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.

Insights into cognitive decline in spinocerebellar Ataxia type 2: a P300 event-related brain potential study.

BACKGROUND: Cognitive decline is a common non-motor feature characterizing Spinocerebellar Ataxia type 2 (SCA2) during the prodromal stage, nevertheless a reduced number of surrogate biomarkers of these alterations have been described. OBJECTIVE: To provide insights into cognitive dysfunction in SCA2 patients using P300 event-related potentials (ERP) and to evaluate these measures as biomarkers of the disease. METHODS: A cross-sectional study was performed with 30 SCA2 patients, 20 preclinical carriers and 33 healthy controls, who underwent visual, auditory P300 ERPs, and neurological examinations and ataxia scoring. RESULTS: SCA2 patients showed significant increase in P300 latencies and decrease of P300 amplitudes for visual and auditory stimuli, whereas preclinical carriers exhibit a less severe, but significant prolongation of P300 latencies. Multiple regression analyses disclosed a significant effect of SARA score on visual P300 abnormalities in patients as well as of the time to ataxia onset on visual P300 latencies in preclinical carriers. CONCLUSIONS: This paper demonstrated the role of P300 ERP for the study of attentional, discriminative and working memory abnormalities in SCA2 patients and for the search of surrogate biomarkers from prodromal to the symptomatic stages. Moreover, our findings provide psychophysiological evidences supporting the cerebellar involvement in cognitive processes and allows us to identify promising outcome measures for future trials focusing on cognitive dysfunction.

Progression of corticospinal tract dysfunction in pre-ataxic spinocerebellar ataxia type 2: A two-years follow-up TMS study.

OBJECTIVE: Corticospinal tract (CST) dysfunction is common in the pre-ataxic stage of spinocerebellar ataxia type 2 (SCA2) but quantitative assessment of its progression over time has not been explored. The aim of this study was to quantify the progression of CST dysfunction in pre-ataxic SCA2 using transcranial magnetic stimulation (TMS). METHODS: Thirty-three pre-ataxic SCA2 mutation carriers and a 33 age- and gender-matched healthy controls were tested at baseline and 2-years follow-up by standardized clinical exams, validated clinical scales, and TMS. RESULTS: Pre-ataxic SCA2 mutation carriers showed a significant increase of resting motor thresholds (RMT) to abductor pollicis brevis (APB) and tibialis anterior (TA) muscles, and of central motor conduction time (CMCT) to TA at 2-years follow-up, over and above changes in healthy controls. The changes in the pre-ataxic SCA2 mutation carriers were independent of the presence of clinical signs of CST dysfunction at baseline, and independent of conversion to clinically definite SCA2 at 2-years follow-up. CONCLUSIONS: TMS markers of CST dysfunction progress significantly during the pre-ataxic stage of SCA2. SIGNIFICANCE: TMS measures of CST dysfunction may provide biomarkers of disease progression prior to clinical disease expression that have potential utility for monitoring neuroprotective therapies in future clinical trials.

The effect of office-based physician's advice on adolescent exercise behavior.

BACKGROUND: This study examines whether the adolescents' current levels of physical activity are increased by their physicians' advice provided in the office, in accordance with the American Medical Association recommendation. METHODS: The first adolescent (12-21 years old) of whichever age and gender, passing through six family physicians' offices during a 6-month period was assigned to the intervention group, and the second adolescent of the same age and gender was assigned to the control group. Each patient was classified as active, partially active, and inactive, according to how they answered the questions about their physical activity levels, and patients in the intervention group were then provided with reinforcement, increase, or initiation counseling, respectively. Identical procedures were repeated at the 6- and 12-month office visits. Changes in prevalence of activity, as well as, duration, frequency, and intensity of exercise and/or sports were verified at each visit. RESULTS: Of the 87.5% of the original sample that completed the survey, 6- and 12-month data were available for 70.1%. Among the 392 adolescents that finished the study, those provided with counseling had 41.5% more active adolescents, as well as 26.8%, 38.0% and 26.2% higher duration, frequency and intensity, respectively, than the control group. CONCLUSIONS: The proportion of active adolescents, as well as, the duration, frequency and intensity of leisure time exercise and/or sports are increased by physician advice.