich Ataxia Consortium for Translational Studies (EFACTS) data from up to five examinations of 602 patients with genetically confirmed FRDA was included. Clinical instruments and important symptoms of FRDA were identified as targets for prediction, while variables such as genetics, age of disease onset and first symptom of the disease were used as predictors. We used modelling techniques including generalised linear models, support-vector-machines and decision trees. The scale for rating and assessment of ataxia (SARA) and the activities of daily living (ADL) could be predicted with predictive errors quantified by root-mean-squared-errors (RMSE) of 6.49 and 5.83, respectively. Also, we were able to achieve reasonable performance for loss of ambulation (ROC-AUC score of 0.83). However, predictions for the SCA functional assessment (SCAFI) and presence of cardiological symptoms were difficult. In conclusion, we demonstrate that some clinical features of FRDA can be predicted with reasonable error; being a first step towards future clinical applications of predictive modelling. In contrast, targets where predictions were difficult raise the question whether there are yet unknown variables driving the clinical phenotype of FRDA.

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.

AbstractObjectiveThe aim was to study the evolution of disability in spinocerebellar ataxias (SCAs) type 1, 2, 3, and 6 (SCA1, 2, 3, 6).MethodsWe analyzed data of two longitudinal cohorts (RISCA, EUROSCA) which recruited ataxic and non‐ataxic SCA1, SCA2, SCA3, and SCA6 mutation carriers. To study disability, we used a five‐stage system for ataxia defined by walking ability (stages 0–3) and death (stage 4). Transitions were analyzed using a multi‐state model with proportional transition hazards. Based on the hazard estimates, transition probabilities and the expected lengths of stay in each stage were calculated. We further studied the effect of sex and CAG repeat length on progression.ResultsData of 3138 visits in 677 participants were analyzed. Median SARA scores for SCA1, SCA2, SCA3, and SCA6 ranged from 1.5 (interquartile range [IQR] = 0.0–3.5) to 3.5 (IQR = 1.4–6.1) in stage 0, 11.5 (IQR = 9.6–14.0) to 13.8 (IQR = 11.0–16.0) in stage 1, 19.0 (IQR = 17.0–21.0) to 23.8 (IQR = 19.5–27.0) in stage 2, and 28.5 (IQR = 26.0–32.5) to 34.0 (IQR = 32.6–37.1) in stage 3. Modeling allowed to calculate the subtype‐specific probability to be in a certain stage at a given age and duration of each stage. CAG repeat length was associated with faster progression in SCA1 (HR, 95% CI: 1.1, 1.1–1.2), SCA2 (1.2, 1.1–1.3), and SCA3 (1.1, 1.0–1.2). In SCA6, female sex was associated with faster progression (1.7, 1.1–2.6).InterpretationOur data are important for counselling of patients, assessment of the relevance of outcome markers, and design of clinical trials.

Quantifying the volume of the cerebellum and its lobes is of profound interest in various neurodegenerative and acquired diseases. Especially for the most common spinocerebellar ataxias (SCA), for which the first antisense oligonculeotide-base gene silencing trial has recently started, there is an urgent need for quantitative, sensitive imaging markers at pre-symptomatic stages for stratification and treatment assessment. This work introduces CerebNet, a fully automated, extensively validated, deep learning method for the lobular segmentation of the cerebellum, including the separation of gray and white matter. For training, validation, and testing, T1-weighted images from 30 participants were manually annotated into cerebellar lobules and vermal sub-segments, as well as cerebellar white matter. CerebNet combines FastSurferCNN, a UNet-based 2.5D segmentation network, with extensive data augmentation, e.g. realistic non-linear deformations to increase the anatomical variety, eliminating additional preprocessing steps, such as spatial normalization or bias field correction. CerebNet demonstrates a high accuracy (on average 0.87 Dice and 1.742mm Robust Hausdorff Distance across all structures) outperforming state-of-the-art approaches. Furthermore, it shows high test-retest reliability (average ICC >0.97 on OASIS and Kirby) as well as high sensitivity to disease effects, including the pre-ataxic stage of spinocerebellar ataxia type 3 (SCA3). CerebNet is compatible with FreeSurfer and FastSurfer and can analyze a 3D volume within seconds on a consumer GPU in an end-to-end fashion, thus providing an efficient and validated solution for assessing cerebellum sub-structure volumes. We make CerebNet available as source-code (https://github.com/Deep-MI/FastSurfer).

