Friedreich’s ataxia (FA) is a rare, autosomal recessive neurodegenerative disease that primarily affects children and adolescents in their transition to adulthood, which is associated with several adverse life events caused by the disease progression. This article aims to describe life events associated with FA and their impact on patient-reported outcomes in pediatric and adult onsets. A newly adapted Life Events Questionnaire was applied within the PROFA study. The questionnaire captured various disease-, relationship-, and work-related life events. The outcomes were stratified by pediatric and adult-onset groups at subcategory and item levels. Non-parametric tests, along with multivariate regressions with adjustments were employed. A total of 73 patients (44 pediatric-/29 adult-onset) completed the Life Events Questionnaire. Both pediatric and adult onset groups reported a similar number of life events (Mevents = 5.3), with disease-related events being the most prevalent. Item-level analyses revealed that adult-onset had a higher likelihood in identifying life events, including positive life events, compared to pediatric-onset group. Regression analyses revealedassociations between increased disability and increased adverse life events particularly relationship-related adverse life events(IRRassist = 2.044, p < 0.05; IRRnon−ambulant = 2.589, p < 0.01), as well as moderating effect of age at onset specifically for non-ambulant patients (IRR = 0.061, p < 0.01). The pediatric onset group were more prone to relationship-related adverse life events, especially in non-ambulant stage. In contrast, with adult-onset may benefit from established social identity in which their partners play a supportive role. Psychosocial support should be offered preemptively at the start of diagnosis for example concurrently with genetic counseling. The findings suggests that disease management strategies should be tailored to different age groups.

Background:Friedreich ataxia (FA) is the most common autosomal recessive ataxia. Little attention has been paid to FA's impact on patient-reported, psychosocial, and health-economic outcomes. This study aimed to report these outcomes across FA's disability stages 1-5. Methods:We assessed patients in Germany, France, and Austria as part of the PROFA study, a European multicenter observational study. The protocol included a study center visit followed by a remote mobile assessment capturing ataxia severity (SARA), daily living deficits (FARS-ADL), cognitive and affective impairments (CCAS), health-related quality of life (HRQoL: PROM-Ataxia short-form, EQ-5D-5L), mental well-being (WEMWBS), communication disabilities (COMATAX), and healthcare and informal care utilization. FARS disability stages were used to demonstrate outcomes with effect size measures (Eta-Squared, Cramér's V). Multivariate regression models evaluated associations between z-standardized outcomes and disability stages. Findings:One hundred one patients (mean [SD]: age 35.0 [11.5]; GAA-repeat size 657 [299]; 50.5% women) were included. Activities of daily living, HRQoL, communication disabilities, and informal care utilization worsened significantly across disability stages with moderate to high effect sizes. Cognitive-affective impairments and mental well-being showed significant associations with small effect sizes. Twenty-three patients (33.3%) received formal care, while 40 (58.0%) received informal care (mean 12.2 h/week). Omaveloxolone was used by 33 patients (32.7%). Annual healthcare costs excluding Omaveloxolone were €13,620 (payer) and €32,679 (societal perspective, including informal care and productivity losses). Interpretation:The results emphasize the multidimensional patient, societal, and economic burden of FA and the need for comprehensive care addressing physical, mental, and psychosocial health. Funding:European Joint Programme on Rare Diseases (EJP RD).

