Serum S100ß Levels Are Linked with Cognitive Decline and Peripheral Inflammation in Spinocerebellar Ataxia Type 2.

Experimental and clinical studies have indicated a potential role of the protein S100ß in the pathogenesis and phenotype of neurodegenerative diseases. However, its impact on spinocerebellar ataxia type 2 (SCA2) remains to be elucidated. The objective of the study is to determine the serum levels of S100ß in SCA2 and its relationship with molecular, clinical, cognitive, and peripheral inflammatory markers of the disease. Serum concentrations of S100ß were measured by enzyme-linked immunosorbent assay in 39 SCA2 subjects and 36 age- and gender-matched controls. Clinical scores of ataxia, non-ataxia symptoms, cognitive dysfunction, and some blood cell count-derived inflammatory indices were assessed. The SCA2 individuals manifested S100ß levels similar to the control group, at low nanomolar concentrations. However, the S100ß levels were directly associated with a better performance of cognitive evaluation within the SCA2 cohort. Moreover, the S100ß levels were inversely correlated with most peripheral inflammatory indices. Indeed, the neutrophil-to-lymphocyte ratio significantly mediated the effect of serum S100ß on cognitive performance, even after controlling for the ataxia severity in the causal mediation analysis. Our findings suggested that, within physiologic concentrations, the protein S100ß exerts a neuroprotective role against cognitive dysfunction in SCA2, likely via the suppression of pro-inflammatory mechanisms.

Structural Brain Correlates of Sleep Microstructure in Spinocerebellar Ataxia Type 2 and its Role on Clinical Phenotype.

The influence of brain atrophy on sleep microstructure in Spinocerebellar Ataxias (SCAs) has not been extensively explored limiting the use of these sleep traits as surrogate biomarkers of neurodegeneration and clinical phenotype. The objective of the study is to explore the relationship between sleep microstructure and brain atrophy in SCA2 and its role in the clinical phenotype. Fourteen SCA2 mutation carriers (7 pre-manifest and 7 manifest subjects) underwent polysomnographic, structural MRI, and clinical assessments. Particularly, markers of REM and non-REM sleep microstructure, measures of cerebellar and brainstem atrophy, and clinical scores were analyzed through correlation and mediation analyses. The sleep spindle activity exhibited a negative correlation with the number of trials required to complete the verbal memory test (VMT), and a positive correlation with the cerebellar volume, but the significance of the latter correlation did not survive multiple testing corrections. However, the causal mediation analyses unveiled that sleep spindle activity significantly mediates the association between cerebellar atrophy and VMT performance. Regarding REM sleep, both phasic EMG activity and REM sleep without atonia exhibited significant associations with pontine atrophy and disease severity measures. However, they did not demonstrate a causal mediation effect between the atrophy measures and disease severity. Our study provides evidence about the association of the pontocerebellar atrophy with sleep microstructure in SCA2 offering insights into the cerebellar involvement in cognition via the control of the sleep spindle activity. Therefore, our findings may help to understand the disease pathogenesis and to better characterize sleep microstructure parameters as disease biomarkers.Clinical trial registration number (TRN): No applicable.

Peripheral Inflammation Links with the Severity of Clinical Phenotype in Spinocerebellar Ataxia 2.

BACKGROUND: The role of peripheral inflammation in spinocerebellar ataxia type 2 (SCA2) is unknown. OBJECTIVE: The objective of this study was to identify peripheral inflammation biomarkers and their relationship with the clinical and molecular features. METHODS: Blood cell count-derived inflammatory indices were measured in 39 SCA2 subjects and their matched controls. Clinical scores of ataxia, nonataxia, and cognitive dysfunction were assessed. RESULTS: The neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), the Systemic Inflammation Index (SII), and the Aggregate Index of Systemic Inflammation (AISI) were significantly increased in SCA2 subjects compared with controls. The increases in PLR, SII, and AISI were even observed in preclinical carriers. NLR, PLR, and SII were correlated with the Scale for the Assessment and Rating of Ataxia speech item score rather than with the total score. The NLR and SII were correlated with the nonataxia and the cognitive scores. CONCLUSIONS: Peripheral inflammatory indices are biomarkers in SCA2, which may help to design future immunomodulatory trials and advance our understanding of the disease. © 2023 International Parkinson and Movement Disorder Society.

