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Spinocerebellar ataxia type 3/Machado–Joseph disease (SCA3) is the most common autosomal dominant ataxia. In view of the development of targeted therapies for SCA3, precise knowledge of stage-dependent fluid and MRI biomarker changes is needed.We analyzed cross-sectional data of 292 SCA3 mutation carriers including 57 pre-ataxic individuals, and 108 healthy controls from the European Spinocerebellar ataxia type 3/Machado-Joseph Disease Initiative (ESMI) cohort. Blood concentrations of mutant ATXN3 and neurofilament light (NfL) were determined, and volumes of pons, cerebellar white matter (CWM) and cerebellar grey matter (CGM) were measured on MRI.Mutant ATXN3 concentrations were high before and after ataxia onset, while NfL continuously increased and deviated from normal 11.9 years before onset. Pons and CWM volumes decreased, but the deviation from normal was only 2.0 years (pons) and 0.3 years (CWM) before ataxia onset. We propose a staging model of SCA3 that includes an initial asymptomatic carrier stage followed by the biomarker stage defined by absence of ataxia, but a significant rise of NfL. The biomarker stage leads into the ataxia stage, defined by manifest ataxia.The present analysis provides a robust framework for further studies aiming at elaboration and differentiation of the staging model of SCA3.

ZUSAMMENFASSUNGAtaxien sind eine heterogene Gruppe von Erkrankungen. Sie können in jedem Lebensalter auftreten und haben verschiedene Ursachen. Die meisten Ataxien gehören zu den seltenen Erkrankungen und viele sind genetisch bedingt. Bislang beschränkt sich die Behandlung von Ataxien meist auf die symptomatische Therapie, insbesondere mittels Physiotherapie und Logopädie sowie auf die medikamentöse Behandlung von Begleitsymptomen. Eine wirksame „antiataktische“ medikamentöse Therapie steht unverändert nicht zur Verfügung. Nur für wenige Ataxien mit bekanntem Stoffwechseldefekt gibt es etablierte, zielgerichtete Therapieansätze. Tierexperimentell werden zunehmend genetische Therapien entwickelt. Erste klinische Sicherheitsstudien mit Antisense-Oligonukleotiden haben begonnen oder stehen kurz davor.

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.

Journal of neurology 269(8), 4363-4374 (2022). doi:10.1007/s00415-022-11071-5, Published by Steinkopff, [Darmstadt]

Die meisten Ataxien gehören zu den seltenen Erkrankungen und viele sind genetisch bedingt. Eine große und unverändert zunehmende Anzahl der zugrunde liegenden Gendefekte ist bekannt. Der Weg zur richtigen Diagnose stellt häufig eine Herausforderung dar. In dieser Übersicht werden die typischen Befunde für die wichtigsten erworbenen, erblichen und nicht erblichen degenerativen Ataxien zusammengefasst. Der Schwerpunkt liegt auf Ataxien mit Beginn im Erwachsenenalter.

Movement disorders 37(2), 405-410 (2022). doi:10.1002/mds.28844, Published by Wiley, New York, NY

The cerebellar nuclei are a brain region with high iron content. Surprisingly, little is known about iron content in the cerebellar nuclei and its possible contribution to pathology in cerebellar ataxias, with the only exception of Friedreich’s ataxia. In the present exploratory cross-sectional study, quantitative susceptibility mapping was used to investigate volume, iron concentration and total iron content of the dentate nuclei in common types of hereditary and non-hereditary degenerative ataxias. Seventy-nine patients with spinocerebellar ataxias of types 1, 2, 3 and 6; 15 patients with Friedreich’s ataxia; 18 patients with multiple system atrophy, cerebellar type and 111 healthy controls were also included. All underwent 3 T MRI and clinical assessments. For each specific ataxia subtype, voxel-based and volumes-of-interest-based group analyses were performed in comparison with a corresponding age- and sex-matched control group, both for volume, magnetic susceptiblity (indicating iron concentration) and susceptibility mass (indicating total iron content) of the dentate nuclei. Spinocerebellar ataxia of type 1 and multiple system atrophy, cerebellar type patients showed higher susceptibilities in large parts of the dentate nucleus but unaltered susceptibility masses compared with controls. Friedreich’s ataxia patients and, only on a trend level, spinocerebellar ataxia of type 2 patients showed higher susceptibilities in more circumscribed parts of the dentate. In contrast, spinocerebellar ataxia of type 6 patients revealed lower susceptibilities and susceptibility masses compared with controls throughout the dentate nucleus. Spinocerebellar ataxia of type 3 patients showed no significant changes in susceptibility and susceptibility mass. Lower volume of the dentate nuclei was found to varying degrees in all ataxia types. It was most pronounced in spinocerebellar ataxia of type 6 patients and least prominent in spinocerebellar ataxia of type 3 patients. The findings show that alterations in susceptibility revealed by quantitative susceptibility mapping are common in the dentate nuclei in different types of cerebellar ataxias. The most striking changes in susceptibility were found in spinocerebellar ataxia of type 1, multiple system atrophy, cerebellar type and spinocerebellar ataxia of type 6. Because iron content is known to be high in glial cells but not in neurons of the cerebellar nuclei, the higher susceptibility in spinocerebellar ataxia of type 1 and multiple system atrophy, cerebellar type may be explained by a reduction of neurons (increase in iron concentration) and/or an increase in iron-rich glial cells, e.g. microgliosis. Hypomyelination also leads to higher susceptibility and could also contribute. The lower susceptibility in SCA6 suggests a loss of iron-rich glial cells. Quantitative susceptibility maps warrant future studies of iron content and iron-rich cells in ataxias to gain a more comprehensive understanding of the pathogenesis of these diseases.