ObjectiveThe natural history of spinocerebellar ataxia type 3 (SCA3) has been reported in several populations and shows heterogeneity in progression rate and affecting factors. However, it remains unexplored in the population of Mainland China. This study aimed to identify the disease progression rate and its potential affecting factors in patients with SCA3 in Mainland China.Participants and MethodsWe enrolled patients with genetically confirmed SCA3 in Mainland China. Patients were seen at three visits, i.e., baseline, 1 year, and 2 years. The primary outcome was the Scale for the Assessment and Rating of Ataxia (SARA), and the secondary outcomes were the Inventory of Non-Ataxia Signs (INAS) as well as the SCA Functional Index (SCAFI).ResultsBetween 1 October 2015, and 30 September 2016, we enrolled 263 patients with SCA3. We analyzed 247 patients with at least one follow-up visit. The annual progression rate of SARA was 1.49 points per year (SE 0.08, 95% confidence interval [CI] 1.33–1.65, p < 0.0001). The annual progression rates of INAS and SCAFI were 0.56 points per year (SE 0.05, 95% CI 0.47–0.66, p < 0.001) and −0.30 points per year (SE 0.01, 95% CI −0.33∼-0.28, p < 0.001), respectively. Faster progression in SARA was associated with longer length of the expanded allele of ATXN3 (p < 0.0001); faster progression in INAS was associated with lower INAS at baseline (p < 0.0001); faster decline in SCAFI was associated with shorter length of the normal allele of ATXN3 (p = 0.036) and higher SCAFI at baseline (p < 0.0001).ConclusionOur results provide quantitative data on the disease progression of patients with SCA3 in Mainland China and its corresponding affecting factors, which could facilitate the sample size calculation and patient stratification in future clinical trials.Trial RegistrationThis study was registered with Chictr.org on 15 September 2015, number ChiCTR-OOC-15007124.

BackgroundCommunity-acquired bacterial meningitis in adults is associated with significant morbidity and mortality; therefore, early prognostication is important to identify severe cases and possibly allocate more intensive treatment. We hypothesized that early intracranial hemorrhage portends a poor prognosis. The objective of this study was to evaluate the prognostic impact of early intracranial hemorrhage regardless of size and location on clinical outcome.MethodsRetrospective analysis of patients with community-acquired bacterial meningitis treated at a tertiary academic center between 2009 and 2019 about patient characteristics, cerebral imaging findings, and clinical outcome. Uni- and multivariable logistic regression analyses were performed to identify independent predictors of poor clinical outcomes defined as a modified Rankin scale score of 5 or 6 upon discharge.ResultsA total of 102 patients were included, of which 22.5% had poor clinical outcomes. Intracranial micro- or macrohemorrhages were present in 7.8% of cases and associated with poor clinical outcomes [odds ratio (OR) 55.75, 95% CI 3.08–1,008.48, p = 0.006] in multivariate analysis, further predictors included ischemic stroke (OR 15.06, 95% CI 1.32–172, p = 0.029), age (OR 2.56, 95% CI 1.4–4.67, p = 0.002), and reduced consciousness (OR 4.21, 95% CI 1.07–16.64, p = 0.04).ConclusionEarly cerebral hemorrhage (ECHO) is a potential prognostic marker for clinicians confronted with decision-making in patients who are critically ill with community-acquired bacterial meningitis.