COVID-19 Impacts the Mental Health and Speech Function in Spinocerebellar Ataxia Type 2: Evidences from a Follow-Up Study.

Limited evidence suggests that the SARS-CoV-2 infection can accelerate the progression of neurodegenerative diseases, but this has been not verified in the spinocerebellar ataxias (SCA). The objective of this study is to assess the impact of COVID-19 on the mental health and motor features of SCA2. A follow-up study was carried out in 170 Cuban SCA2 subjects and 87 community controls between 2020 and 2021. All subjects underwent a structured questionnaire to assess the risks of exposure to COVID-19, the confirmation of COVID-19 diagnosis, and the Hospital Anxiety and Depression Scale (HADS). Moreover, 36 subjects underwent the Scale for the Assessment and Rating of ataxia (SARA). The risk of exposure to SARS-CoV-2 and the frequency of COVID-19 were similar between the ataxia cohort and the community controls. Within the ataxia group, significantly increased HADS scores existed at the 2nd visit in both groups, but this increase was more evident for the infected group regarding the depression score. Moreover, a significant within-group increase of SARA score was observed in the infected group but not the non-infected group, which was mainly mediated by the significant increase of the speech item score in the infected group. Similar results were observed within the subgroup of preclinical carriers. Our study identified no selective vulnerability nor protection to COVID-19 in SCA2, but once infected, the patients experienced a deterioration of mental health and speech function, even at preclinical disease stage. These findings set rationales for tele-health approaches that minimize the detrimental effect of COVID-19 on SCA2 progression and identify SCA2 individuals as clinical model to elucidate the link between SARS-CoV-2 infection and neurodegeneration.

Erythropoietin in Spinocerebellar Ataxia Type 2: Feasibility and Proof-of-Principle Issues from a Randomized Controlled Study.

BACKGROUND: Several pieces of evidence have shown the neurotrophic effect of erythropoietin (EPO) and its introduction in the therapeutic practice of neurological diseases. However, its usefulness in the treatment of spinocerebellar ataxia type 2 (SCA2) has not been proven despite the fact that it is endogenously reduced in these patients. OBJECTIVE: The study aims to investigate the safety, tolerability, and clinical effects of a nasally administered recombinant EPO in SCA2 patients. METHODS: Thirty-four patients were enrolled in this double-blind, randomized, placebo-controlled, phase I-II clinical trial of the nasally administered human-recombinant EPO (NeuroEPO) for 6 months. The primary outcome was the change in the spinocerebellar ataxia functional index (SCAFI), while other motor, neuropsychological, and oculomotor measures were assessed. RESULTS: The 6-month changes in SCAFI score were slightly higher in the patients allocated to NeuroEPO treatment than placebo in spite of the important placebo effect observed for this parameter. However, saccade latency was significantly decreased in the NeuroEPO group but not in placebo. The frequency and severity of adverse events were similar between both groups, without evidences of hematopoietic activity of the drug. CONCLUSIONS: This study demonstrated the safety and tolerability of NeuroEPO in SCA2 patients after 6 months of treatments and suggested a small clinical effect of this drug on motor and cognitive abnormalities, but confirmatory studies are warranted. © 2022 International Parkinson and Movement Disorder Society.

Cognitive Decline Is Closely Associated with Ataxia Severity in Spinocerebellar Ataxia Type 2: a Validation Study of the Schmahmann Syndrome Scale.

The cerebellar cognitive affective syndrome scale (CCAS-S) was designed to detect specific cognitive dysfunctions in cerebellar patients but is scarcely validated in spinocerebellar ataxias (SCA). The objective of this study is to determine the usefulness of the CCAS-S in a Cuban cohort of SCA2 patients and the relationship of its scores with disease severity. The original scale underwent a forward and backward translation into Spanish language, followed by a pilot study to evaluate its comprehensibility. Reliability, discriminant, and convergent validity assessments were conducted in 64 SCA2 patients and 64 healthy controls matched for sex, age, and education. Fifty patients completed the Montreal Cognitive Assessment (MoCA) test. The CCAS-S showed an acceptable internal consistency (Cronbach's alpha = 0.74) while its total raw score and the number of failed tests showed excellent (ICC = 0.94) and good (ICC = 0.89) test-retest reliability, respectively. Based on original cut-offs, the sensitivity of CCAS-S to detect possible/probable/definite CCAS was notably high (100%/100%/91%), but specificities were low (6%/30/64%) because the decreased specificity observed in four items. CCAS-S performance was significantly influenced by ataxia severity in patients and by education in both groups. CCAS-S scores correlated with MoCA scores, but showed higher sensitivity than MoCA to detect cognitive impairments in patients. The CCAS-S is particularly useful to detect cognitive impairments in SCA2 but some transcultural and/or age and education-dependent adaptations could be necessary to improve its diagnostic properties. Furthermore, this scale confirmed the parallelism between cognitive and motor deficits in SCA2, giving better insights into the disease pathophysiology and identifying novel outcomes for clinical trials.