During recent decades, many studies have yielded evidence for cerebellar involvement in cognitive, emotional and affective processes besides the well-known cerebellar contribution to motor performance and learning (Koziol et al., 2014; Marien et al., 2014; Van Overwalle et al., 2014; Strata, 2015; Adamaszek et al., 2017; Kansal et al., 2017; Guell et al., 2018; King et al., 2019). Cerebellar diseases can result in executive, linguistic and visuospatial dysfunctions as well as problems with the regulation of emotion and affect. This combination of non-motor symptoms has been named cerebellar cognitive affective/Schmahmann syndrome (CCAS) (Schmahmann and Sherman, 1998). For many years, diagnosis has relied on non-standardized bedside cognitive examination and, if available, detailed neuropsychological test batteries. 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. We therefore believe that it is important to share our recent findings that the reference values published by Hoche and colleagues may apply only within a limited age and education range, while their more universal application may lead to a substantial number of false-positive test results.

[Background] Mutations in the mitochondrial DNA polymerase gamma are causing a wide phenotypic spectrum including ataxia as one of the most common presentations., [Objective] The objective of this study was to determine the course of disease of polymerase gamma–related ataxia., [Methods] In a prospective natural history study, we assessed 24 adult ataxia patients with biallelic polymerase gamma mutations for (1) severity of cerebellar dysfunction using the Scale for the Assessment and Rating of Ataxia score, (2) presence of nonataxia signs using the Inventory of Non-Ataxia Symptoms, (3) gray- and white-matter changes in brain MRI, and (4) findings in nerve conduction studies., [Results] Assessment included follow-up visits up to 11.6 years. The Scale for the Assessment and Rating of Ataxia showed a mean annual increase of 1.02 ± 0.78 points/year. Disease progression was faster in patients with age at onset ≤ 30 years (1.5 Scale for the Assessment and Rating of Ataxia points/year) than with later onset (0.5 points/year); P = 0.008. The Inventory of Non-Ataxia Symptoms count increased by 0.30 ± 0.4 points/year. External ophthalmoplegia, brain stem oculomotor signs, areflexia, and sensory deficits were the most common nonataxic features. On MRI cerebellar atrophy was mild. T2 signal alterations affected mostly cerebellar white matter, middle cerebellar peduncles, thalamus, brain stem, and occipital and frontal white matter. Within 4 years, progression was primarily observed in the context of repeated epileptic seizures. Nerve conduction studies revealed axonal sensory peripheral neuropathy with mild motor nerve involvement. Exploratory sample size calculation implied 38 patients per arm as sufficient to detect a reduction of progression by 50% in hypothetical interventions within a 1-year trial., [Conclusion] The results recommend the Scale for the Assessment and Rating of Ataxia as a primary outcome measure for future interventional trials in polymerase gamma–related ataxia. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., This work was supported, in part, via the European Union's Horizon 2020 research and innovation program under the ERA-NET Cofund action no. 643578. It was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) no. 441409627, as part of the PROSPAX consortium under the frame of EJP RD, the European Joint Programme on Rare Diseases, under the EJP RD COFUND-EJP no. 825575 (to M.S. and B.v.d.W.) and to the PREPARE consortium (01GM1607; to M.S. and B.v.d.W.).

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).

Manchmal vermitteln Worte einen falschen Eindruck: zum Beispiel die Bezeichnung Grobblech. Für den Außenstehenden ergibt sich zunächst der Eindruck, dass sich dahinter etwas Grobes, Ungetümes verbirgt. Dies relativiert sich spätestens, wenn die hochgenauen Prüfverfahren für die Bleche betrachtet werden, die kleinste Details detektieren können.