This study investigated cerebellar involvement in reinforcement learning and prediction error (RL-PE) processing. Participants with pure cerebellar degeneration and demographically matched healthy controls performed a probabilistic feedback-based learning task while brain activity was recorded using electroencephalography (EEG). Structural magnetic resonance imaging was used to quantify cerebellar gray matter volume (GMV). Data from 21 cerebellar and 25 control participants were included in the analysis. We aimed to determine if feedback-based learning was impaired in patients relative to controls, and if single-trial RL-PEs were reflected in FRN, P3a, and P3b in the event-related potential (ERP) in patients and controls. Analysis of behavioral data revealed no differences in accuracy between patients and controls. Crucially, ERP analysis revealed that, while in controls, coding of RL-PEs was found in FRN and P3a for positive and in P3b for positive and negative feedback, these effects were absent in patients. Voxel-based morphometry revealed widely distributed cerebellar GMV reduction in patients, most pronounced in bilateral Crus I/ II and bilateral lobules I-IV. Multiple regressions in patients revealed a negative correlation between GMV in bilateral Crus I and II and FRN amplitudes. The present study extends previous evidence for cerebellar involvement in RL-PE processing in humans and advances our understanding of the cerebellum's role in performance monitoring and adaptive control of behavior.

Cerebellar disease may result in Cerebellar Cognitive Affective Syndrome (CCAS). The CCAS-Scale, designed to screen for CCAS, has been validated in English Hoche (Brain 141:248–270, 2018) and adapted to other languages. Here, the German CCAS-Scale Thieme (Neurol Res Pract 2:39, 2020) was validated in 209 patients with cerebellar disorders and 232 healthy controls. Correction formulas for the outcome parameters [failed test items (range: 1–10) and sum raw score (range: 0–120)] were developed, controlling for age, education, and sex effects. Diagnostic accuracy and reliability were assessed. Correction formulas improved selectivity in controls, reducing false positives (failed items: 40

RNA polymerase III (RNA Pol III)-related disorders (POLR3-RDs) are a group of clinical entities characterized by causal variants in genes encoding RNA Pol III subunits, including POLR3A, POLR3B, POLR1C, POLR1D, POLR3D, POLR3E, POLR3F, POLR3GL, POLR3H, and POLR3K. These typically cause developmental phenotypes affecting the central nervous system; the eyes; connective tissues including bones, teeth, and endocrine axes; and the reproductive system. Similar phenotypes can be caused by variants in separate subunit genes (multigenic). In contrast, variants in the same gene can cause different phenotypes (pleiotropy), making genotype-phenotype correlation challenging. POLR3-RDs, though individually rare, have never been analyzed collectively. To bridge this gap, we developed an extensive database encompassing all published and unpublished cases of POLR3-RDs and conducted the first comprehensive genotype-phenotype correlation study across their entire spectrum. This work contributed new cases, representing 13% of all documented cases in the literature, along with 31 novel variants, accounting for 8% of all identified variants. This database was constructed by systematically reviewing the literature and integrating data from patients under the care of our international network of collaborators. The dataset includes genotype curation, bioinformatics, prior publications, and individual patient outcome information. By leveraging these comprehensive data, we were able to establish clear genotype-phenotype correlations for some pathogenic variants, which will help provide optimal clinical care and genetic counseling (including insights into disease phenotypes and progression) and offer valuable guidance for future clinical trial design and patient stratification.

To survive and thrive in our ever-changing environment, we need to be able to predict the consequences of our actions. We update these predictions by learning through trial and error, and associated prediction errors (PEs). Recent rodent data suggest that the cerebellum – a region typically associated with processing sensory PEs in supervised error-based learning – also processes PEs in reinforcement learning (RL-PEs; i.e., learning from action outcomes). A proxy of action outcome processing in regions traditionally associated with RL-PE coding, such as striatum and anterior cingulate cortex, can be measured in a component of the feedback-locked event-related potential (ERP), i.e., the feedback-related negativity (FRN). We tested the hypothesis that cerebellar output is necessary for this RL-PE coding in the FRN in a probabilistic feedback learning task. In that case, altered cerebellar output should result in changes in the FRN. Two complementary experiments were performed. First, patients with chronic cerebellar stroke were tested. Second, single-pulse cerebellar transcranial magnetic stimulation (TMS) was applied in healthy participants, thus implementing a virtual lesion approach. Different from controls and control (vertex) TMS, no significant RL-PE processing was observed in the FRN in patients with cerebellar stroke, and in participants receiving cerebellar TMS. Only minor deficits in behavioural flexibility were found, with learning success preserved, possibly due to compensation by other brain areas within the reinforcement learning network. Findings in both experiments show that frontal RL-PE processing depends on cerebellar output. Our results provide evidence for involvement of the cerebellum in processing of RL-PEs in humans, complementing and extending previous findings in rodents.