Gene Therapy for Polyglutamine Spinocerebellar Ataxias: Advances, Challenges, and Perspectives.

Polyglutamine spinocerebellar ataxias (SCAs) comprise a heterogeneous group of six autosomal dominant ataxias caused by cytosine-adenine-guanine repeat expansions in the coding region of single genes. Currently, there is no curative or disease-slowing treatment for these disorders, but their monogenic inheritance has informed rationales for development of gene therapy strategies. In fact, RNA interference strategies have shown promising findings in cellular and/or animal models of SCA1, SCA3, SCA6, and SCA7. In addition, antisense oligonucleotide therapy has provided encouraging proofs of concept in models of SCA1, SCA2, SCA3, and SCA7, but they have not yet progressed to clinical trials. On the contrary, the gene editing strategies, such as the clustered regularly interspaced short palindromic repeat (CRISPR/Cas9), have been introduced to a limited extent in these disorders. In this article, we review the available literature about gene therapy in polyglutamine SCAs and discuss the main technological and ethical challenges toward the prospect of their use in future clinical trials. Although antisense oligonucleotide therapies are further along the path to clinical phases, the recent failure of three clinical trials in Huntington's disease may delay their utilization for polyglutamine SCAs, but they offer lessons that could optimize the likelihood of success in potential future clinical studies. © 2021 International Parkinson and Movement Disorder Society.

Prodromal Spinocerebellar Ataxia Type 2 Subjects Have Quantifiable Gait and Postural Sway Deficits.

BACKGROUND: The search for valid preclinical biomarkers of cerebellar dysfunction is a key research goal for the upcoming era of early interventional approaches in spinocerebellar ataxias. This study aims to describe novel preclinical biomarkers of subtle gait and postural sway abnormalities in prodromal spinocerebellar ataxia type 2 (pre-SCA2). METHODS: Thirty pre-SCA2 patients and their matched healthy controls underwent quantitative assessments of gait and postural sway using a wearable sensor-based system and semiquantitative evaluation of cerebellar features by SARA (Scale for the Assessment and Rating of Ataxia) score. RESULTS: Quantitative analysis of natural gait showed a significantly larger variability of the swing period, toe-off angle and toe-out angle in pre-SCA2, and larger mean coronal and transverse ranges of motion of the trunk at the lumbar location and of the sagittal range of motion of the trunk at the sternum location compared to controls. During tandem gait, pre-SCA2 subjects showed larger lumbar, trunk, and arm ranges of motion than controls. Postural sway analysis showed excessive body oscillation that was increased in tandem stance. Overall, these abnormalities were detected in pre-SCA2 patients without clinical evidence of abnormalities in SARA. The toe-off angle and swing time variability were significantly correlated with the time to ataxia onset, whereas the toe-off angle and transverse range of motion at trunk position during tandem gait were significantly associated with the SARA score. CONCLUSIONS: This study demonstrates early alteration of gait and postural sway control in prodromal SCA2 using a wearable sensor-based system. This offers new pathophysiological hints into this early disease stage and provides novel potential biomarkers for future clinical trials. © 2020 International Parkinson and Movement Disorder Society.

Impacts of the COVID-19 Pandemic on the Mental Health and Motor Deficits in Cuban Patients with Cerebellar Ataxias.

