Early-Life Social Determinants of SCA6 Age at Onset, Severity, and Progression.

SCA6 patients with the same size CAG repeat allele can vary significantly in age at onset (AAO) and clinical progression. The specific external factors affecting SCA6 have yet to be investigated. We assessed the effect of early life events on AAO, severity, and progression in SCA6 patients using a social determinant of health approach. We performed a survey of biological and social factors in SCA6 patients enrolled in the SCA6 Network at the University of Chicago. AAO of ataxia symptoms and patient-reported outcome measure (PROM) of ataxia were used as primary outcome measures. Least absolute shrinkage and selection operation (LASSO) regressions were used to identify which early life factors are predictive of SCA6 AAO, severity, and progression. Multiple linear regression models were then used to assess the degree to which these determinants influence SCA6 health outcomes. A total of 105 participants with genetically confirmed SCA6 completed the assessments. SCA6 participants with maternal difficulty during pregnancy, active participation in school sports, and/or longer CAG repeats were determined to have earlier AAO. We found a 13.44-year earlier AAO for those with maternal difficulty in pregnancy than those without (p = 0.008) and a 12.31-year earlier AAO for those active in school sports than those who were not (p < 0.001). Higher education attainment was associated with decreased SCA6 severity and slower progression. Early life biological and social factors can have a strong influence on the SCA6 disease course, indicating that non-genetic factors can contribute significantly to SCA6 health outcomes.

The Efficacy and Safety of Transcranial Direct Current Stimulation for Cerebellar Ataxia: a Systematic Review and Meta-Analysis.

A promising new approach, transcranial direct current stimulation (tDCS) has recently been used as a therapeutic modality for cerebellar ataxia. However, the strength of the conclusions drawn from individual studies in the current literature may be constrained by the small sample size of each trial. Following a systematic literature retrieval of studies, meta-analyses were conducted by pooling the standardized mean differences (SMDs) using random-effects models to assess the efficacy of tDCS on cerebellar ataxia, measured by standard clinical rating scales. Domain-specific effects of tDCS on gait and hand function were further evaluated based on 8-m walk and 9-hole peg test performance times, respectively. To determine the safety of tDCS, the incidences of adverse effects were analyzed using risk differences. Out of 293 citations, 5 randomized controlled trials involving a total of 72 participants with cerebellar ataxia were included. Meta-analysis indicated a 26.1% (p = 0.003) improvement in ataxia immediately after tDCS with sustained efficacy over months (28.2% improvement after 3 months, p = 0.04) when compared with sham stimulation. tDCS seems to be domain-specific as the current analysis suggested a positive effect on gait (16.3% improvement, p = 0.04) and failed to reveal differences for hand function (p = 0.10) with respect to sham. The incidence of adverse events in tDCS and sham groups was similar. tDCS is an effective intervention for mitigating ataxia symptoms with lasting results that can be sustained for months. This treatment shows preferential effects on gait ataxia and is relatively safe.

Exploration biases forelimb reaching strategies.

The brain can generate actions, such as reaching to a target, using different movement strategies. We investigate how such strategies are learned in a task where perched head-fixed mice learn to reach to an invisible target area from a set start position using a joystick. This can be achieved by learning to move in a specific direction or to a specific endpoint location. As mice learn to reach the target, they refine their variable joystick trajectories into controlled reaches, which depend on the sensorimotor cortex. We show that individual mice learned strategies biased to either direction- or endpoint-based movements. This endpoint/direction bias correlates with spatial directional variability with which the workspace was explored during training. Model-free reinforcement learning agents can generate both strategies with similar correlation between variability during training and learning bias. These results provide evidence that reinforcement of individual exploratory behavior during training biases the reaching strategies that mice learn.

Fatigue Impacts Quality of Life in People with Spinocerebellar Ataxias.