BACKGROUND:Gait and balance impairment is a disabling clinical feature in people with degenerative cerebellar ataxia. OBJECTIVES:We performed a rater-blinded, parallel 3-arm randomized controlled trial with delayed-start-design (exploratory proof-of-concept study) to assess whether, compared to control, people with mild/moderate hereditary ataxia benefit from additional video-based training with different frequencies, and how clinical characteristics interact with training success. METHODS:Digital gait/balance measures were assessed before and after a three-week video-based training program at home (Train20: 4 × 20min/week, n = 11; Train40: 2 × 40min/week, n = 11; control: standard medical care, n = 10). Group differences at baseline and changes over time were assessed using ANOVA. Linear mixed models were conducted to examine the influence of clinical variables on outcomes over time. Further exploratory analyses were performed using intraclass correlation coefficients (ICC), and paired t-tests within each group. RESULTS:All variables showed good to excellent test-retest reliability (ICC ≥0.69). No significant interactions between group and measurement time were found for clinical or gait/balance variables (p ≥ 0.338). However, participants with higher initial disease severity, greater impairment in activities of daily living, and better well-being showed significant improvements in feet-together stance (p = 0.04), normal (p = 0.01), and backward gait (p = 0.03). Exploratory analyses showed improvement only in Train40. CONCLUSIONS:Although the protocol did not lead to general improvements in people with mild/moderate ataxia, irrespective of training frequency, those with higher initial disease severity, higher functional impairment, and better mental well-being showed significant benefits. Greater attention should be given to the impact of well-being to enhance motor training outcomes. Longer, less frequent sessions may offer greater potential for improvement.

There is increasing evidence that the cerebellum contributes to feedback processing in reinforcement learning. As yet, it has not been investigated whether the cerebellum also contributes to error processing in reinforcement learning. Studies have shown, however, that the cerebellum is involved in the processing of response errors in non-reinforcement learning contexts, for example, in response conflict tasks. In the present study, we aimed to extend these findings to the processing of response errors, which slowly emerges as a result of reinforcement learning. To this end, we inhibited the cerebellum via single-pulse transcranial magnetic stimulation (spTMS) and recorded cerebral electroencephalography (EEG) measures associated with error processing. If input from the cerebellum is required for error processing, error-correct differentiation should be decreased for cerebellar compared to vertex (control) stimulation. Cerebellar spTMS was applied and EEG was recorded while healthy adults performed a probabilistic feedback learning task. The error-related negativity (ERN), a component in the response-locked event-related potential (ERP), was used as a measure of error processing. It reflects a rapidly detected mismatch between representations of the actual and the desired response and is typically larger for errors than correct responses. Error-correct differentiation in the ERN was diminished for cerebellar compared to control TMS. However, increased error-correct differentiation was found in a later ERP component, the error positivity (Pe), which is more strongly associated with error awareness. Cerebellar spTMS thus impaired fast error processing reflected in the ERN and facilitated later, conscious error processing reflected in the Pe. These findings provide causal evidence of cerebellar contributions to error processing within reinforcement learning.