Although there are no convincing evidences of detrimental effect of SARS-CoV2 infection on the cerebellum, the COVID-19 pandemic could impact the life quality of patients with cerebellar ataxias, but few studies have addressed this concern. To assess the motor and mental health changes caused by the COVID-19 pandemics in Cuban patients with cerebellar ataxias, three hundred four patients with cerebellar ataxias and 167 healthy controls were interviewed for risks of exposure to COVID-19, and the self-perception of the pandemics' impact on the disease progression and on the mental health. All subjects underwent the Hospital Anxiety and Depression Scale. The patients reported low exposition to SARS-CoV2 infection, but one case was confirmed with a mild COVID-19. Overall, depressive and anxiety symptoms were significantly and marginally increased in patients, respectively, with higher scores in cases with severe and moderate ataxia. Positive patient's impression of psychopathological changes was associated to increased age, age at onset, and anxiety. Sixty-seven patients had a positive self-perception of ataxia progression, which was mainly influenced by higher anxiety scores but not by the adherence to at-home exercise programs. However, the practice of physical exercise was related with lower depression and anxiety scores, but this therapeutical effect was not significantly influenced by the disease stage. We demonstrated the negative effect of the COVID-19 pandemic on the mental and motor deficits in Cuban patients with cerebellar ataxias and the positive effect of the at-home physical exercise programs on their mental well-being. These findings give rationales to develop tele-medicine approaches to minimize these health impacts and to study the long-term effects of such sequelae and accordingly define their treatments.

Glutamate, Glutamine, GABA and Oxidative Products in the Pons Following Cortical Injury and Their Role in Motor Functional Recovery.

Brain injury leads to an excitatory phase followed by an inhibitory phase in the brain. The clinical sequelae caused by cerebral injury seem to be a response to remote functional inhibition of cerebral nuclei located far from the motor cortex but anatomically related to the injury site. It appears that such functional inhibition is mediated by an increase in lipid peroxidation (LP). To test this hypothesis, we report data from 80 rats that were allocated to the following groups: the sham group (n = 40), in which rats received an intracortical infusion of artificial cerebrospinal fluid (CSF); the injury group (n = 20), in which rats received CSF containing ferrous chloride (FeCl2, 50 mM); and the recovery group (n = 20), in which rats were injured and allowed to recover. Beam-walking, sensorimotor and spontaneous motor activity tests were performed to evaluate motor performance after injury. Lipid fluorescent products (LFPs) were measured in the pons. The total pontine contents of glutamate (GLU), glutamine (GLN) and gamma-aminobutyric acid (GABA) were also measured. In injured rats, the motor deficits, LFPs and total GABA and GLN contents in the pons were increased, while the GLU level was decreased. In contrast, in recovering rats, none of the studied variables were significantly different from those in sham rats. Thus, motor impairment after cortical injury seems to be mediated by an inhibitory pontine response, and functional recovery may result from a pontine restoration of the GLN-GLU-GABA cycle, while LP may be a primary mechanism leading to remote pontine inhibition after cortical injury.

Founder Effects of Spinocerebellar Ataxias in the American Continents and the Caribbean.

Spinocerebellar ataxias (SCAs) comprise a heterogeneous group of autosomal dominant disorders. The relative frequency of the different SCA subtypes varies broadly among different geographical and ethnic groups as result of genetic drifts. This review aims to provide an update regarding SCA founders in the American continents and the Caribbean as well as to discuss characteristics of these populations. Clusters of SCAs were detected in Eastern regions of Cuba for SCA2, in South Brazil for SCA3/MJD, and in Southeast regions of Mexico for SCA7. Prevalence rates were obtained and reached 154 (municipality of Báguano, Cuba), 166 (General Câmara, Brazil), and 423 (Tlaltetela, Mexico) patients/100,000 for SCA2, SCA3/MJD, and SCA7, respectively. In contrast, the scattered families with spinocerebellar ataxia type 10 (SCA10) reported all over North and South Americas have been associated to a common Native American ancestry that may have risen in East Asia and migrated to Americas 10,000 to 20,000 years ago. The comprehensive review showed that for each of these SCAs corresponded at least the development of one study group with a large production of scientific evidence often generalizable to all carriers of these conditions. Clusters of SCA populations in the American continents and the Caribbean provide unusual opportunity to gain insights into clinical and genetic characteristics of these disorders. Furthermore, the presence of large populations of patients living close to study centers can favor the development of meaningful clinical trials, which will impact on therapies and on quality of life of SCA carriers worldwide.

