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Spinocerebellar ataxia 38 (SCA 38) is a very rare autosomal dominant inherited disorder caused by a mutation in ELOV5 gene, specifically expressed in cerebellar Purkinje cells, encoding an enzyme involved in the synthesis of fatty acids. Seven symptomatic SCA 38 patients of a Sardinian family were administered 15 sessions of cerebellar anodal transcranial direct current stimulation (tDCS) in a cross-over study, employing deltoid cerebellar-only (C-tDCS) and cerebello-spinal (CS-tDCS) cathodal montage. Clinical evaluation was performed at baseline (T0), after 15 sessions of tDCS (T1) and after 1 month of follow-up (T2). Modified International Cooperative Ataxia Rating Scale (MICARS) and the Robertson dysarthria profile were used to rate ataxic and dysarthric symptoms, respectively. Alertness and split attention tests from Zimmermann test battery for attentional performance were employed to rate attentive functions. Moreover, 3D computerized gait analysis was employed to obtain a quantitative measure of efficacy of tDCS on motor symptoms. While clinical data showed that both CS and C-tDCS improved motor, dysarthric, and cognitive scores, the quantitative analysis of gait revealed significant improvement in spatio-temporal parameters only for C-tDCS treatment. Present findings, yet preliminary and limited by the small size of the tested sample, confirm the therapeutic potential of cerebellar tDCS in improving motor and cognitive symptoms in spinocerebellar ataxias and underline the need to obtain quantitative and objective measures to monitor the efficacy of a therapeutic treatment and to design tailored rehabilitative interventions. ClinicalTrials.gov identifier: NCT05951010

Spinocerebellar ataxia (SCA) results in balance and coordination impairment, and current treatments have limited efficacy. Recent evidence suggests that combining postural training with cerebellar transcranial direct current stimulation (ctDCS) can improve these symptoms. However, the combined effects of ctDCS and postural training on individuals with spinocerebellar ataxia remain underexplored. Ten volunteers with (SCA type 3) participated in a triple-blind, randomized, crossover study to receive a single session of ctDCS (2 mA for 20 min) and a sham ctDCS session separated by at least one week. The Biodex Balance System was used to assess balance at each session, measuring overall stability index, anteroposterior stability index, and medial-lateral stability index. As secondary outcomes, cerebellar ataxia symptoms were evaluated using the 8-item Scale for Assessment and Rating of Ataxia. The assessments were conducted before and after each session. The results indicated that ctDCS enhanced the overall stability index when compared to sham ctDCS (Z = -2.10, p  = 0.03), although it did not significantly affect the anteroposterior or medial-lateral stability indices. Compared to the baseline, a single session of ctDCS reduced appendicular symptoms related to cerebellar ataxia, as evidenced by improvements in the nose-finger test (Z = -2.07, p  = 0.04), fast alternating hand movements (Z = -2.15, p  = 0.03), and heel-to-shin slide (Z = -1.91, p  = 0.05). In conclusion, our study suggests that a single session of ctDCS, in combination with postural training, can enhance balance and alleviate ataxia symptoms in individuals with cerebellar ataxia. This study was approved by the local research ethics committee (No. 2.877.813) and registered on clinicaltrials.org (NCT04039048 - https://www.clinicaltrials.gov/study/NCT04039048 ) on 2019-07-28.

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant disorder. Lithium is able to stimulate autophagy, and to reduce Ca 2+ efflux from the inositol-1,4,5-triphosphate receptor. We designed a phase II, randomized, placebo-controlled, double-blind, 48-week trial with lithium carbonate in 20 patients with SCA2. The primary objective was to determine safety and tolerability of lithium. The secondary objectives were to determine disease progression, quality of life, mood, and brain volume change. Sixteen patients completed the trial, 8 randomized to lithium, 8 to placebo. Forty adverse events (AEs) were reported during the trial, twenty-eight in the lithium and 12 in the placebo group ( p  = 0.11). Mean AE duration was 57.4 ± 60.8 and 77.4 ± 68.5 days ( p  = 0.37). Non-significant differences were observed for the SARA and for brain volume change, whereas a significant reduction in the BDI-II was observed for lithium group ( p  < 0.05). Lithium was well tolerated and reported AEs were similar to those previously described for bipolar disorder patients. A correctly powered phase III trial is needed to assess if lithium may slow disease progression in SCA2.