BACKGROUND: Fatigue is a prevalent and debilitating symptom in neurological disorders, including spinocerebellar ataxias (SCAs). However, the risk factors of fatigue in the SCAs as well as its impact have not been well investigated. OBJECTIVES: To study the prevalence of fatigue in SCAs, the factors contributing to fatigue, and the influence of fatigue on quality of life. METHODS: Fatigue was assessed in 418 participants with SCA1, SCA2, SCA3, and SCA6 from the Clinical Research Consortium for the Study of Cerebellar Ataxia using the Fatigue Severity Scale. We conducted multi-variable linear regression models to examine the factors contributing to fatigue as well as the association between fatigue and quality of life. RESULTS: Fatigue was most prevalent in SCA3 (52.6%), followed by SCA1 (36.7%), SCA6 (35.7%), and SCA2 (35.6%). SCA cases with fatigue had more severe ataxia and worse depressive symptoms. In SCA3, those with fatigue had a longer disease duration and longer pathological CAG repeat numbers. In multi-variable models, depressive symptoms, but not ataxia severity, were associated with more severe fatigue. Fatigue, independent of ataxia and depression, contributed to worse quality of life in SCA3 and SCA6 at baseline, and fatigue continued affecting quality of life throughout the disease course in all types of SCA. CONCLUSIONS: Fatigue is a common symptom in SCAs and is closely related to depression. Fatigue significantly impacts patients' quality of life. Therefore, screening for fatigue should be considered a part of standard clinical care for SCAs.

Severe Contour Deformity of the Hip Following Corticosteroid Injection.

A 50-year-old woman developed severe soft tissue atrophy of the hip following a triamincolone acetonide injection to the greater trochanteric bursa. Saline injection therapy was initially attempted without improvement and the defect was ultimately treated effectively with serial fat grafting. Adverse soft tissue reactions are rare but potentially devastating complications of corticosteroid injections, and the use of soluble steroid preparations and proper injection techniques can minimize the risk to surrounding tissue. Serial fat grafting represents a promising treatment option for severe cases of steroid-induced soft tissue atrophy.

Gambling associated risk-taking decision in cerebellar ataxia.

INTRODUCTION: People with cerebellar ataxia (CA) can develop impulsive and compulsive behaviors that significantly affect their and their family's quality of life. To further assess the decision-making process associated with these behaviors, we used the Iowa Gambling Task (IGT) to study people with CA. METHODS: Sixty individuals with CA and thirty age-matched controls were enrolled in the study to complete the IGT. No participants had a prior or comorbid neurologic or psychiatric disorder associated with impulsivity. IGT performance in each of the five 20-trial blocks was compared between groups and the progression of participants' performance was assessed with simple linear regression models. Subgroup analyses were performed with genetic and non-genetic CA cases. RESULTS: CA cases obtained significantly lower IGT total scores than controls (-5.30 ± 37.53 vs. 21.30 ± 37.37, p = 0.004). In addition, those with CA made riskier decisions throughout the task compared to controls. Although both CA and controls learned to make decisions with more favorable outcomes over the course of completing the IGT, CA participants never matched the controls' performance. IGT performance did not correlate with ataxia severity or depressive symptoms. CONCLUSION: The IGT may capture a unique behavioral symptom of CA. Future studies may help elucidate the mechanisms underlying impaired decision-making in CA and further the understanding of a broader spectrum of cerebellar cognitive affective syndrome.

Cerebellar impulsivity-compulsivity assessment scale.

OBJECTIVE: The cerebellum has been identified as the key brain region that modulates reward processing in animal models. Consistently, we recently found that people with cerebellar ataxia have impulsive and compulsive behaviors (ICBs), the main symptoms related to abnormal reward processing. Due to the lack of a validated scale to quantitatively measure ICBs in cerebellar disorders, we aim to develop and validate a new scale, Cerebellar Impulsivity-Compulsivity Assessment (CIA). METHODS: We recruited 62 cerebellar ataxia cases, categorized into those with ICBs and those without. We developed a preliminary version of CIA, containing 17 questions. We studied the internal consistency, test-retest reliability, and inter-rater reliability to formulate the final version of CIA, which constitutes only 10 questions. The receiver operating characteristic curve (ROC) was generated to assess the sensitivity and specificity of CIA. RESULTS: Cerebellar ataxia cases with ICBs have threefold higher total preliminary CIA scores than those without ICBs (12.06 ± 5.96 vs. 4.68 ± 3.50, p = 0.038). Cronbach's alpha revealed good internal consistency across all items (α > 0.70). By performing the test-retest reliability and inter-rater reliability on the preliminary version of CIA, we excluded seven questions (r < 0.70) and generated the final version of CIA. Based on the ROC, a score of 8.0 in CIA was chosen as the cut-off for ICBs in individuals with cerebellar ataxia with 81% sensitivity and 81% specificity. INTERPRETATION: CIA is a novel tool to assess ICBs in cerebellar ataxia and broaden our understanding of the cerebellum-related cognitive and behavioral symptoms.