Hereditary Ataxias in Cuba: A Nationwide Epidemiological and Clinical Study in 1001 Patients.

The prevalence estimations of hereditary ataxias are biased since most epidemiological studies are confined to isolated geographical regions and few nationwide studies are available. The study aims to assess the prevalence, distribution, and neurological features of the Cuban population with hereditary ataxias. A nationwide epidemiological study of hereditary ataxias was conducted in Cuba between March 2017 and June 2018. Patients were scheduled at the Cuban ataxia research center, various hospitals, or at their homes. Demographic and clinical variables were obtained through standardized questionnaires and validated clinical tools. Overall, 1001 patients were diagnosed with hereditary ataxias for a nationwide prevalence of 8.91 cases/100.000 inhabitants. Spinocerebellar ataxia type 2 (SCA2) was the commonest subtype, with highest prevalences at Holguín province (47.86/100.000), and a broad dissemination in the whole country. Most of neurological features were common between all SCA cohorts, but the frequencies of some of them varied between distinct subtypes. Within the SCA2 cohort, significant influences of long mutation size and higher disease duration over the muscle atrophy and oculomotor disorders were observed. Besides, higher disease durations were associated with resting tremor and dysphagia, whereas shorter disease durations were associated with hyperreflexia. The spreading of SCA2 to whole country and the documented raising of its prevalence set the rationales for higher-scope medical care and research strategies, supported in collaborative research networks. The wide epidemiological, clinical, and genetic characterization of this founder SCA2 population identifies this homogeneous cohort as an attractive source for the development of future clinical-genetic and therapeutic researches.

Neurorehabilitation Improves the Motor Features in Prodromal SCA2: A Randomized, Controlled Trial.

BACKGROUND: The search for early interventions is a novel approach in spinocerebellar ataxias, but there are few studies supporting this notion. This article aimed to assess the efficacy of neurorehabilitation treatment in prodromal spinocerebellar ataxia type 2. METHODS: Thirty spinocerebellar ataxia type 2 preclinical carriers were enrolled in a randomized, controlled trial using neurorehabilitation. The intervention in the treated group was 4 hours per day, 5 days per week for 12 weeks, emphasizing static balance, gait, and limb coordination. The control group did not receive rehabilitation. The primary outcome measure was the time for 5-m tandem gait over the floor. Secondary outcomes included other timed tests with increased motor complexity, as well as the scores of the SARA and the Inventory of Non-ataxia Symptoms. RESULTS: The times for 5-m tandem gait over the floor and the mattress were significantly reduced only in the rehabilitated group. Moreover, the times upholding the tandem stance over a mattress and the seesaw were notably increased only in this group. Likewise, the finger-nose and the heel-shin tests were improved in the rehabilitated group alone. The SARA score and the count of nonataxia symptoms were unchanged. CONCLUSIONS: This rehabilitation program improves the subtle gait, postural and coordinative deficits in prodromal spinocerebellar ataxia type 2, which provided novel hints about the preservation of motor learning and neural plasticity mechanisms in early disease stages, leading chances for other interventional approaches in this and other spinocerebellar ataxias. © 2019 International Parkinson and Movement Disorder Society.

Corticomuscular Coherence: a Novel Tool to Assess the Pyramidal Tract Dysfunction in Spinocerebellar Ataxia Type 2.

Clinical signs of corticospinal tract dysfunction are a common feature of spinocerebellar ataxia type 2 (SCA2) patients. The objective of this study is to assess dysfunction of the corticospinal tract in SCA2 using corticomuscular coherence. Testing corticomuscular coherence and rating of ataxia severity and non-ataxia symptoms were performed in 19 SCA2 patients and 24 age-matched controls. Central motor conduction times (CMCT) to upper and lower right limbs were obtained for the SCA2 group using Transcraneal magnetic stimulation (TMS). SCA2 patients exhibited a significant reduction of corticomuscular coherence for lower limbs, but not for upper limbs. This difference remained significant, even when excluding those individuals with clinical signs of corticospinal tract dysfunction. Corticomuscular coherence for lower limbs correlated inversely with CMCT to tibialis anterior muscle. Corticomuscular coherence could be a valuable electrophysiological tool to assess the corticospinal tract involvement in SCA2, even in the absence of clinical signs of corticospinal tract dysfunction.