Abstract Background Patient involvement in research increases the impact of research and the likelihood of adoption in clinical practice. A first step is to know which research themes are important for patients. We distributed a survey on research priorities to ERN-RND members, both patient representatives and healthcare professionals, asking them to prioritize five research themes for rare neurological diseases on a scale ranging from 1 (most important) to 5 (least important). A follow-up e-mail interview was conducted with patient representatives and professionals to assess potential reasons for differences in opinions between these two groups. Results In total, 156 responses were analysed: 61 from professionals and 95 from patient representatives. They covered all ERN-RND disease groups and came from 20 different EU countries. Almost half of the respondents considered ‘Developing therapies and preventive strategies’ the most important research theme. In particular, patient representatives prioritized this theme more often than professionals, while professionals prioritized ‘Disease mechanisms and models’. Patient representatives indicated that therapies and prevention were of the utmost importance to them, because their lives are often heavily impacted by the disease and their main goal is to relief the burden of disease. Professionals indicated that investigating disease mechanisms will lead to more knowledge and is indispensable for finding new treatments. Conclusions Patients and professionals have different opinions on which research theme should have priority. A qualitative follow-up shows that they respect each others’ view points. Different stakeholders involved in research should be aware of their differences in research theme priority. Explaining these differences to each other leads to more understanding, and could improve patient engagement in research. Graphical Abstract

Abstract Background Traditionally, cerebellar disorders including ataxias have been associated with deficits in motor control and motor learning. Since the 1980’s growing evidence has emerged that cerebellar diseases also impede cognitive and affective processes such as executive and linguistic functions, visuospatial abilities and regulation of emotion and affect. This combination of non-motor symptoms has been named Cerebellar Cognitive Affective/ Schmahmann Syndrome (CCAS). To date, diagnosis relies on non-standardized bedside cognitive examination and, if available, detailed neuropsychological test batteries. Recently, a short and easy applicable bedside test (CCAS Scale) has been developed to screen for CCAS. It has been validated in an US-American cohort of adults with cerebellar disorders and healthy controls. As yet, the CCAS Scale has only been available in American English. We present a German version of the scale and the study protocol of its ongoing validation in a German-speaking patient cohort. Methods A preliminary German version has been created from the original CCAS Scale using a standardized translation procedure. This version has been pre-tested in cerebellar patients and healthy controls including medical experts and laypersons to ensure that instructions are well understandable, and that no information has been lost or added during translation. This preliminary German version will be validated in a minimum of 65 patients with cerebellar disease and 65 matched healthy controls. We test whether selectivity and sensitivity of the German CCAS Scale is comparable to the original CCAS Scale using the same cut-off values for each of the test items, and the same pass/ fail criteria to determine the presence of CCAS. Furthermore, internal consistency, test-retest and interrater reliability will be evaluated. In addition, construct validity will be tested in a subset of patients and controls in whom detailed neuropsychological testing will be available. Secondary aims will be examination of possible correlations between clinical features (e.g. disease duration, clinical ataxia scores) and CCAS scores. Perspective The overall aim is to deliver a validated bedside test to screen for CCAS in German-speaking patients which can also be used in future natural history and therapeutic trials. Study registration The study is registered at the German Clinical Study Register (DRKS-ID: DRKS00016854 ).

Abstract With molecular treatments coming into reach for spinocerebellar ataxia type 3 (SCA3), easily accessible, cross‐species validated biomarkers for human and preclinical trials are warranted, particularly for the preataxic disease stage. We assessed serum levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in ataxic and preataxic subjects of two independent multicentric SCA3 cohorts and in a SCA3 knock‐in mouse model. Ataxic SCA3 subjects showed increased levels of both NfL and pNfH. In preataxic subjects, NfL levels increased with proximity to the individual expected onset of ataxia, with significant NfL elevations already 7.5 years before onset. Cross‐sectional NfL levels correlated with both disease severity and longitudinal disease progression. Blood NfL and pNfH increases in human SCA3 were each paralleled by similar changes in SCA3 knock‐in mice, here also starting already at the presymptomatic stage, closely following ataxin‐3 aggregation and preceding Purkinje cell loss in the brain. Blood neurofilaments, particularly NfL, might thus provide easily accessible, cross‐species validated biomarkers in both ataxic and preataxic SCA3, associated with earliest neuropathological changes, and serve as progression, proximity‐to‐onset and, potentially, treatment‐response markers in both human and preclinical SCA3 trials.