Recent rodent data suggest that the cerebellum-a region typically associated with processing sensory prediction errors (PEs)-also processes PEs in reinforcement learning (RL-PEs; i.e., learning from action outcomes). We tested whether cerebellar output is necessary for RL-PE processing in regions more traditionally associated with action-outcome processing, such as the striatum and anterior cingulate cortex. The feedback-related negativity (FRN) was measured as a proxy of cerebral RL-PE processing in a probabilistic feedback learning task using electroencephalography. Two complementary experiments were performed in humans. First, patients with chronic cerebellar stroke (20 male, 6 female) and matched healthy controls (19 male, 7 female) were tested. Second, single-pulse cerebellar transcranial magnetic stimulation (TMS) was applied in healthy participants (7 male, 17 female), thus implementing a virtual lesion approach. Consistent with previous studies, learning of action-outcome associations was intact with only minor changes in behavioral flexibility. Importantly, no significant RL-PE processing was observed in the FRN in patients with cerebellar stroke and in participants receiving cerebellar TMS. Findings in both experiments show that RL-PE processing in the forebrain depends on cerebellar output in humans, complementing and extending previous findings in rodents.

Excessive stride variability is a characteristic feature of cerebellar ataxias, even in pre-ataxic or prodromal disease stages. This study explores the relation of variability of arm swing and trunk deflection in relationship to stride length and gait speed in previously described cohorts of cerebellar disease and healthy elderly: we examined 10 patients with spinocerebellar ataxia type 14 (SCA), 12 patients with essential tremor (ET), and 67 healthy elderly (HE). Using inertial sensors, recordings of gait performance were conducted at different subjective walking speeds to delineate gait parameters and respective coefficients of variability (CoV). Comparisons across cohorts and walking speed categories revealed slower stride velocities in SCA and ET patients compared to HE, which was paralleled by reduced arm swing range of motion (RoM), peak velocity, and increased CoV of stride length, while no group differences were found for trunk deflections and their variability. Larger arm swing RoM, peak velocity, and stride length were predicted by higher gait velocity in all cohorts. Lower gait velocity predicted higher CoV values of trunk sagittal and horizontal deflections, as well as arm swing and stride length in ET and SCA patients, but not in HE. These findings highlight the role of arm movements in ataxic gait and the impact of gait velocity on variability, which are essential for defining disease manifestation and disease-related changes in longitudinal observations.

The present study investigated temporal aspects of cerebellar contributions to the processing of performance errors as indexed by the error-related negativity (ERN) in the response-locked event-related potential (ERP). We co-registered EEG and applied single-pulse transcranial magnetic stimulation (spTMS) to the left posterolateral cerebellum and an extra-cerebellar control region (vertex) while healthy adult volunteers performed a Go/Nogo Flanker Task. In Go trials, TMS pulses were applied at four different time points, with temporal shifts of -100 ms, -50 ms, 0 ms, or +50 ms relative to the individual error latency (IEL, i.e., individual ERN peak latency + median error response time). These stimulation timings were aggregated into early (-100 ms, -50 ms) and late (0 ms, +50 ms) stimulation for the analysis. In Nogo trials, TMS pulses occurred 0 ms, 100 ms, or 300 ms after stimulus onset. Mixed linear model analyses revealed that cerebellar stimulation did not affect error rates overall. No effects were found for response times. As hypothesized, ERN amplitudes were decreased for cerebellar stimulation. No significant differences were found for the error positivity (Pe). Similar to TMS application to probe cerebellar-brain inhibition in the motor domain, the inhibitory tone of the cerebellar cortex may have been disrupted by the pulses. Reduced inhibitory output of the cerebellar cortex may have facilitated the processing of error information for response selection, which is reflected in a decreased ERN.

This review aimed to systematically identify and comprehensively review the role of the cerebellum in performance monitoring, focusing on learning from and on processing of external feedback in non-motor learning. While 1078 articles were screened for eligibility, ultimately 36 studies were included in which external feedback was delivered in cognitive tasks and which referenced the cerebellum. These included studies in patient populations with cerebellar damage and studies in healthy subjects applying neuroimaging. Learning performance in patients with different cerebellar diseases was heterogeneous, with only about half of all patients showing alterations. One patient study using EEG demonstrated that damage to the cerebellum was associated with altered neural processing of external feedback. Studies assessing brain activity with task-based fMRI or PET and one resting-state functional imaging study that investigated connectivity changes following feedback-based learning in healthy participants revealed involvement particularly of lateral and posterior cerebellar regions in processing of and learning from external feedback. Cerebellar involvement was found at different stages, e.g., during feedback anticipation and following the onset of the feedback stimuli, substantiating the cerebellum’s relevance for different aspects of performance monitoring such as feedback prediction. Future research will need to further elucidate precisely how , where, and when the cerebellum modulates the prediction and processing of external feedback information, which cerebellar subregions are particularly relevant, and to what extent cerebellar diseases alter these processes.

