Cerebellar Volumetry in Ataxias: Relation to Ataxia Severity and Duration.

Cerebellar atrophy is the neuropathological hallmark of most ataxias. Hence, quantifying the volume of the cerebellar grey and white matter is of great interest. In this study, we aim to identify volume differences in the cerebellum between spinocerebellar ataxia type 1 (SCA1), SCA3 and SCA6 as well as multiple system atrophy of cerebellar type (MSA-C). Our cross-sectional data set comprised mutation carriers of SCA1 (N=12), SCA3 (N=62), SCA6 (N=14), as well as MSA-C patients (N=16). Cerebellar volumes were obtained from T1-weighted magnetic resonance images. To compare the different atrophy patterns, we performed a z-transformation and plotted the intercept of each patient group's model at the mean of 7 years of ataxia duration as well as at the mean ataxia severity of 14 points in the SARA sum score. In addition, we plotted the extrapolation at ataxia duration of 0 years as well as 0 points in the SARA sum score. Patients with MSA-C demonstrated the most pronounced volume loss, particularly in the cerebellar white matter, at the late time intercept. Patients with SCA6 showed a pronounced volume loss in cerebellar grey matter with increasing ataxia severity compared to all other patient groups. MSA-C, SCA1 and SCA3 showed a prominent atrophy of the cerebellar white matter. Our results (i) confirmed SCA6 being considered as a pure cerebellar grey matter disease, (ii) emphasise the involvement of cerebellar white matter in the neuropathology of SCA1, SCA3 and MSA-C, and (iii) reflect the rapid clinical progression in MSA-C.

Factors Influencing Health-Related Quality of Life of Patients with Spinocerebellar Ataxia.

BACKGROUND: Little is known about the progression of health-related quality of life (HRQoL) and predicting factors in spinocerebellar ataxia (SCA). Such knowledge is crucial to identify modifiable factors promoting everyday life with SCA and attenuating HRQoL decline. OBJECTIVES: This study is to assess HRQoL progression and identify factors affecting SCA patients' HRQoL. METHODS: Longitudinal data (three-year follow-up) of 310 SCA patients of the European SCA3/Machado-Joseph-Disease Initiative (ESMI) (2016-2022) and 525 SCA patients (SCA1, SCA2, SCA3 or SCA6) of the EUROSCA natural history study cohort (2006-2015) were assessed. Both large cohort studies share standardized assessments of clinical measures, SARA, INAS, PHQ-9, and HRQoL (EQ-5D-3L). The association between HRQoL and clinical measures was assessed by Spearman Correlation (rs). Multivariable panel regression models were performed to evaluate the impact of patients' socio-demographics, age of onset, SCA type and body mass index (BMI), and clinical measures on HRQoL progression. RESULTS: HRQoL significantly decreased over one (- 0.014, p = 0.095), two (- 0.028, p = 0.003), and three years (- 0.032, p = 0.002). Ataxia severity and mental health strongly correlated with HRQoL (rsSARA = - 0.589; rsPHQ-9 = - 0.507). HRQoL more intensively declined in male (ß = - 0.024, p = 0.038) patients with an earlier age of onset (ß = 0.002, p = 0.058). Higher progression of ataxia severity (ß = - 0.010, p ≤ 0.001), mental health problems (ß = - 0.012, p < 0.001), and higher BMI (ß = - 0.003, p = 0.029) caused more severe decline of patients' HRQoL over time. DISCUSSION: In absence of curative treatments, stronger focus on mental health and weight influence could help clinical evaluation and accompany treatment improving SCA patients' HRQoL, especially in male patients with early disease onset.

Altered binaural hearing in pre-ataxic and ataxic mutation carriers of spinocerebellar ataxia type 3.