In patients with Friedreich ataxia, structural MRI is typically used to detect abnormalities primarily in the brainstem, cerebellum, and spinal cord. The aim of the present study was to additionally investigate possible metabolic changes in Friedreich ataxia using in vivo sodium MRI that may precede macroanatomical alterations, and to explore potential associations with clinical parameters of disease progression.Tissue sodium concentration across the whole brain was estimated from sodium MRI maps acquired at 3 T and compared between 24 patients with Friedreich ataxia (21–57 years old, 13 females) and 23 controls (21–60 years old, 12 females). Tensor-based morphometry was used to assess volumetric changes. Total sodium concentrations and volumetric data in brainstem and cerebellum were correlated with clinical parameters, such as severity of ataxia, activity of daily living and disability stage, age, age at onset, and disease duration.Compared to controls, patients showed reduced brain volume in the right cerebellar lobules I-V (difference in means: −0.039% of total intracranial volume [TICV]; Cohen’s d = 0.83), cerebellar white matter (WM) (-0.105%TICV; d = 1.16), and brainstem (-0.167%TICV; d = 1.22), including pons (-0.102%TICV; d = 1.00), medulla (-0.036%TICV; d = 1.72), and midbrain (-0.028%TICV; d = 1.05). Increased sodium concentration was additionally detected in the total cerebellum (difference in means: 2.865 mmol; d = 0.68), and in several subregions with highest effect sizes in left (5.284 mmol; d = 1.01) and right cerebellar lobules I-V (5.456 mmol; d = 1.00), followed by increases in the vermis (4.261 mmol; d = 0.72), and in left (2.988 mmol; d = 0.67) and right lobules VI-VII (2.816 mmol; d = 0.68). In addition, sodium increases were also detected in all brainstem areas (3.807 mmol; d = 0.71 to 5.42 mmol; d = 1.19). After controlling for age, elevated total sodium concentrations in right cerebellar lobules IV were associated with younger age at onset (r = -0.43) and accordingly with longer disease duration in patients (r = 0.43).Our findings support the potential of in vivo sodium MRI to detect metabolic changes of increased total sodium concentration in the cerebellum and brainstem, the key regions in Friedreich ataxia. In addition to structural changes, sodium changes were present in cerebellar hemispheres and vermis without concomitant significant atrophy. Given the association with age at disease onset or disease duration, metabolic changes should be further investigated longitudinally and in larger cohorts of early disease stages to determine the usefulness of sodium MRI as a biomarker for early neuropathological changes in Friedreich ataxia and efficacy measure for future clinical trials.

Autosomal recessive cerebellar ataxias (ARCAs) form an ultrarare yet expanding group of neurodegenerative multisystemic diseases affecting the cerebellum and other neurological or non-neurological systems. With the advent of targeted therapies for ARCAs, disease registries have become a precious source of real-world quantitative and qualitative data complementing knowledge from preclinical studies and clinical trials. Here, we review the ARCA Registry, a global collaborative multicenter platform (>15 countries, >30 sites) with the overarching goal to advance trial readiness in ARCAs. It presents a good clinical practice (GCP)- and general data protection regulation (GDPR)-compliant professional-reported registry for multicenter web-based capture of cross-center standardized longitudinal data. Modular electronic case report forms (eCRFs) with core, extended, and optional datasets allow data capture tailored to the participating site's variable interests and resources. The eCRFs cover all key data elements required by regulatory authorities [European Medicines Agency (EMA)] and the European Rare Disease (ERD) platform. They capture genotype, phenotype, and progression and include demographic data, biomarkers, comorbidity, medication, magnetic resonance imaging (MRI), and longitudinal clinician- or patient-reported ratings of ataxia severity, non-ataxia features, disease stage, activities of daily living, and (mental) health status. Moreover, they are aligned to major autosomal-dominant spinocerebellar ataxia (SCA) and sporadic ataxia (SPORTAX) registries in the field, thus allowing for joint and comparative analyses not only across ARCAs but also with SCAs and sporadic ataxias. The registry is at the core of a systematic multi-component ARCA database cluster with a linked biobank and an evolving study database for digital outcome measures. Currently, the registry contains more than 800 patients with almost 1,500 visits representing all ages and disease stages; 65% of patients with established genetic diagnoses capture all the main ARCA genes, and 35% with unsolved diagnoses are targets for advanced next-generation sequencing. The ARCA Registry serves as the backbone of many major European and transatlantic consortia, such as PREPARE, PROSPAX, and the Ataxia Global Initiative, with additional data input from SPORTAX. It has thus become the largest global trial-readiness registry in the ARCA field.