While the analysis of gait and balance can be an important indicator of age- or disease-related changes, it remains unclear if repeated performance of gait and balance tests in healthy adults leads to habituation effects, if short-term gait and balance training can improve gait and balance performance, and whether the placement of wearable sensors influences the measurement accuracy. Healthy adults were assessed before and after performing weekly gait and balance tests over three weeks by using a force plate, motion capturing system and smartphone. The intervention group (n = 25) additionally received a home-based gait and balance training plan. Another sample of healthy adults (n = 32) was assessed once to analyze the impact of sensor placement (lower back vs. lower abdomen) on gait and balance analysis. Both the control and intervention group exhibited improvements in gait/stance. However, the trends over time were similar for both groups, suggesting that targeted training and repeated task performance equally contributed to the improvement of the measured variables. Since no significant differences were found in sensor placement, we suggest that a smartphone used as a wearable sensor could be worn both on the lower abdomen and the lower back in gait and balance analyses.

BACKGROUND:Cognitive and neuropsychiatric impairment, known as cerebellar cognitive affective syndrome (CCAS), may be present in cerebellar disorders. This study identified distinct CCAS subtypes in cerebellar patients using cluster analysis. METHODS:The German CCAS-Scale (G-CCAS-S), a brief screening test for CCAS, was assessed in 205 cerebellar patients and 200 healthy controls. K-means cluster analysis was applied to G-CCAS-S data to identify cognitive clusters in patients. Demographic and clinical variables were used to characterize the clusters. Multiple linear regression quantified their relative contribution to cognitive performance. The ability of the G-CCAS-S to correctly distinguish between patients and controls was compared across the clusters. RESULTS:Two clusters explained the variance of cognitive performance in patients' best. Cluster 1 (30%) exhibited severe impairment. Cluster 2 (70%) displayed milder dysfunction and overlapped substantially with that of healthy controls. Cluster 1 patients were on average older, less educated, showed more severe ataxia and more extracerebellar involvement than cluster 2 patients. The cluster assignment predicted cognitive performance even after adjusting for all other covariates. The G-CCAS-S demonstrated good discriminative ability for cluster 1, but not for cluster 2. CONCLUSIONS:The variance of cognitive impairment in cerebellar disorders is best explained by one severely affected and one mildly affected cluster. Cognitive performance is not only predicted by demographic/clinical characteristics, but also by cluster assignment itself. This indicates that factors that have not been captured in this study likely have effects on cognitive cerebellar functions. Moreover, the CCAS-S appears to have a relative weakness in identifying patients with only mild cognitive deficits. STUDY REGISTRATION:The study has prospectively been registered at the German Clinical Study Register ( https://www.drks.de ; DRKS-ID: DRKS00016854).