Brainstem degeneration is a prominent feature of spinocerebellar ataxia type 3 (SCA3), involving structures that execute binaural synchronization with microsecond precision. As a consequence, auditory processing may deteriorate during the course of disease. We tested whether the binaural "Huggins pitch" effect is suitable to study the temporal precision of brainstem functioning in SCA3 mutation carriers. We expected that they would have difficulties perceiving Huggins pitch at high frequencies, and that they would show attenuated neuromagnetic responses to Huggins pitch. The upper limit of Huggins pitch perception was psychoacoustically determined in 18 pre-ataxic and ataxic SCA3 mutation carriers and in 18 age-matched healthy controls. Moreover, the cortical N100 response following Huggins pitch onset was acquired by means of magnetoencephalography (MEG). MEG recordings were analyzed using dipole source modeling and comprised a monaural pitch condition and a no-pitch condition with simple binaural correlation changes. Compared with age-matched controls, ataxic but not pre-ataxic SCA3 mutation carriers had significantly lower frequency limits up to which Huggins pitch could be heard. Listeners with lower frequency limits also showed diminished MEG responses to Huggins pitch, but not in the two control conditions. Huggins pitch is a promising tool to assess brainstem functioning in ataxic SCA3 patients. Future studies should refine the psychophysiological setup to capture possible performance decrements also in pre-ataxic mutation carriers. Longitudinal observations will be needed to prove the potential of the assessment of Huggins pitch as a biomarker to track brainstem functioning during the disease course in SCA3.

Stage-Dependent Biomarker Changes in Spinocerebellar Ataxia Type 3.

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.

Cerebellar volumetry in ataxias: Relation to ataxia severity and duration.

Background: Cerebellar atrophy is the neuropathological hallmark of most ataxias. Hence, quantifying the volume of the cerebellar grey and white matter is of great interest. In this study, we aim to identify volume differences in the cerebellum between spinocerebellar ataxia type 1 (SCA1), SCA3 and SCA6 as well as multiple system atrophy of cerebellar type (MSA-C). Methods: Our cross-sectional data set comprised mutation carriers of SCA1 (N=12), SCA3 (N=62), SCA6 (N=14), as well as MSA-C patients (N=16). Cerebellar volumes were obtained from T1-weighted magnetic resonance images. To compare the different atrophy patterns, we performed a z-transformation and plotted the intercept of each patient group's model at the mean of 7 years of ataxia duration as well as at the mean ataxia severity of 14 points in the SARA sum score. In addition, we plotted the extrapolation at ataxia duration of 0 years as well as 0 points in the SARA sum score. Results: Patients with MSA-C demonstrated the most pronounced volume loss, particularly in the cerebellar white matter, at the late time intercept. Patients with SCA6 showed a pronounced volume loss in cerebellar grey matter with increasing ataxia severity compared to all other patient groups. MSA-C, SCA1 and SCA3 showed a prominent atrophy of the cerebellar white matter. Conclusion: Our results (i) confirmed SCA6 being considered as a pure cerebellar gray matter disease, (ii) emphasise the involvement of cerebellar white matter in the neurophatology of SCA1, SCA3 and MSA-C, and (iii) reflect the rapid clinical progression in MSA-C.

Health-Related Quality of Life in Patients with Spinocerebellar Ataxia: a Validation Study of the EQ-5D-3L.

Although health-related quality of life (HRQoL) has developed into a crucial outcome parameter in clinical research, evidence of the EQ-5D-3L validation performance is lacking in patients with spinocerebellar ataxia (SCA) types 1, 2, 3, and 6. The objective of this study is to assess the acceptability, validity, reliability, and responsiveness of the EQ-5D-3L. For n = 842 predominantly European SCA patients of two longitudinal cohort studies, the EQ-5D-3L, PHQ-9 (Patient Health Questionnaire), and ataxia-specific clinical assessments (SARA: Scale for Assessment and Rating of Ataxia; ADL: activities of daily living as part of Friedreich's Ataxia Rating Scale; INAS: Inventory of Non-Ataxia Signs) were assessed at baseline and multiple annual follow-ups. The EQ-5D-3L was evaluated regarding acceptability, distribution properties, convergent and known-groups validity, test-retest reliability, and effect size measures to analyze health changes. The non-item response was low (EQ-5D-3L index: 0.8%; EQ-VAS: 3.4%). Ceiling effects occurred in 9.9% (EQ-5D-3L) and 3.0% (EQ-VAS) with a mean EQ-5D-3L index of 0.65 ± 0.21. In total, convergent validity showed moderate to strong Spearman's rho (rs > 0.3) coefficients comparing EQ-5D-3L and EQ-VAS with PHQ-9, SARA, ADL, and INAS. EQ-5D-3L could discriminate between groups of age, SARA, ADL, and INAS. Intra-class correlation coefficients (EQ-5D-3LICC: 0.95/EQ-VASICC: 0.88) and Kappa statistics (range 0.44 to 0.93 for EQ-5D-3L items) indicated tolerable reliability. EQ-5D-3L shows small (effect size < 0.3) to moderate (effect size 0.3-0.59) health changes regarding ataxia severity. The analysis confirms an acceptable, reliable, valid, and responsive recommended EQ-5D-3L in SCA patients, measuring the HRQoL adequately, besides well-established clinical instruments.