Clinicopathological correlates of pyramidal signs in multiple system atrophy.

OBJECTIVE: Pyramidal signs are common but often under-recognized in multiple system atrophy (MSA). The clinicopathological correlates of pyramidal signs in MSA are not well characterized. The present study aims to understand the role of pyramidal signs in MSA. METHODS: We examined 40 autopsy-confirmed MSA cases in New York Brain Bank. The pyramidal signs were quantified by an established rating scale, summarized as the pyramidal score. We assessed whether pyramidal scores are associated with autonomic, parkinsonism, and cerebellar features and survival. We also examined whether the density of glial cytoplasmic inclusions (GCIs) in the motor cortex and its underlying white matter is associated with the pyramidal score. RESULTS: MSA parkinsonian type cases have higher pyramidal scores compared to cerebellar type cases (p = 0.017). MSA cases with high pyramidal scores are more likely to have laryngeal stridor (OR = 4.89, p = 0.022), but less likely to have orthostatic hypotension (OR = 0.11, p = 0.006) and erectile dysfunction (OR = 0.05, p = 0.018). MSA cases with high pyramidal scores do not differ from those with low pyramidal scores in terms of bowel dysfunction, dry eyes and mouth, and survival. Finally, MSA cases with more GCIs in the motor cortex have higher pyramidal scores compared to those with few GCIs (p = 0.017). INTERPRETATION: Pyramidal signs in MSA are associated with the parkinsonian subtype, laryngeal stridor, and certain autonomic dysfunction.

Impulsivity Trait Profiles in Patients With Cerebellar Ataxia and Parkinson Disease.

BACKGROUND AND OBJECTIVES: Individuals with cerebellar ataxia (CA) can develop impulsive behavioral symptoms, often resulting in negative interpersonal consequences, detrimentally affecting their quality of life. Limited evidence exists concerning impulsivity in CA and its associated behavioral changes. We assessed impulsive traits in CA using the Barratt Impulsivity Scale (BIS-11) and compared them with those of Parkinson disease (PD) to investigate the differences in the impulsive trait profiles between CA and PD. METHODS: We conducted a dual-center cross-sectional study with individuals with CA and PD enrolled through consecutive sampling from movement disorders clinics at Columbia University Medical Center and Vanderbilt University Medical Center, respectively. Age-matched controls were recruited at the respective institutions. Participants were excluded if they had prior or comorbid neurologic and psychiatric diseases known to be associated with impulsivity. All participants completed the BIS-11 questionnaire as a measure of impulsive traits. We used a general linear model and a least absolute shrinkage and selection operation regression to compare the total, subscale, and individual items of the BIS-11 scores between groups. Subgroup analyses were performed to isolate cerebellar contributions to impulsivity from potential effects of extracerebellar pathology and dopaminergic dysfunction or medications. RESULTS: A total of 190 participants-90 age-matched controls, 50 participants with CA, and 50 with PD-completed the assessments. Persons with CA reported 9.7% higher BIS-11 scores than controls (p < 0.001), while persons with PD reported 24.9% higher scores than controls (p < 0.001). In CA, the most affected domain of impulsivity was nonplanning. In contrast, persons with PD noted greater impulsivity across the nonplanning, attentional, and motor domains. DISCUSSION: Impulsivity in CA is uniquely driven by the nonplanning trait, unlike in PD. This suggests that the cerebellum and basal ganglia may differentially govern impulsive behaviors with the cerebellum contributing to the brain circuitry of impulsivity in a domain-specific manner.