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The cerebellum, traditionally associated with motor coordination and balance, also plays a crucial role in various aspects of higher-order function and dysfunction. Emerging research has shed light on the cerebellum's broader contributions to cognitive, emotional, and reward processes. The cerebellum's influence on autonomic function further highlights its significance in regulating motivational and emotional states. Perturbations in cerebellar development and function have been implicated in various neurodevelopmental disorders, including autism spectrum disorder and attention deficit hyperactivity disorder. An increasing appreciation for neuropsychiatric symptoms that arise from cerebellar dysfunction underscores the importance of elucidating the circuit mechanisms that underlie complex interactions between the cerebellum and other brain regions for a comprehensive understanding of complex behavior. By briefly discussing new advances in mapping cerebellar function in affective, cognitive, autonomic, and social processing and reviewing the role of the cerebellum in neuropathology beyond the motor domain, this Mini-Symposium review aims to provide a broad perspective of cerebellar intersections with the limbic brain in health and disease.

With many viable strategies in the therapeutic pipeline, upcoming clinical trials in hereditary and sporadic degenerative ataxias will benefit from non-invasive MRI biomarkers for patient stratification and the evaluation of therapies. The MRI Biomarkers Working Group of the Ataxia Global Initiative therefore devised guidelines to facilitate harmonized MRI data acquisition in clinical research and trials in ataxias. Recommendations are provided for a basic structural MRI protocol that can be used for clinical care and for an advanced multi-modal MRI protocol relevant for research and trial settings. The advanced protocol consists of modalities with demonstrated utility for tracking brain changes in degenerative ataxias and includes structural MRI, magnetic resonance spectroscopy, diffusion MRI, quantitative susceptibility mapping, and resting-state functional MRI. Acceptable ranges of acquisition parameters are provided to accommodate diverse scanner hardware in research and clinical contexts while maintaining a minimum standard of data quality. Important technical considerations in setting up an advanced multi-modal protocol are outlined, including the order of pulse sequences, and example software packages commonly used for data analysis are provided. Outcome measures most relevant for ataxias are highlighted with use cases from recent ataxia literature. Finally, to facilitate access to the recommendations by the ataxia clinical and research community, examples of datasets collected with the recommended parameters are provided and platform-specific protocols are shared via the Open Science Framework. [ABSTRACT FROM AUTHOR]

Objective: The Scale for the Assessment and Rating of Ataxia (SARA) is the most widely applied clinical outcome assessment (COA) for genetic ataxias, but presents metrological and regulatory challenges. To facilitate trial planning, we characterize its responsiveness (including subitem‐level relations to ataxia severity and patient‐focused outcomes) across a large number of ataxias, and provide first natural history data for several of them. Methods: Subitem‐level correlation and distribution‐based analysis of 1,637 SARA assessments in 884 patients with autosomal recessive/early onset ataxia (370 with 2–8 longitudinal assessments) were complemented by linear mixed effects modeling to estimate progression and sample sizes. Results: Although SARA subitem responsiveness varied between ataxia severities, gait/stance showed a robust granular linear scaling across the broadest range (SARA < 25). Responsiveness was diminished by incomplete subscale use at intermediate or upper levels, nontransitions ("static periods"), and fluctuating decreases/increases. All subitems except nose‐finger showed moderate‐to‐strong correlations to activities of daily living, indicating that metric properties—not content validity—limit SARA responsiveness. SARA captured mild‐to‐moderate progression in many genotypes (eg, SYNE1‐ataxia: 0.55 points/yr, ataxia with oculomotor apraxia type 2: 1.14 points/yr, POLG‐ataxia: 1.56 points/yr), but no change in others (autosomal recessive spastic ataxia of Charlevoix‐Saguenay, COQ8A‐ataxia). Whereas sensitivity to change was optimal in mild ataxia (SARA < 10), it substantially deteriorated in advanced ataxia (SARA > 25; 2.7‐fold sample size). Use of a novel rank‐optimized SARA without subitems finger‐chase and nose‐finger reduces sample sizes by 20 to 25%. Interpretation: This study comprehensively characterizes COA properties and annualized changes of the SARA across and within a large number of ataxias. It suggests specific approaches for optimizing its responsiveness that might facilitate regulatory qualification and trial design. ANN NEUROL 2023;94:470–485 [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "MR Imaging in Ataxias: Consensus Recommendations by the Ataxia Global Initiative Working Group on MRI Biomarkers" published in the journal Cerebellum. The original article did not properly capture the list of collaborating authors in PubMed, but this has been corrected in both the original article and the PubMed listing. The correction notice includes the names and affiliations of the collaborating authors, who are members of the AGI MR Biomarkers Study Group. The correction notice also includes a note from the publisher, Springer Nature, stating their neutrality regarding jurisdictional claims and institutional affiliations. [Extracted from the article]

Background: Lifestyle could influence the course of hereditary ataxias, but representative data are missing. Objective: The objective of this study was to characterize lifestyle in spinocerebellar ataxia type 3 (SCA3) and investigate possible associations with disease parameters. Methods: In a prospective cohort study, data on smoking, alcohol consumption, physical activity, physiotherapy, and body mass index (BMI) were collected from 243 patients with SCA3 and 119 controls and tested for associations with age of onset, disease severity, and progression. Results: Compared with controls, patients with SCA3 were less active and consumed less alcohol. Less physical activity and alcohol abstinence were associated with more severe disease, but not with progression rates or age of onset. Smoking, BMI, or physiotherapy did not correlate with disease parameters. Conclusion: Differences in lifestyle factors of patients with SCA3 and controls as well as associations of lifestyle factors with disease severity are likely driven by the influence of symptoms on behavior. No association between lifestyle and disease progression was detected. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