Disease progression of spinocerebellar ataxia types 1, 2, 3 and 6 before and after ataxia onset.

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.

Peripheral nerve involvement in hereditary spastic paraplegia characterized by quantitative magnetic resonance neurography.

BACKGROUND AND OBJECTIVES: Hereditary spastic paraplegias (HSPs) are heterogenous genetic disorders. While peripheral nerve involvement is frequent in spastic paraplegia 7 (SPG7), the evidence of peripheral nerve involvement in SPG4 is more controversial. We aimed to characterize lower extremity peripheral nerve involvement in SPG4 and SPG7 by quantitative magnetic resonance neurography (MRN). METHODS: Twenty-six HSP patients carrying either the SPG4 or SPG7 mutation and 26 age-/sex-matched healthy controls prospectively underwent high-resolution MRN with large coverage of the sciatic and tibial nerve. Dual-echo turbo-spin-echo sequences with spectral fat-saturation were utilized for T2-relaxometry and morphometric quantification, while two gradient-echo sequences with and without an off-resonance saturation rapid frequency pulse were applied for magnetization transfer contrast (MTC) imaging. HSP patients additionally underwent detailed neurologic and electroneurographic assessments. RESULTS: All microstructural (proton spin density [ρ], T2-relaxation time, magnetization transfer ratio) and morphometric (cross-sectional area) quantitative MRN markers were decreased in SPG4 and SPG7 indicating chronic axonopathy. ρ was superior in differentiating subgroups and identifying subclinical nerve damage in SPG4 and SPG7 without neurophysiologic signs of polyneuropathy. MRN markers correlated well with clinical scores and electroneurographic results. CONCLUSIONS: MRN characterizes peripheral nerve involvement in SPG4 and SPG7 as a neuropathy with predominant axonal loss. Evidence of peripheral nerve involvement in SPG4 and SPG7, even without electroneurographically manifest polyneuropathy, and the good correlation of MRN markers with clinical measures of disease progression, challenge the traditional view of the existence of HSPs with isolated pyramidal signs and suggest MRN markers as potential progression biomarkers in HSP.

Stage-dependent biomarker changes in spinocerebellar ataxia type 3.

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.

SCAview: an Intuitive Visual Approach to the Integrative Analysis of Clinical Data in Spinocerebellar Ataxias.

With SCAview, we present a prompt and comprehensive tool that enables scientists to browse large datasets of the most common spinocerebellar ataxias intuitively and without technical effort. Basic concept is a visualization of data, with a graphical handling and filtering to select and define subgroups and their comparison. Several plot types to visualize all data points resulting from the selected attributes are provided. The underlying synthetic cohort is based on clinical data from five different European and US longitudinal multicenter cohorts in spinocerebellar ataxia type 1, 2, 3, and 6 (SCA1, 2, 3, and 6) comprising > 1400 patients with overall > 5500 visits. First, we developed a common data model to integrate the clinical, demographic, and characterizing data of each source cohort. Second, the available datasets from each cohort were mapped onto the data model. Third, we created a synthetic cohort based on the cleaned dataset. With SCAview, we demonstrate the feasibility of mapping cohort data from different sources onto a common data model. The resulting browser-based visualization tool with a thoroughly graphical handling of the data offers researchers the unique possibility to visualize relationships and distributions of clinical data, to define subgroups and to further investigate them without any technical effort. Access to SCAview can be requested via the Ataxia Global Initiative and is free of charge.