Progress in next-generation sequencing has led to an explosion of novel genes and phenotypes of autosomal recessive cerebellar ataxias (ARCAs) in the last decade, with >170 recessive conditions manifesting with ataxia identified.1 With large-scale natural history and mechanistic treatment trials on the horizon for many ARCAs, up-to-date knowledge is required not only on relative frequencies but also on real-world age and disease severity distributions as key information for trial design planning and recruitment. In this multicenter study, we provide data on the relative frequency of ARCAs in Europe, delineate the spectrum of age at disease onset, and present real-world data on disease severity distributions of patients with ARCA that help to inform future trial planning. Prospective cross-sectional and longitudinal data from consecutive patients enrolled between 2013 and June 2022 from 23 European sites (Fig. 1A) were included, all collected through the international ARCA Registry.2 Patients had been eligible for inclusion into the ARCA Registry if they had (1) a genetically confirmed ARCA; and/or (2) onset before age 40 years without evidence of an autosomal dominant family history, repeat expansion in spinocerebellar ataxia genes, or acquired cause, thus representing a stratum of patients with ataxia known to be enriched for recessive ataxia disease.3, 4 Patients with Friedreich's ataxia (FA; n = 112) were not included because (1) FA is already covered in parallel by other European natural history registries (eg, EFACTS),5 which would lead to a distorted, nonrepresentative frequency estimate in the current study; (2) this study focused on the rare and less well-studied ARCAs; and (3) disease data as investigated in this study are thus already available elsewhere.5 A total of 677 patients were included in this study, rendering it the largest European ARCA frequency study to date. Fifty-nine percent had a genetic diagnosis (Fig. 1B), with autosomal recessive spastic ataxia Charlevoix-Saguenay (ARSACS; 13%) and spastic paraplegia type 7 (SPG7; 10%) being the most frequent, followed by RFC1, ataxia with oculomotor apraxia type 2 (AOA2), ataxia telangiectasia (AT), and SYNE1 (all 7%), and then in decreasing frequency, COQ8A (5%), POLG (4%), ANO10 (3%), and AOA1 (3%), and a large number of 62 ultra-rare ARCAs (each ≤2%, often only n = 1–3 patients/ARCA) (Fig. 1C). Age of onset of ARSACS, AT, and COQ8A was typically in the first decade of life (Fig. 1D), whereas SPG7, POLG, and ANO10 started on average in the fourth decade. Patients with RFC1 mutations had a later onset, on average at age 53 (interquartile range: 49–61) years (Fig. 1D). Cross-sectional disease progression estimates (Scale for the Assessment and Rating of Ataxia score [SARA]/disease duration) suggest a relatively faster disease progression for AT (median: 1.4 SARA points/years), but a slower disease progression for ARSACS (0.6 SARA point/years), RFC1 (0.9 SARA point/years), and SPG7 (0.6 SARA point/years) (Fig. 1F,G). Most patients with ARCA currently attending ataxia clinics already have on average >10 years' disease duration, with patients with ARSACS even being on average 26 years into their disease (Fig. 1E). Most SPG7, COQ8, and ANO10 patients currently attending ataxia clinics are still ambulatory, whereas >40% of patients with ARSACS, SYNE1, AOA2, or POLG cannot walk independently anymore (Fig. 1H). This large multicenter study provides a comprehensive overview on the frequency of non-FA ARCAs in Europe. It confirms the relatively high frequency of ARSACS, RFC1, and AT in ARCAs, as recently observed in a large South American ARCA cohort.3 The high frequency of SPG7 might have been missed in the South American ARCA cohort because SPG7 has for long not been sequenced as part of the ataxia genetic workup. The larger number and more comprehensive spread of rare ARCAs in this European cohort probably reflect broader availability of large-scale next-generation sequencing as a diagnostic tool in Europe. This study takes the next step toward trial readiness for ARCAs in Europe. The large number of ultra-rare ARCAs highlights the need for novel treatment programs focusing on nano-rare ARCAs, developing, eg, even mutation-specific treatments for these n-of-few ARCAs.6 Molecular treatment trials will need to consider that most ARCA patients available for recruitment in real-world settings will already be >10 years into their disease, with a substantial share of patients no longer walking independently (in particular from ARSACS, SYNE1, AOA2, or POLG). Also, some ARCAs show a fairly slow disease progression (ARSACS, RFC1, SPG7; for detailed analyses, see Traschütz et al7), indicating the need for either large sample sizes, longer trial duration, and/or more sensitive nonclinical outcome measures