Spinocerebellar ataxia type 2: Measures of saccade changes improve power for clinical trials.

BACKGROUND: Saccadic eye movement abnormalities are common in patients with spinocerebellar ataxia type 2, but it is unclear how these alterations progress over time. The aim of this study was to assess the progression of saccade involvement in spinocerebellar ataxia type 2 patients, identify its main determinants, and evaluate its usefulness as outcome measures in clinical trials. METHODS: A prospective 5-year follow-up study was performed with 30 spinocerebellar ataxia type 2 patients and their matched healthy controls, who were evaluated a total of four times by clinical and electrooculographical assessments of horizontal saccades and by the scoring of ataxia. RESULTS: Patients showed significant decreases in saccade peak velocity and saccade accuracy as well as increases of saccadic latency during the follow-up period. Annual progression rates were significantly higher in patients compared to controls. Faster progression rates of saccade slowing were associated with higher trinucleotide cytosine-adenine-guanine repeat expansions. Sample-size estimates for two-arm trials would require 19 patients per group to detect a 50% reduction in disease progression using saccade peak velocity as outcome variable, but 44 and 124 patients using saccade latency and accuracy, respectively (power, 80%; alpha = 0.05). CONCLUSIONS: Electrooculographical measures of saccade changes are useful for the objective quantification of disease course in spinocerebellar ataxia type 2. The progression rate of saccade slowing is influenced by the expansion size, providing novel insight into the cumulative polyglutamine neurotoxicity, and supporting the usefulness of saccade peak velocity as a sensitive biomarker during the natural history of the disease, and as suitable outcome measure for therapeutic trials.

Strategy use, planning, and rule acquisition deficits in spinocerebellar ataxia type 2 patients.

Our goal was to improve spinocerebellar ataxia type 2 (SCA2) cognitive profile characterization by testing the hypothesis that strategy, planning and rule acquisition capacities are affected in SCA2. Forty one patients with SCA2 were evaluated with the Spatial Working Memory (SWM), the Stockings of Cambridge (SOC), and the Intra-Extra Dimensional Shift (IED) tests of the Executive module of the Cambridge Neuropsychological Testing Automated Battery (CANTAB). Paired Associates Learning (PAL) and Delayed Matching to Sample (DMS) from the CANTAB memory module were also assessed to corroborate previous findings. Motor deterioration was measured using the Scale for the Assessment and Rating of Ataxia (SARA). We found significant SCA2 related deficits in strategy, planning, and rule acquisition. Our results also corroborated significant memory deficits in these patients with SCA2. Further analysis also showed that patients with large motor deterioration had poorer associative learning and spatial planning scores. Patients with SCA2 show strategy, planning, and rule acquisition deficits as revealed with the CANTAB battery. These deficits should be noted when planning an effective therapy for these patients.

Recessive spinocerebellar ataxia with paroxysmal cough attacks: a report of five cases.

Hereditary ataxias are a heterogeneous group of neurological diseases characterized by progressive cerebellar syndrome and numerous other features, which result in great diversity of ataxia subtypes. Despite the characterization of a number of both autosomal dominant and autosomal recessive ataxias, it is thought that a large group of these conditions remains to be identified. In this study, we report the characterization of five patients (three Mexicans and two Italians) who exhibit a peculiar form of recessive ataxia associated with coughing. The main clinical and neurophysiological features of these patients include cerebellar ataxia, paroxysmal cough, restless legs syndrome (RLS), choreic movements, atrophy of distal muscles, and oculomotor disorders. Brain magnetic resonance imaging (MRI) revealed cerebellar atrophy, while video polysomnography (VPSG) studies showed a severe pattern of breathing-related sleep disorder, including sleep apnea, snoring, and significant oxygen saturation in the absence of risk factors. All patients share clinical features in the peripheral nervous system, including reduction of amplitude and prolonged latency of sensory potentials in median and sural nerves. Altogether, clinical criteria as well as molecular genetic testing that was negative for different autosomal dominant and autosomal recessive ataxias suggest the presence of a new form of recessive ataxia. This ataxia, in which cerebellar signs are preceded by paroxysmal cough, affects not only the cerebellum and its fiber connections, but also the sensory peripheral nervous system and extracerebellar central pathways.

Comprehensive study of early features in spinocerebellar ataxia 2: delineating the prodromal stage of the disease.