The frequency of non-motor symptoms in SCA3 and their association with disease severity and lifestyle factors.

BACKGROUND: Non-motor symptoms (NMS) are a substantial burden for patients with SCA3. There are limited data on their frequency, and their relation with disease severity and activities of daily living is not clear. In addition, lifestyle may either influence or be affected by the occurrence of NMS. OBJECTIVE: To characterize NMS in SCA3 and investigate possible associations with disease severity and lifestyle factors. METHODS: In a prospective cohort study, we performed a cross-sectional analysis of NMS in 227 SCA3 patients, 42 pre-ataxic mutation carriers, and 112 controls and tested for associations with SARA score, activities of daily living, and the lifestyle factors alcohol consumption, smoking and physical activity. RESULTS: Sleep disturbance, restless legs syndrome, mild cognitive impairment, depression, bladder dysfunction and pallhypesthesia were frequent among SCA3 patients, while mainly absent in pre-ataxic mutation carriers. Except for restless legs syndrome, NMS correlated significantly with disease severity and activities of daily living. Alcohol abstinence was associated with bladder dysfunction. Patients with higher physical activity showed less cognitive impairment and fewer depressive symptoms, but these differences were not significant. CONCLUSION: This study revealed a clear association between disease severity and NMS, likely driven by the progression of the widespread neurodegenerative process. Associations between lifestyle and NMS can probably be attributed to the influence of NMS on lifestyle.

Differential Temporal Dynamics of Axial and Appendicular Ataxia in SCA3.

BACKGROUND: Disease severity in spinocerebellar ataxia type 3 (SCA3) is commonly defined by the Scale for the Assessment and Rating of Ataxia (SARA) sum score, but little is known about the contributions and progression patterns of individual items. OBJECTIVES: To investigate the temporal dynamics of SARA item scores in SCA3 patients and evaluate if clinical and demographic factors are differentially associated with evolution of axial and appendicular ataxia. METHODS: In a prospective, multinational cohort study involving 11 European and 2 US sites, SARA scores were determined longitudinally in 223 SCA3 patients with a follow-up assessment after 1 year. RESULTS: An increase in SARA score from 10 to 20 points was mainly driven by axial and speech items, with a markedly smaller contribution of appendicular items. Finger chase and nose-finger test scores not only showed the lowest variability at baseline, but also the least deterioration at follow-up. Compared with the full set of SARA items, omission of both tests would result in lower sample size requirements for therapeutic trials. Sex was associated with change in SARA sum score and appendicular, but not axial, subscore, with a significantly faster progression in men. Despite considerable interindividual variability, the average annual progression rate of SARA score was approximately three times higher in subjects with a disease duration over 10 years than in those within 10 years from onset. CONCLUSION: Our findings provide evidence for a difference in temporal dynamics between axial and appendicular ataxia in SCA3 patients, which will help inform the design of clinical trials and development of new (etiology-specific) outcome measures. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The CCAS-scale in hereditary ataxias: helpful on the group level, particularly in SCA3, but limited in individual patients.

BACKGROUND: A brief bedside test has recently been introduced by Hoche et al. (Brain, 2018) to screen for the Cerebellar Cognitive Affective Syndrome (CCAS) in patients with cerebellar disease. OBJECTIVE: This multicenter study tested the ability of the CCAS-Scale to diagnose CCAS in individual patients with common forms of hereditary ataxia. METHODS: A German version of the CCAS-Scale was applied in 30 SCA3, 14 SCA6 and 20 FRDA patients, and 64 healthy participants matched for age, sex, and level of education. Based on original cut-off values, the number of failed test items was assessed, and CCAS was considered possible (one failed item), probable (two failed items) or definite (three failed items). In addition a total sum raw score was calculated. RESULTS: On a group level, failed items were significantly higher and total sum scores were significantly lower in SCA3 patients compared to matched controls. SCA6 and FRDA patients performed numerically below controls, but respective group differences failed to reach significance. The ability of the CCAS-Scale to diagnose CCAS in individual patients was limited to severe cases failing three or more items. Milder cases failing one or two items showed a great overlap with the performance of controls exhibiting a substantial number of false-positive test results. The word fluency test items differentiated best between patients and controls. CONCLUSIONS: As a group, SCA3 patients performed below the level of SCA6 and FRDA patients, possibly reflecting additional cerebral involvement. Moreover, the application of the CCAS-Scale in its present form results in a high number of false-positive test results, that is identifying controls as patients, reducing its usefulness as a screening tool for CCAS in individual patients.