Abstract Introduction Currently, no treatment that delays with the progression of Friedreich ataxia is available. In the majority of patients Friedreich ataxia is caused by homozygous pathological expansion of GAA repeats in the first intron of the FXN gene. Nicotinamide acts as a histone deacetylase inhibitor. Dose escalation studies have shown, that short term treatment with dosages of up to 4 g/day increase the expression of FXN mRNA and frataxin protein up to the levels of asymptomatic heterozygous gene carriers. The long-term effects and the effects on clinical endpoints, activities of daily living and quality of life are unknown. Methods The aim of the NICOFA study is to investigate the efficacy and safety of nicotinamide for the treatment of Friedreich ataxia over 24 months. An open-label dose adjustment wash-in period with nicotinamide (phase A: weeks 1–4) to the individually highest tolerated dose of 2–4 g nicotinamide/day will be followed by a 2 (nicotinamide group): 1 (placebo group) randomization (phase B: weeks 5–104). In the nicotinamide group, patients will continue with their individually highest tolerated dose between 2 and 4 g/d per os once daily and the placebo group patients will be receiving matching placebo. Safety assessments will consist of monitoring and recording of all adverse events and serious adverse events, regular monitoring of haematology, blood chemistry and urine values, regular measurement of vital signs and the performance of physical examinations including cardiological signs. The primary outcome is the change in the Scale for the Assessment and Rating of Ataxia (SARA) over time as compared with placebo in patients with Friedreich ataxia based on the linear mixed effect model (LMEM) model. Secondary endpoints are measures of quality of life, functional motor and cognitive measures, clinician’s and patient’s global impression-change scales as well as the up-regulation of the frataxin protein level, safety and survival/death. Perspective The NICOFA study represents one of the first attempts to assess the clinical efficacy of an epigenetic therapeutic intervention for this disease and will provide evidence of possible disease modifying effects of nicotinamide treatment in patients with Friedreich ataxia. Trial registration EudraCT-No.: 2017-002163-17, ClinicalTrials.gov NCT03761511.

Abstract Background Spinocerebellar ataxia type 3 (SCA3) is the most common subtype among the autosomal dominant cerebellar ataxias, a group of neurodegenerative disorders for which currently no disease-specific therapy is available. Evidence-based options for symptomatic treatment of ataxia are also limited. Recent investigations in a heterogeneous group of hereditary and acquired ataxias showed promising, prolonged effects of a two-week course with daily sessions of cerebellar anodal transcranial direct current stimulation (tDCS) on ataxia severity, gait speed, and upper limb dexterity. The aim of the SCA3-tDCS study is to further examine whether tDCS improves ataxia severity and various (cerebellar) non-motor symptoms in a homogeneous cohort of SCA3 patients and to explore the time course of these effects. Methods/design An investigator-initiated, double-blind, randomized, sham-controlled, single-center trial will be conducted. Twenty mildly to moderately affected SCA3 patients (Scale for the Assessment and Rating of Ataxia score between 3 and 20) will be included and randomly assigned in a 1:1 ratio to either cerebellar anodal tDCS or sham cerebellar tDCS. Patients, investigators, and outcome assessors are unaware of treatment allocation. Cerebellar tDCS (20 min, 2 mA, ramp-up and down periods of 30 s each) will be delivered over ten sessions, distributed in two groups of five consecutive days with a two-day break in between. Outcomes are assessed after a single session of tDCS, after the tenth stimulation (T1), and after three, six, and twelve months. The primary outcome measure is the absolute change of the SARA score between baseline and T1. In addition, effects on a variety of other motor and neuropsychological functions in which the cerebellum is known to be involved will be evaluated using quantitative motor tests, static posturography, neurophysiological measurements, cognitive assessment, and questionnaires. Discussion The results of this study will inform us whether repeated sessions of cerebellar anodal tDCS benefit SCA3 patients and whether this form of non-invasive stimulation might be a novel therapeutic approach to consider in a neurorehabilitation setting. Combined with two earlier controlled trials, a positive effect of the SCA3-tDCS study will encourage implementation of this intervention and stimulate further research in other SCAs and heredodegenerative ataxias. Trial registration NL7321, registered October 8, 2018.