The original CCAS Scale was developed in a US cohort of 77 patients with various cerebellar diseases and 58 healthy controls (exploratory cohort) and was validated in another US cohort of 39 adult cerebellar patients and 55 healthy control subjects (validation cohort). The CCAS Scale consists of 12 test items that capture deficits in the core domains of CCAS. Age effects likely explain the differences in selectivity in our German study cohort compared to the validation cohort Figure 1 Age and education effects on CCAS Scale performance. A short and easily applicable bedside test (CCAS Scale), published by Hoche et al. (2018) in Brain, was developed to screen for CCAS and is already in widespread use. [Extracted from the article]

Spinocerebellar ataxia type 3/Machado-Joseph disease is the most common autosomal dominant ataxia. In view of the development of targeted therapies, knowledge of early biomarker changes is needed. We analyzed cross-sectional data of 292 spinocerebellar ataxia type 3/Machado-Joseph disease mutation carriers. Blood concentrations of mutant ATXN3 were high before and after ataxia onset, whereas neurofilament light deviated from normal 13.3 years before onset. Pons and cerebellar white matter volumes decreased and deviated from normal 2.2 years and 0.6 years before ataxia onset. We propose a staging model of spinocerebellar ataxia type 3/Machado-Joseph disease that includes a biomarker stage characterized by objective indicators of neurodegeneration before ataxia onset. ANN NEUROL 2024;95:400-406., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

The European Spinocerebellar Ataxia Type 3/Machado-Joseph Disease Initiative (ESMI) is a consortium established with the ambition to set up the largest European longitudinal trial-ready cohort of Spinocerebellar Ataxia Type 3/Machado-Joseph Disease (SCA3/MJD), the most common autosomal dominantly inherited ataxia worldwide. A major focus of ESMI has been the identification of SCA3/MJD biomarkers to enable future interventional studies. As biosample collection and processing variables significantly impact the outcomes of biomarkers studies, biosampling procedures standardisation was done previously to study visit initiation. Here, we describe the ESMI consensus biosampling protocol, developed within the scope of ESMI, that ultimately might be translated to other neurodegenerative disorders, particularly ataxias, being the first step to protocol harmonisation in the field., (© 2023 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)

Ataxias are a heterogeneous group of diseases. They can occur at any age and have various causes. Most ataxias are rare diseases and many are genetic disorders. A large and steadily increasing number of underlying gene defects are known. The path to the correct diagnosis is often challenging. This overview summarizes the typical findings for the most important acquired, hereditary and non-hereditary degenerative ataxias. The focus is on ataxias with adult onset., Competing Interests: Erklärung zu finanziellen Interessen Forschungsförderung erhalten: ja, von einer anderen Institution; Honorar/geldwerten Vorteil für Referententätigkeit erhalten: ja, von einer anderen Institution; Bezahlter Berater/interner Schulungsreferent/Gehaltsempfänger: nein; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an im Bereich der Medizin aktiven Firma: ja, Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an zu Sponsoren dieser Fortbildung bzw. durch die Fortbildung in ihren Geschäftsinteressen berührten Firma: nein Erklärung zu nichtfinanziellen Interessen Andreas Thieme ist Mitglied in der Deutschen Gesellschaft für Neurologie (DGN).Dagmar Timmann ist im ärztlichen Beirat der der Deutschen Heredoataxie Gesellschaft (DHAG) und sie ist Mitglied in der DGN und in der Deutschen Gesellschaft für Klinische Neurophysiologie und funktionelle Bildgebung (DGKN)., (Thieme. All rights reserved.)

The cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a late-onset and recessively inherited ataxia. For many years, CANVAS has been diagnosed based on the clinical phenotype. Only recently, a large biallelic pentanucleotide repeat expansion in the replication factor C subunit 1 ( RFC1 ) gene has been identified as the underlying genetic cause for the large majority of CANVAS cases. Subsequently, other phenotypes such as ataxia with chronic cough, incomplete CANVAS and MSA-C-like phenotypes have been associated with biallelic RFC1 repeat expansions. Because of this heterogeneity it has been suggested to change the name of the disease to "RFC1 disease". Chronic cough is characteristic and can precede neurological symptoms by years or decades. In the neurological examination signs of cerebellar, sensory, and vestibular ataxia are frequently observed. Nerve conduction studies usually show absent or markedly reduced sensory nerve action potentials. On brain MRI cerebellar degeneration and spinal cord alterations are common. In later disease stages more widespread neurodegeneration with additional involvement of the brainstem and basal ganglia is possible. As yet, the exact incidence of RFC1 -associated neurological diseases remains uncertain although first studies suggest that RFC1 -related ataxia is common. Moreover, the pathophysiological mechanisms caused by the large biallelic pentanucleotide repeat expansions in RFC1 remain elusive. Future molecular and genetic research as well as natural history studies are highly desirable to pave the way towards personalized treatment approaches., Competing Interests: Competing interests: Andreas Thieme has received research grants unrelated to this manuscript from the University Medicine Essen Clinician Scientist Academy (UMEA)/Deutsche Forschungsgemeinschaft (DFG) [FU365/12-1], the German Heredoataxia Society (DHAG), Förderverein der Neurologie an der Universitätsmedizin Essen and the Mercator Research Foundation. He has received honoraria for educational articles from the Springer publishing company and holds stocks of Pfizer and Viatris. Dagmar Timmann has received research grants unrelated to this manuscript from Deutsche Forschungsgemeinschaft (DFG), the European Union (EU), the German Heredoataxia Society (DHAG) and the Bernd Fink Foundation. She has received honoraria from the German Society of Neurology (DGN). Christel Depienne has no competing interests., (© 2021 Thieme et al., published by De Gruyter.)