Levels of Neurofilament Light at the Preataxic and Ataxic Stages of Spinocerebellar Ataxia Type 1.

BACKGROUND AND OBJECTIVES: Neurofilament light (NfL) appears to be a promising fluid biomarker in repeat-expansion spinocerebellar ataxias (SCAs), with piloting studies in mixed SCA cohorts suggesting that NfL might be increased at the ataxic stage of SCA type 1 (SCA1). We here hypothesized that NfL is increased not only at the ataxic stage of SCA1, but also at its (likely most treatment-relevant) preataxic stage. METHODS: We assessed serum NfL (sNfL) and CSF NfL (cNfL) levels in both preataxic and ataxic SCA1, leveraging a multicentric cohort recruited at 6 European university centers, and clinical follow-up data, including actually observed (rather than only predicted) conversion to the ataxic stage. Levels of sNfL and cNfL were assessed by single-molecule array and ELISA technique, respectively. RESULTS: Forty individuals with SCA1 (23 preataxic, 17 ataxic) and 89 controls were enrolled, including 11 preataxic individuals converting to the ataxic stage. sNfL levels were increased at the preataxic (median 15.5 pg/mL [interquartile range 10.5-21.1 pg/mL]) and ataxic stage (31.6 pg/mL [26.2-37.7 pg/mL]) compared to controls (6.0 pg/mL [4.7-8.6 pg/mL]), yielding high age-corrected effect sizes (preataxic: r = 0.62, ataxic: r = 0.63). sNfL increases were paralleled by increases of cNfL at both the preataxic and ataxic stage. In preataxic individuals, sNfL levels increased with proximity to predicted ataxia onset, with significant sNfL elevations already 5 years before onset, and confirmed in preataxic individuals with actually observed ataxia onset. sNfL increases were detected already in preataxic individuals with SCA1 without volumetric atrophy of cerebellum or pons, suggesting that sNfL might be more sensitive to early preataxic neurodegeneration than the currently known most change-sensitive regions in volumetric MRI. Using longitudinal sNfL measurements, we estimated sample sizes for clinical trials with the reduction of sNfL as the endpoint. DISCUSSION: sNfL levels might provide easily accessible peripheral biomarkers in both preataxic and ataxic SCA1, allowing stratification of preataxic individuals regarding proximity to onset, early detection of neurodegeneration even before volumetric MRI alterations, and potentially capture of treatment response in clinical trials. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT01037777. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that NfL levels are increased in both ataxic and preataxic SCA1 and are associated with ataxia onset.

Evolution of disability in spinocerebellar ataxias type 1, 2, 3, and 6.

OBJECTIVE: The aim was to study the evolution of disability in spinocerebellar ataxias (SCAs) type 1, 2, 3, and 6 (SCA1, 2, 3, 6). METHODS: We 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. RESULTS: Data 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). INTERPRETATION: Our data are important for counselling of patients, assessment of the relevance of outcome markers, and design of clinical trials.

Quantitative magnetic resonance neurographic characterization of peripheral nerve involvement in manifest and pre-ataxic spinocerebellar ataxia type 3.