Abstract Background IgG-class autoantibodies to N-Methyl-D-Aspartate (NMDA)-type glutamate receptors define a novel entity of autoimmune encephalitis. Studies examining the prevalence of NMDA IgA/IgM antibodies in patients with Parkinson disease with/without dementia produced conflicting results. We measured NMDA antibodies in a large, well phenotyped sample of Parkinson patients without and with cognitive impairment (n = 296) and controls (n = 295) free of neuropsychiatric disease. Detailed phenotyping and large numbers allowed statistically meaningful correlation of antibody status with diagnostic subgroups as well as quantitative indicators of disease severity and cognitive impairment. Methods NMDA antibodies were analysed in the serum of patients and controls using well established validated assays. We used anti-NMDA antibody positivity as the main independent variable and correlated it with disease status and phenotypic characteristics. Results The frequency of NMDA IgA/IgM antibodies was lower in Parkinson patients (13%) than in controls (22%) and higher than in previous studies in both groups. NMDA IgA/IgM antibodies were neither significantly associated with diagnostic subclasses of Parkinson disease according to cognitive impairment, nor with quantitative indicators of disease severity and cognitive impairment. A positive NMDA antibody status was positively correlated with age in controls but not in Parkinson patients. Conclusion It is unlikely albeit not impossible that NMDA antibodies play a significant role in the pathogenesis or progression of Parkinson disease e.g. to Parkinson disease with dementia, while NMDA IgG antibodies define a separate disease of its own.

While rare diseases (RDs) are by definition of low prevalence, the total number of patients suffering from an RD is high, and the majority of them have neurologic manifestations, involving central, peripheral nerve, and muscle. In 2017, 24 European Reference Networks (ERNs), each focusing on a specific group of rare or low-prevalence complex diseases, were formed to improve the care for patients with an RD. One major aim is to have “the knowledge travel instead of the patient,” which has been put into practice by the implementation of the Clinical Patient Management System (CPMS) that enables clinicians to perform pan-European virtual consultations. The European Reference Network for Rare Neurological Diseases (ERN-RND) provides an infrastructure for knowledge sharing and care coordination for patients affected by a rare neurological disease (RND) involving the most common central nervous system pathological conditions. It covers the following disease groups: (i) Cerebellar Ataxias and Hereditary Spastic Paraplegias; (ii) Huntington's disease and Other Choreas; (iii) Frontotemporal dementia; (iv) Dystonia, (non-epileptic) paroxysmal disorders, and Neurodegeneration with Brain Iron Accumulation; (v) Leukoencephalopathies; and (vi) Atypical Parkinsonian Syndromes. At the moment, it unites 32 expert centers and 10 affiliated partners in 21 European countries, as well as patient representatives, but will soon cover nearly all countries of the European Union as a result of the ongoing expansion process. Disease expert groups developed and consented on diagnostic flowcharts and disease scales to assess the different aspects of RNDs. ERN-RND has started to discuss diagnostically unclear patients in the CPMS, is one of four ERNs that serve as foundation of Solve-RD, and has established an RND training and education program. The network will facilitate trial readiness through the establishment of an ERN-RND registry with a minimal data of all patients seen at the ERN-RND centers, thus providing a unique overview of existing genotype-based cohorts. The overall aim of the ERNs is to improve access for patients with RDs to quality diagnosis, care, and treatment. Based on this objective, ERNs are monitored by the European Commission on a regular basis to provide transparency and reassurance to the RD community and the general public.