The prodromal phase of spinocerebellar ataxias (SCAs) has not been systematically studied. Main findings come from a homogeneous SCA type 2 (SCA2) population living in Cuba. The aim of this study was to characterize extensively the prodromal phase of SCA2 by several approaches. Thirty-seven non-ataxic SCA2 mutation carriers and its age- and sex-matched controls underwent clinical assessments, including standardized neurological exam, structured interviews and clinical scales, and looking for somatic and autonomic features, as well as a neuropsychological battery, antisaccadic recordings, and MRI scans. Main clinical somatic features of non-ataxic mutation carriers were cramps, sensory symptoms, sleep disorders, and hyperreflexia, whereas predominating autonomic symptoms were pollakiuria/nocturia, constipation, and frequent throat clearing. Cognitive impairments included early deficits of executive functions and visual memory, suggesting the involvement of cerebro-cerebellar-cerebral loops and/or reduced cholinergic basal forebrain input to the cortex. Antisaccadic task revealed impaired oculomotor inhibitory control but preserved ability for error correction. Cognitive and antisaccadic deficits were higher as carriers were closer to the estimated onset of ataxia, whereas higher Scale for the Assessment and Rating of Ataxia (SARA) scores were associated most notably to vermis atrophy. The recognition of early features of SCA2 offers novel insights into the prodromal phase and physiopathological base of the disease, allowing the assessment of its progression and the efficacy of treatments, in particular at early phases when therapeutical options should be most effective.

Executive deficit in spinocerebellar ataxia type 2 is related to expanded CAG repeats: evidence from antisaccadic eye movements.

Although antisaccadic task is a sensitive research tool in psychopathology, it has not been systematically studied in patients with spinocerebellar ataxia type 2 (SCA2). To identify putative biomarkers of executive dysfunction in SCA2 we assessed the antisaccade performance in 41 SCA2 patients and their sex-and-age matched controls using an electronystagmography device. We studied the relationship between findings in the antisaccade task and CAG repeat length and motor function as assessed using the Scale for the Assessment and Rating of Ataxia (SARA), Nine-Hole Pegboard Test and a validated battery for executive dysfunctions. SCA2 patients showed a significant increase of inhibition and omission antisaccadic error rates, decrease of corrected antisaccadic errors and prolongation of antisaccadic latency and antisaccadic correction latency. Multiple regression predictions identified the expanded CAG repeat as a significant contributing factor on inhibition antisaccadic error rate and percentage of corrected antisaccadic errors. Impaired antisaccadic performance was associated to higher Stroop interference task and verbal fluency test deficits. In conclusion, antisaccadic eye movement abnormalities are a newly recognized association with the genetic abnormality in SCA2 and correlate with executive dysfunction in SCA2. Antisaccade parameters are a promising source of cognitive biomarkers for exploring the disease pathophysiology, and assessing the efficacy of therapeutic options.

Lisuride reduces involuntary periodic leg movements in spinocerebellar ataxia type 2 patients.

Periodic leg movements (PLMs) are a common sleep disorder in spinocerebellar ataxia type 2 (SCA2) being associated to higher disease severity and altered sleep patterns. To assess the efficacy and safety of lisuride for the treatment of PLMs in SCA2 patients, an open-label clinical trial was conducted in 12 SCA2 patients suffering from PLMs associated to other subjective sleep complaints. All subjects received 0.1 mg of oral lisuride daily for 4 weeks. Primary outcome measure was the change of PLMs index. Changes in the subjective sleep quality, other polysomnographical sleep parameters, Scale for the Assessment and Rating of Ataxia score, and saccadic velocity were assessed as secondary outcome parameters. Safety assessments included hemoglobin, hematocrit, cholesterol, creatinine, and TGP. A significant decrease in both the PLMs index and R stage latency were observed during the treatment, associated to subjective improvement of frequent awakenings, early insomnia, restless leg syndrome, and nocturnal limb paresthesias in most cases. Ataxia score and saccadic pathology were unchanged. No significantly adverse events were observed. Our study suggests the efficacy of dopamine agonist therapy in the treatment of PLMs in SCA2, improving various subjective sleep complaints. These findings serve to promote the adequate management of sleep-related disorders in SCA2, which could improve the life quality of the patients.