Cuban patients with Spinocerebellar Ataxia type 2 (SCA2) have reduced concentrations of zinc in serum and cerebrospinal fluid (CSF). To assess the effect and safety of zinc supplementation, 36 Cuban SCA2 patients were randomly assigned to receive daily either 50 mg ZnSO 4 or placebo, together with neurorehabilitation therapy in a randomized, double-blind, placebo-controlled clinical trial during 6 months. Outcome measures included the changes of zinc levels in CSF and serum, ataxia score, oxidative stress and saccadic eye movements. At the end of the study, the Zinc-treated group showed: (i) a significant increase of the Zn levels in the CSF, (ii) mild decrease in the ataxia scale subscores for gait, posture, stance and dysdiadochocinesia (iii) reduction of lipid’s oxidative damage, and (iv) reduction of saccadic latency when compared with the placebo group. The treatment was safe and well tolerated by all subjects. This study demonstrated the efficacy and safety of Zn supplementation, combined with neurorehabilitation for SCA2 patients and therefore it may encourage further studies on the clinical effect of zinc supplementation in SCA2 based in the conduction of future clinical trials with higher number of subjects.

Key Points Among the diverse group of dominantly inherited spinocerebellar ataxias (SCAs), those attributable to the expansion of polyglutamine (polyQ)-encoding CAG repeats include the most prevalent and severe forms (SCA1, SCA2, SCA3, SCA6, SCA7 and SCA17). The polyQ SCAs typically present with gait ataxia, limb incoordination, speech disturbance and oculomotor abnormalities, and death is caused by brainstem failure; however, SCA7 is uniquely characterized by retinal degeneration, and SCA6 is usually a pure cerebellar disease that does not reduce lifespan. In the polyQ SCAs, the Purkinje cells of the cerebellar cortex are a prominent pathological target. An exception is SCA3, in which Purkinje cells are less involved. Changes in the expression of receptors and ion channels important for regulating membrane excitability contribute to motor dysfunction, as well as to structural changes in neurons that lead to cell death and thus may be targets for the treatment of motor dysfunction. The diverse biological functions of the polyQ SCA proteins, which include regulation of transcription, RNA splicing and metabolism, and deubiquitinase activity, help to specify the disease pathogenesis of each disease. Several cellular pathways are implicated in the pathogenesis of each polyQ SCA; hence, developing therapies that directly target the expression of the mutant gene or protein is a major current focus of research in this field. Several of the spinocerebellar ataxias (SCAs) result from expansion of polyglutamine (polyQ)-encoding regions in different genes. Here, Orr and colleagues examine the clinical features of the the polyQ SCAs, and suggest that understanding the molecular and physiological mechanisms underlying polyQ SCAs can inform therapeutic strategies for these and other polyQ disorders. The dominantly inherited spinocerebellar ataxias (SCAs) are a large and diverse group of neurodegenerative diseases. The most prevalent SCAs (SCA1, SCA2, SCA3, SCA6 and SCA7) are caused by expansion of a glutamine-encoding CAG repeat in the affected gene. These SCAs represent a substantial portion of the polyglutamine neurodegenerative disorders and provide insight into this class of diseases as a whole. Recent years have seen considerable progress in deciphering the clinical, pathological, physiological and molecular aspects of the polyglutamine SCAs, with these advances establishing a solid base from which to pursue potential therapeutic approaches.