Dementia affects approximately 50 million people in the world today, the majority suffering from Alzheimer’s disease (AD). The availability of long-term patient data is one of the most important prerequisites for a better understanding of diseases. Worldwide, many prospective, longitudinal cohort studies have been initiated to understand AD. However, this approach takes years to enroll and follow up with a substantial number of patients, resulting in a current lack of data. This raises the question of whether clinical routine datasets could be utilized to extend collected registry data. It is, therefore, necessary to assess what kind of information is available in memory clinic routine databases. We did exactly this based on the example of the University Hospital Bonn. Whereas a number of data items are available in machine readable formats, additional valuable information is stored in textual documents. The extraction of information from such documents is only applicable via text mining methods. Therefore, we set up modular, rule-based text mining workflows requiring minimal sets of training data. The system achieves F1-scores over 95% for the most relevant classes, i.e., memory disturbances from medical reports and quantitative scores from semi-structured neuropsychological test protocols. Thus, we created a machine-readable core dataset for over 8000 patient visits over a ten-year period.

ObjectivesThe aim of this study was to examine the natural history of brain involvement in adult-onset myotonic dystrophies type 1 and 2 (DM1, DM2).MethodsWe conducted a longitudinal observational study to examine functional and structural cerebral changes in myotonic dystrophies. We enrolled 16 adult-onset DM1 patients, 16 DM2 patients, and 17 controls. At baseline and after 5.5 ± 0.4 years participants underwent neurological, neuropsychological, and 3T-brain MRI examinations using identical study protocols that included voxel-based morphometry and diffusion tensor imaging. Data were analyzed by (i) group comparisons between patients and controls at baseline and follow-up, and (ii) group comparisons using difference maps (baseline-follow-up in each participant) to focus on disease-related effects over time.ResultsWe found minor neuropsychological deficits with mild progression in DM1 more than DM2. Daytime sleepiness was restricted to DM1, whereas fatigue was present in both disease entities and stable over time. Comparing results of cross-sectional neuroimaging analyses at baseline and follow-up revealed an unchanged pattern of pronounced white matter alterations in DM1. There was mild additional gray matter reduction in DM1 at follow-up. In DM2, white matter reduction was of lesser extent, but there were some additional alterations at follow-up. Gray matter seemed unaffected in DM2. Intriguingly, longitudinal analyses using difference maps and comparing them between patients and controls did not reveal any significant differences of cerebral changes over time between patients and controls.ConclusionThe lack of significant disease-related progression of gray and white matter involvement over a period of five years in our cohort of DM1 and DM2 patients suggests either a rather slowly progressive process or even a stable course of cerebral changes in middle-aged adult-onset patients. Being the first longitudinal neuroimaging trial in DM1 and DM2, this study provides useful additional information regarding the natural history of brain involvement.

Many studies have used functional magnetic resonance imaging to unravel the neuronal underpinnings of motor system abnormalities in Parkinson's disease, indicating functional inhibition at the level of basal ganglia-thalamo-cortical motor networks. The study aim was to extend the characterization of functional motor changes in Parkinson's Disease by dissociating between two phases of action (i.e. motor planning and motor execution) during an automated unilateral finger movement sequence with the left and right hand, separately. In essence, we wished to identify neuronal dysfunction and potential neuronal compensation before (planning) and during (execution) automated sequential motor behavior in unmedicated early stage Parkinson's Disease patients. Twenty-two Parkinson's Disease patients (14 males; 53 ± 11 years; Hoehn and Yahr score 1.4 ± 0.6; UPDRS (part 3) motor score 16 ± 6) and 22 healthy controls (14 males; 49 ± 12 years) performed a pre-learnt four finger sequence (index, ring, middle and little finger, in order), either self-initiated (FREE) or externally triggered (REACT), within an 8-second time window. Findings were most pronounced during FREE with the clinically most affected side, where motor execution revealed significant underactivity of contralateral primary motor cortex, contralateral posterior putamen (sensorimotor territory), ipsilateral anterior cerebellum / cerebellar vermis, along with underactivity in supplementary motor area (based on ROI analyses only), corroborating previous findings in Parkinson's Disease. During motor planning, Parkinson's Disease patients showed a significant relative overactivity in dorsolateral prefrontal cortex (DLPFC), suggesting a compensatory overactivity. To a variable extent this relative overactivity in the DLPFC went along with a relative overactivity in the precuneus and the ipsilateral anterior cerebellum/cerebellar vermis Our study illustrates that a refined view of disturbances in motor function and compensatory processes can be gained from experimental designs that try to dissociate motor planning from motor execution, emphasizing that compensatory mechanisms are triggered in Parkinson's Disease when voluntary movements are conceptualized for action. Keywords: Parkinson's disease, Self-initiated movement, Functional MRI, Motor networks, Compensation, Basal ganglia