BACKGROUND AND PURPOSE: Knowledge about the exact underlying pathophysiological changes involved in the genesis and progression of spinocerebellar ataxia type 3 (SCA3) is limited. Lower extremity peripheral nerve lesions in clinically, genetically and electrophysiologically classified ataxic and pre-ataxic SCA3 mutation carriers were characterized and quantified by magnetic resonance neurography (MRN). METHODS: Eighteen SCA3 mutation carriers and 20 age-/sex-matched healthy controls were prospectively enrolled. All SCA3 mutation carriers underwent detailed neurological and electrophysiological examinations. 3 T MRN covered the lumbosacral plexus and proximal thigh to the tibiotalar joint by using T2-weighted inversion recovery sequences, dual-echo relaxometry sequences with spectral fat saturation, and two gradient-echo sequences with and without an off-resonance saturation rapid frequency pulse. Detailed quantification of nerve lesions by morphometric and microstructural MRN markers, including T2 relaxometry and magnetization transfer contrast imaging, was conducted in all study participants. RESULTS: MRN detected peripheral nerve damage in ataxic and pre-ataxic SCA3. The quantitative markers proton spin density (ρ), T2 relaxation time, magnetization transfer ratio and cross-sectional area were decreased in SCA3, indicating chronic axonopathy. MTR and ρ identified early, subclinical nerve damage in pre-ataxic SCA3 and in SCA3 mutation carriers without polyneuropathy and were superior in differentiating between all subgroups. Additionally, microstructural markers correlated well with clinical symptom scores and electrophysiological results. CONCLUSIONS: Our data provide a comprehensive characterization of peripheral nerve damage in SCA3 and assist in understanding the mechanisms of the multisystemic disease evolution. Evidence of peripheral nerve involvement prior to the onset of clinically overt ataxia might have important implications for designing early intervention studies.

Characterization of Lifestyle in Spinocerebellar Ataxia Type 3 and Association with Disease Severity.

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.

Safety and Efficacy of Acetyl-DL-Leucine in Certain Types of Cerebellar Ataxia: The ALCAT Randomized Clinical Crossover Trial.

Importance: Cerebellar ataxia is a neurodegenerative disease impairing motor function characterized by ataxia of stance, gait, speech, and fine motor disturbances. Objective: To investigate the efficacy, safety, and tolerability of the modified essential amino acid acetyl-DL-leucine in treating patients who have cerebellar ataxia. Design, Setting, and Participants: The Acetyl-DL-leucine on Cerebellar Ataxia (ALCAT) trial was an investigator-initiated, multicenter, double-blind, randomized, placebo-controlled, clinical crossover trial. The study was conducted at 7 university hospitals in Germany and Austria between January 25, 2016, and February 17, 2017. Patients were aged at least 18 years and diagnosed with cerebellar ataxia of hereditary (suspected or genetically confirmed) or nonhereditary or unknown type presenting with a total score of at least 3 points on the Scale for the Assessment and Rating of Ataxia (SARA). Statistical analysis was performed from April 2018 to June 2018 and January 2020 to March 2020. Interventions: Patients were randomly assigned (1:1) to receive acetyl-DL-leucine orally (5 g per day after 2 weeks up-titration) followed by a matched placebo, each for 6 weeks, separated by a 4-week washout, or vice versa. The randomization was done via a web-based, permuted block-wise randomization list (block size, 2) that was stratified by disease subtype (hereditary vs nonhereditary or unknown) and site. Main Outcomes and Measures: Primary efficacy outcome was the absolute change of SARA total score from (period-dependent) baseline to week 6. Results: Among 108 patients who were randomly assigned to sequence groups (54 patients each), 55 (50.9%) were female; the mean (SD) age was 54.8 (14.4) years; and the mean (SD) SARA total score was 13.33 (5.57) points. The full analysis set included 105 patients (80 patients with hereditary, 25 with nonhereditary or unknown cerebellar ataxia). There was no evidence of a difference in the mean absolute change from baseline to week 6 in SARA total scores between both treatments (mean treatment difference: 0.23 points [95% CI, -0.40 to 0.85 points]). Conclusions and Relevance: In this large multicenter, double-blind, randomized, placebo-controlled clinical crossover trial, acetyl-DL-leucine in the investigated dosage and treatment duration was not superior to placebo for the symptomatic treatment of certain types of ataxia. The drug was well tolerated; and ALCAT yielded valuable information about the duration of treatment periods and the role of placebo response in cerebellar ataxia. These findings suggest that further symptom-oriented trials are needed for evaluating the long-term effects of acetyl-DL-leucine for well-defined subgroups of cerebellar ataxia. Trial Registration: EudraCT 2015-000460-34.