in upcoming trials. This study is limited by its incomplete coverage of all ataxia centers in Europe and its focus on non-FA ARCAs. However, it might provide a representative perspective on the real-world trial availability of these rare, so far grossly understudied ARCAs in Europe. This study was approved by the Ethics Committee of the Medical Faculty Tübingen (598/2011BO1). Andreas Traschütz, Jonathan Baets, Björn H. Falkenburger, Janina Gburek-Augustat, Sarah Doss, Christoph Kamm, Peter Klivenyi, Marcus Grobe-Einsler, Thomas Klopstock, Martina Minnerop, Alexander Münchau, Chiara Pane, Mathilde Renaud, Filippo M. Santorelli, Stefan Vielhaber, Tobias B. Haack, Bart P. van de Warrenburg, and Ginevra Zanni have nothing to disclose. Astrid D. Adarmes-Gomez has received honorarium for lecturing from AbbVie, Bial, Italfarmaco, Merz, UCB, and Zambon, all unrelated to the present manuscript. Mathieu Anheim received consultancy honoraria from Merz, Orkyn, AbbVie, Ipsen, Reata, and Ever Pharma, all unrelated to the present manuscript. Ludger Schöls received consultancy honoraria from Vico Therapeutics, unrelated to the present manuscript. Dagmar Timmann received funding from the DFG, EU, and Bernd Fink Foundation, unrelated to the present manuscript. Matthis Synofzik received consultancy honoraria from Janssen, Orphazyme, Servier, Reata, AviadoBio, GenOrph, and Ionis Pharmaceuticals, all unrelated to the present manuscript. This work was supported by the European Union's Horizon 2020 research and innovation program as part of the innovation project EVIDENCE-RND under the EJP RD COFUND-EJP (825575 to M.S.), as part of Solve-RD (779257 to J.B., M.S., and B.P.v.d.W.), by the DFG under the frame of EJP-RD network PROSPAX (441409627 to M.S. and B.P.v.d.W.), and by the Clinician Scientist program "PRECISE.net" funded by the Else Kröner-Fresenius-Stiftung (to A.T.). The study was further funded by the Federal Ministry of Education and Research, Germany, and through the TreatHSP network (01GM1905 to L.S.). B.P.v.d.W. receives additional research support from ZonMW, NWO, Hersenstichting, Brugling fonds, Gossweiler Foundation, and Radboud university medical center. L.S., T.K., G.Z., B.P.v.d.W., and M.S. are members of the European Reference Network for Rare Neurological Diseases—Project ID 739510. A.T. receives funding from the University of Tübingen, medical faculty, for the Clinician Scientist Program Grant 439-0-0. P.K. receives funding from University of Szeged (Hetényi Géza: 5S330 A202) and Ministry of Innovation and Technology of Hungary, National Research, Development and Innovation Fund (TKP2021-EGA). J.B. was supported by a Senior Clinical Researcher mandate of the Research Fund—Flanders (FWO) under grant agreement number 1805021N and is a member of the μNEURO Research Centre of Excellence of the University of Antwerp. F.M.S. was supported by the Italian Ministry of Health (the EJP-RD network PROSPAX; Ricerca Finalizzata RF-2016-02361610; RF-2019-12370417; Ricerca Corrente, RC 5x1000). Several authors of this publication are members of the European Reference Network for Rare Neuromuscular Diseases (ERN EURO-NMD) and of the European Reference Network for Rare Neurological Diseases (ERN-RND). Open Access funding enabled and organized by Projekt DEAL. A. Traschütz: 1A, 1B, 1C, 2A, 3A, 3B. A. D. Adarmes-Gomez: 2A, 3B. M. Anheim: 2A, 3B. J. Baets: 2A, 3B. B. H. Falkenburger: 2A, 3B. J. Gburek-Augustat: 2A, 3B. S. Doss: 2A, 3B. C. Kamm: 2A, 3B. P. Klivenyi: 2A, 3B. M. Grobe-Einsler: 2A, 3B. T. Klopstock: 2A, 3B. M. Minnerop: 2A, 3B. M. Münchau: 2A, 3B. C. Pane: 2A, 3B. M. Renaud: 2A, 3B. F. M. Santorelli: 2A, 3B. L. Schöls: 2A, 3B. D. Timmann: 2A, 3B. S. Vielhaber: 2A, 3B. T. B. Haack: 2A, 3B. B. P. van de Warrenburg: 2A, 3B. G. Zanni: 2A, 3B. M. Synofzik: 1A, 1B, 1C, 2A, 3A, 3B. Additional study group contributors of the ARCA Registry/PREPARE consortium: Roderick Maas, MD, Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, the Netherlands; Enrico Bertini, MD, Unit of Neuromuscular and Neurodegenerative Diseases, Department of Neurosciences, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy; Peter de Jonghe, MD, PhD, Translational Neurosciences, Faculty of Medicine and Health Sciences, UAntwerpen, Antwerp, Belgium; Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; and Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, Antwerp, Belgium; Ivana Ricca, MD, IRCCS Fondazione Stella Maris, Pisa, Italy; Andreas Thieme, MD, Department of Neurology and Center for Translational Neuro- and Behavioral Sciences, Essen University Hospital, University of Duisburg-Essen, Essen, Germany; Jennifer Faber, MD, Department of Neurology, University Hospital Bonn, and German Center for Neurodegenerative Diseases, Bonn, Germany. Data available on request from the authors.