Antisense oligonucleotides against ATXN2 improved motor neuron function and restored firing frequency in cerebellar Purkinje cells in mouse models of spinocerebellar ataxia type 2. Neurodegeneration therapy Ataxin-2 polyglutamine expansions increase the risk for amyotrophic lateral sclerosis (ALS) and cause spinocerebellar ataxia type 2 (SCA2), two neurodegenerative diseases without a cure. A pair of papers this week report therapeutic approaches towards reducing ataxin 2. Daniel Scoles et al . test antisense oligonucleotides (ASOs) against ataxin-2 in mice models of SCA2 that recreate progressive adult-onset dysfunction and degeneration of the neuronal network. The most promising therapeutic lead is ASO7, which downregulates ATXN2 mRNA and protein and delays the onset of SCA2 phenotypes. Moreover, treatment of symptomatic mice normalizes firing of cerebellar Purkinje cells and improves motor functioning. Nearly all ALS patients have toxic aggregates of the protein TDP-43 in the brain and spinal cord. Lowering ataxin-2 has been shown to suppress TDP-43 toxicity in yeast and flies, and, elsewhere in this issue, Lindsay Becker et al . show that lowering ataxin-2 in mice, genetically or with antisense oligonucleotides, reduces TDP-43 aggregation and toxicity, improves motor function and increases lifespan. Both papers suggest that antisense oligonucleotide-based therapeutic approaches could be used to tackle neurodegeneration. There are no disease-modifying treatments for adult human neurodegenerative diseases. Here we test RNA-targeted therapies 1 in two mouse models of spinocerebellar ataxia type 2 (SCA2), an autosomal dominant polyglutamine disease 2 . Both models recreate the progressive adult-onset dysfunction and degeneration of a neuronal network that are seen in patients, including decreased firing frequency of cerebellar Purkinje cells and a decline in motor function 3 , 4 . We developed a potential therapy directed at the ATXN2 gene by screening 152 antisense oligonucleotides (ASOs). The most promising oligonucleotide, ASO7, downregulated ATXN2 mRNA and protein, which resulted in delayed onset of the SCA2 phenotype. After delivery by intracerebroventricular injection to ATXN2-Q127 mice, ASO7 localized to Purkinje cells, reduced cerebellar ATXN2 expression below 75% for more than 10 weeks without microglial activation, and reduced the levels of cerebellar ATXN2. Treatment of symptomatic mice with ASO7 improved motor function compared to saline-treated mice. ASO7 had a similar effect in the BAC-Q72 SCA2 mouse model, and in both mouse models it normalized protein levels of several SCA2-related proteins expressed in Purkinje cells, including Rgs8, Pcp2, Pcp4, Homer3, Cep76 and Fam107b. Notably, the firing frequency of Purkinje cells returned to normal even when treatment was initiated more than 12 weeks after the onset of the motor phenotype in BAC-Q72 mice. These findings support ASOs as a promising approach for treating some human neurodegenerative diseases.

The Cerebellar Cognitive Affective/Schmahmann Syndrome (CCAS) manifests as impaired executive control, linguistic processing, visual spatial function, and affect regulation. The CCAS has been described in the spinocerebellar ataxias (SCAs), but its prevalence is unknown. We analyzed results of the CCAS/Schmahmann Scale (CCAS-S), developed to detect and quantify CCAS, in two natural history studies of 309 individuals Symptomatic for SCA1, SCA2, SCA3, SCA6, SCA7, or SCA8, 26 individuals Pre-symptomatic for SCA1 or SCA3, and 37 Controls. We compared total raw scores, domain scores, and total fail scores between Symptomatic, Pre-symptomatic, and Control cohorts, and between SCA types. We calculated scale sensitivity and selectivity based on CCAS category designation among Symptomatic individuals and Controls, and correlated CCAS-S performance against age and education, and in Symptomatic patients, against genetic repeat length, onset age, disease duration, motor ataxia, depression, and fatigue. Definite CCAS was identified in 46% of the Symptomatic group. False positive rate among Controls was 5.4%. Symptomatic individuals had poorer global CCAS-S performance than Controls, accounting for age and education. The domains of semantic fluency, phonemic fluency, and category switching that tap executive function and linguistic processing consistently separated Symptomatic individuals from Controls. CCAS-S scores correlated most closely with motor ataxia. Controls were similar to Pre-symptomatic individuals whose nearness to symptom onset was unknown. The use of the CCAS-S identifies a high CCAS prevalence in a large cohort of SCA patients, underscoring the utility of the scale and the notion that the CCAS is the third cornerstone of clinical ataxiology.

Background Spinocerebellar ataxia 27B is the most common genetic late onset cerebellar ataxia (LOCA). However, it commonly overlaps with other genetic LOCA as with the cerebellar form of multiple system atrophy (MSA-C). Objectives To pinpoint which clinical signs and symptoms best discriminate between FGF14  + from FGF14  − patients at symptoms’ onset. Methods Twenty SCA27B (≥ 250 GAA repeat expansion) patients were retrospectively matched by gender and age at disease onset with 20 negative FGF14 (−) LOCA patients and with 20 MSA-C patients. Clinical features were ranked based on their contribution towards distinguishing between the groups (feature importance ranking). Results SCA27B patients had significantly higher rates of episodic symptoms, cerebellar oculomotor signs, dysdiadochokinesia, and alcohol intolerance than LOCA- FGF14  − ataxia patients. The lack of autonomic symptoms and MRI signs in SCA27B patients were the most discriminating features from MSA-C. An AUC of 0.87 was obtained if using the “top 3 clinical features model” (episodic symptoms, cerebellar oculomotor signs and dysdiadochokinesia) to distinguish SCAB27 from LCOA FGF14  − . Regarding MRI findings, no significant differences were found between SCA27B and FGF14  − patients, while a positive hot cross buns sign and the presence of brainstem atrophy were key distinguishing features between SCA27B from MSA-C patients ( p  < 0.005). Conclusion Our pilot case–control study contributes to the identification of early clinical symptoms to differentiate SCA27B to LOCA patients including FGF14 - and MSA-C ones. From a feature perspective, while clinical features are crucial, identifying surrogate biomarkers—such as ocular or gait parameters—could aid in the early diagnosis and follow-up of SCA27B patients.