Context dependency of extinction is well known and has extensively been studied in fear conditioning, but has rarely been assessed in eyeblink conditioning. One way to demonstrate context dependency of extinction is the renewal effect. ABA paradigms are most commonly used to show the renewal effect of extinguished learned fear: if acquisition takes place in context A, and extinction takes place in context B (extinction phase), learned responses will recover in subsequent extinction trials presented in context A (renewal phase). The renewal effect of the visual threat eyeblink response (VTER), a conditioned eyeblink response, which is naturally acquired in early infancy, was examined in a total of 48 young and healthy participants with two experiments using an ABA paradigm. Twenty paired trials were performed in context A (baseline trials), followed by 50 extinction trials in context B (extinction phase) and 50 extinction trials in context A (renewal phase). In 24 participants, contexts A and B were two different rooms, and in the other 24 participants, two different background colors (orange and blue) and noises were used. To rule out spontaneous recovery, an AAA design was used for comparison. There were significant effects of extinction in both experiments. No significant renewal effects were observed. In experiment 2, however, extinction was significantly less using orange background during extinction compared to the blue background. The present findings suggest that extinction of conditioned eyeblinks depends on the physical context. Findings add to the animal literature that context can play a role in the acquisition of classically conditioned eyeblink responses. Future studies, however, need to be performed to confirm the present findings. Lack of renewal effect may be explained by the highly overlearned character of the VTER.

Acquisition of conditioned eyeblink responses is known to decline with age, and age-related decline has been related to a reduction of cerebellar size and function. The aim of the present study was to investigate age-related effects on storage-related processes and extinction of visual threat eyeblink responses (VTERs), conditioned responses which are naturally acquired in early childhood. Storage and extinction of VTERs were tested in 34 healthy participants with an age range from 21 to 74 years (mean age 41.6±16.3 years). High-resolution structural magnetic resonance images (MRI) were acquired in all subjects. Conventional volumetric measures and voxel-based morphometry (VBM) were performed at the level of the cerebellum. Storage and extinction of VTERs showed a significant age-dependent decline. Likewise, cerebellar volume decreased with age. Storage, but not extinction showed a significant positive correlation with age-dependent reduction of total cerebellar volume. VBM analysis showed that gray matter volume in circumscribed areas of intermediate lobules VI, and Crus I and II bilaterally were positively correlated with VTER storage (p

Previous findings suggested that the human cerebellum is involved in the acquisition but not the long-term storage of motor associations. The finding of preserved retention in cerebellar patients was fundamentally different from animal studies which show that both acquisition and retention depends on the integrity of the cerebellum. The present study investigated whether retention had been preserved because critical regions of the cerebellum were spared. Visual threat eye-blink responses, that is, the anticipatory closure of the eyes to visual threats, have previously been found to be naturally acquired conditioned responses. Because acquisition is known to take place in very early childhood, visual threat eye-blink responses can be used to test retention in patients with adult onset cerebellar disease. Visual threat eye-blink responses were tested in 19 adult patients with cerebellar degeneration, 27 adult patients with focal cerebellar lesions due to stroke, 24 age-matched control subjects, and 31 younger control subjects. High-resolution structural magnetic resonance images were acquired in patients to perform lesion-symptom mapping. Voxel-based morphometry was performed in patients with cerebellar degeneration, and voxel-based lesion-symptom mapping in patients with focal disease. Visual threat eye-blink responses were found to be significantly reduced in patients with cerebellar degeneration. Visual threat eye-blink responses were also reduced in patients with focal disease, but to a lesser extent. Visual threat eye-blink responses declined with age. In patients with cerebellar degeneration the degree of cerebellar atrophy was positively correlated with the reduction of conditioned responses. Voxel-based morphometry showed that two main regions within the superior and inferior parts of the posterior cerebellar cortex contributed to expression of visual threat eye-blink responses bilaterally. Involvement of the more inferior parts of the posterior lobe was further supported by voxel-based lesion symptom mapping in focal cerebellar patients. The present findings show that the human cerebellar cortex is involved in long-term storage of learned responses. © 2013 The Author (2013).

Auf dem Weg in die Informationsgesellschaft tragt die Wirtschaftsforderung Sachsen GmbH (WFS) zur Einbindung des Wirtschaftsstandortes Sachsen in die internationalen Wirtschaftsbeziehungen unter den Bedingungen des verstarkten Einsatzes von Multimedia und Neuen Medien bei. Dies geschieht insbesondere durch die Konzipierung und Umsetzung von Multimedia-Offline-Systemen sowie von Online-Systemen fur den Freistaat Sachsen.