Pain is a common non-motor symptom in Parkinson's disease. As dopaminergic dysfunction is suggested to affect intrinsic nociceptive processing, this study was designed to characterize laser-induced pain processing in early-stage Parkinson's disease patients in the dopaminergic OFF state, using a multimodal experimental approach at behavioral, autonomic, imaging levels.13 right-handed early-stage Parkinson's disease patients without cognitive or sensory impairment were investigated OFF medication, along with 13 age-matched healthy control subjects. Measurements included warmth perception thresholds, heat pain thresholds, and central pain processing with event-related functional magnetic resonance imaging (erfMRI) during laser-induced pain stimulation at lower (E = 440 mJ) and higher (E = 640 mJ) target energies. Additionally, electrodermal activity was characterized during delivery of 60 randomized pain stimuli ranging from 440 mJ to 640 mJ, along with evaluation of subjective pain ratings on a visual analogue scale.No significant differences in warmth perception thresholds, heat pain thresholds, electrodermal activity and subjective pain ratings were found between Parkinson's disease patients and controls, and erfMRI revealed a generally comparable activation pattern induced by laser-pain stimuli in brain areas belonging to the central pain matrix. However, relatively reduced deactivation was found in Parkinson's disease patients in posterior regions of the default mode network, notably the precuneus and the posterior cingulate cortex.Our data during pain processing extend previous findings suggesting default mode network dysfunction in Parkinson's disease. On the other hand, they argue against a genuine pain-specific processing abnormality in early-stage Parkinson's disease. Future studies are now required using similar multimodal experimental designs to examine pain processing in more advanced stages of Parkinson's disease.

Children with hereditary severe hyperhomocysteinemia present with a variety of neurological impairment, and mild hyperhomocysteinemia has been associated with neurodegeneration in the elderly. The link of hyperhomocysteinemia to neurological dysfunction is unknown. We investigated mitochondrial mechanisms of homocysteine (HCys) neurotoxicity in rat dopaminergic pheochromocytoma cells, human neuroblastoma cells and primary rat cerebellar granule neurons. HCys dose dependently impaired cytochrome c oxidase (COX) activity as well as stability and induced reactive oxygen species and apoptotic cell death. We found that HCys binds the COX cofactor Cu2+, and Cu2+ supplementation prior to HCys treatment preserved COX activity and prevented cell death. The Cu2+ chelating action of HCys and impairement of COX activity represent novel mechanisms of HCys neurotoxicity, which might be preventable by supplementation of Cu2+.

Electrophysiological and behavioral studies in primary dystonia suggest abnormalities during movement preparation, but this crucial phase preceding movement onset has not yet been studied specifically with functional magnetic resonance imaging (fMRI). To identify abnormalities in brain activation during movement preparation, we used event-related fMRI to analyze behaviorally unimpaired sequential finger movements in 18 patients with task-specific focal hand dystonia (FHD) and 18 healthy subjects. Patients and controls executed self-initiated or externally cued prelearnt four-digit sequential movements using either right or left hands. In FHD patients, motor performance of the sequential finger task was not associated with task-related dystonic posturing and their activation levels during motor execution were highly comparable with controls. On the other hand reduced activation was observed during movement preparation in the FHD patients in left premotor cortex / precentral gyrus for all conditions, and for self-initiation additionally in supplementary motor area, left mid-insula and anterior putamen, independent of effector side. Findings argue for abnormalities of early stages of motor control in FHD, manifesting during movement preparation. Since deficits map to regions involved in the coding of motor programs, we propose that task-specific dystonia is characterized by abnormalities during recruitment of motor programs: these do not manifest at the behavioral level during simple automated movements, however, errors in motor programs of complex movements established by extensive practice (a core feature of FHD), trigger the inappropriate movement patterns observed in task-specific dystonia.