Spinocerebellar ataxias are dominantly inherited neurodegenerative diseases. As potential treatments for these diseases are being developed, precise knowledge of their natural history is needed. We aimed to study the long-term disease progression of the most common spinocerebellar ataxias: SCA1, SCA2, SCA3, and SCA6. Furthermore, we aimed to establish the order and occurrence of non-ataxia symptoms, and identify predictors of disease progression. In this longitudinal cohort study (EUROSCA), we enrolled men and women with positive genetic testing for SCA1, SCA2, SCA3, or SCA6 and with progressive, otherwise unexplained ataxia who were aged 18 years or older from 17 ataxia referral centres in ten European countries. Patients were seen every year for 3 years, and at irregular intervals thereafter. The primary outcome was the scale for the assessment and rating of ataxia (SARA), and the inventory of non-ataxia signs (INAS). We used linear mixed models to analyse progression. To account for dropouts, we applied a pattern-mixture model. This study is registered with ClinicalTrials.gov, number NCT02440763. Between July 1, 2005, and Aug 31, 2006, 526 patients with SCA1, SCA2, SCA3, or SCA6 were enrolled. We analysed data for 462 patients with at least one follow-up visit. Median observation time was 49 months (IQR 35–72). SARA progression data were best fitted with a linear model in all genotypes. Annual SARA score increase was 2·11 (SE 0·12) in patients with SCA1, 1·49 (0·07) in patients with SCA2, 1·56 (0·08) in patients with SCA3, and 0·80 (0·09) in patients with SCA6. The increase of the number of non-ataxia signs reached a plateau in SCA1, SCA2, and SCA3. In patients with SCA6, the number of non-ataxia symptoms increased linearly, but more slowly than in patients with SCA1, SCA2, and SCA3 (p<0·0001). Factors that were associated with faster progression of the SARA score were short duration of follow-up (p=0·0179), older age at inclusion (0.04 [SE 0·02] per additional year; p=0·0476), and longer repeat expansions (0·06 [SE 0·02] per additional repeat unit; p=0·0128) in SCA1, short duration of follow-up (p<0·0001), lower age at onset (–0·02 [SE 0·01] per additional year; p=0·0014), and lower baseline SARA score (–0·02 [SE 0·01] per additional SARA point; p=0·0083) in SCA2, and lower baseline SARA score (–0·03 [SE 0·01] per additional SARA point; p=0·0195) in SCA6. In SCA3, we did not identify factors that affected progression of the SARA score. Our study provides quantitative data on the progression of the most common spinocerebellar ataxias based on a follow-up period that exceeds those of previous studies. Our data could prove useful for sample size calculation and patient stratification in interventional trials. EU FP6 (EUROSCA), German Ministry of Education and Research (BMBF; GeneMove), Polish Ministry of Science, EU FP7 (NEUROMICS).

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease marked by progressive motor deficits and Purkinje cell (PC) degeneration, driven by polyglutamine expansion in ataxin-1. While oligodendroglial dysfunction precedes PC loss, its direct contribution toward SCA1 pathogenesis remains unclear. Here, using an oligodendroglia-specific SCA1 conditional knockin mouse model, we demonstrate that mutant ataxin-1 in oligodendrocytes is sufficient to drive aspects of SCA1-related pathology, including dysregulated myelination, PC axonal shrinkage, and torpedo formation, ultimately impairing motor coordination. Transcriptomic analysis uncovers cerebellar oligodendrocyte subtypes with distinct gene expression signatures and aberrant abundance that contribute to demyelination. This, compounded by a progressive decline in the neuroprotective functions of a cerebellum-specific oligodendrocyte subtype, establishes a critical link between demyelination, axo-myelinic dysfunction, and axonal pathology in SCA1. Upstream transcriptional regulator analysis in oligodendroglia identifies transcription factor 7-like 2 (TCF7L2) and huntingtin (HTT) as key mediators of oligodendroglial dysfunction in SCA1, suggesting shared pathogenic mechanisms with other polyglutamine diseases. Collectively, these findings establish oligodendroglia as key mediators of SCA1 pathogenesis and underscore their critical role in preserving PC axonal integrity.