Understanding cerebellar alterations due to healthy aging provides a reference point against which pathological findings in late-onset disease, for example spinocerebellar ataxia type 6 (SCA6), can be contrasted. In the present study, we investigated the impact of aging on the cerebellar nuclei and cerebellar cortex in 109 healthy controls (age range: 16 - 78 years) using 3 Tesla magnetic resonance imaging (MRI). Findings were compared with 25 SCA6 patients (age range: 38 - 78 years). A subset of 16 SCA6 (included: 14) patients and 50 controls (included: 45) received an additional MRI scan at 7 Tesla and were re-scanned after one year. MRI included T1-weighted, T2-weighted FLAIR, and multi-echo T2*-weighted imaging. The T2*-weighted phase images were converted to quantitative susceptibility maps (QSM). Since the cerebellar nuclei are characterized by elevated iron content with respect to their surroundings, two independent raters manually outlined them on the susceptibility maps. T1-weighted images acquired at 3T were utilized to automatically identify the cerebellar gray matter (GM) volume. Linear correlations revealed significant atrophy of the cerebellum due to tissue loss of cerebellar cortical GM in healthy controls with increasing age. Reduction of the cerebellar GM was substantially stronger in SCA6 patients. The volume of the dentate nuclei did not exhibit a significant relationship with age, at least in the age range between 18 and 78 years, whereas mean susceptibilities of the dentate nuclei increased with age. As previously shown, the dentate nuclei volumes were smaller and magnetic susceptibilities were lower in SCA6 patients compared to age- and sex-matched controls. The significant dentate volume loss in SCA6 patients could also be confirmed with 7T MRI. Linear mixed effects models and individual paired t-tests accounting for multiple comparisons revealed no statistical significant change in volume and susceptibility of the dentate nuclei after one year in neither patients nor controls. Importantly, dentate volumes were more sensitive to differentiate between SCA6 (Cohen's d = 3.02) and matched controls than the cerebellar cortex volume (d = 2.04). In addition to age-related decline of the cerebellar cortex and atrophy in SCA6 patients, age-related increase of susceptibility of the dentate nuclei was found in controls, whereas dentate volume and susceptibility was significantly decreased in SCA6 patients. Because no significant changes of any of these parameters was found at follow-up, these measures do not allow to monitor disease progression at short intervals.