Digital Gait Measures Capture 1-Year Progression in Early-Stage Spinocerebellar Ataxia Type 2.

BACKGROUND: With disease-modifying drugs in reach for cerebellar ataxias, fine-grained digital health measures are highly warranted to complement clinical and patient-reported outcome measures in upcoming treatment trials and treatment monitoring. These measures need to demonstrate sensitivity to capture change, in particular in the early stages of the disease. OBJECTIVE: Our aim is to unravel gait measures sensitive to longitudinal change in the-particularly trial-relevant-early stage of spinocerebellar ataxia type 2 (SCA2). METHODS: We performed a multicenter longitudinal study with combined cross-sectional and 1-year interval longitudinal analysis in early-stage SCA2 participants (n = 23, including nine pre-ataxic expansion carriers; median, ATXN2 CAG repeat expansion 38 ± 2; median, Scale for the Assessment and Rating of Ataxia [SARA] score 4.8 ± 4.3). Gait was assessed using three wearable motion sensors during a 2-minute walk, with analyses focused on gait measures of spatio-temporal variability that have shown sensitivity to ataxia severity (eg, lateral step deviation). RESULTS: We found significant changes for gait measures between baseline and 1-year follow-up with large effect sizes (lateral step deviation P = 0.0001, effect size rprb = 0.78), whereas the SARA score showed no change (P = 0.67). Sample size estimation indicates a required cohort size of n = 43 to detect a 50% reduction in natural progression. Test-retest reliability and minimal detectable change analysis confirm the accuracy of detecting 50% of the identified 1-year change. CONCLUSIONS: Gait measures assessed by wearable sensors can capture natural progression in early-stage SCA2 within just 1 year-in contrast to a clinical ataxia outcome. Lateral step deviation represents a promising outcome measure for upcoming multicenter interventional trials, particularly in the early stages of cerebellar ataxia. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Tracking longitudinal thalamic volume changes during early stages of SCA1 and SCA2.

PURPOSE: Spinocerebellar ataxia SCA1 and SCA2 are adult-onset hereditary disorders, due to triplet CAG expansion in their respective causative genes. The pathophysiology of SCA1 and SCA2 suggests alterations of cerebello-thalamo-cortical pathway and its connections to the basal ganglia. In this framework, thalamic integrity is crucial for shaping efficient whole-brain dynamics and functions. The aims of the study are to identify structural changes in thalamic nuclei in presymptomatic and symptomatic SCA1 and SCA2 patients and to assess disease progression within a 1-year interval. MATERIAL AND METHODS: A prospective 1-year clinical and MRI assessment was conducted in 27 presymptomatic and 23 clinically manifest mutation carriers for SCA1 and SCA2 expansions. Cross-sectional and longitudinal changes of thalamic nuclei volume were investigated in SCA1 and SCA2 individuals and in healthy participants (n = 20). RESULTS: Both SCA1 and SCA2 patients had significant atrophy in the majority of thalamic nuclei, except for the posterior and partly medial nuclei. The 1-year longitudinal evaluation showed a specific pattern of atrophy in ventral and posterior thalamus, detectable even at the presymptomatic stage of the disease. CONCLUSION: For the first time in vivo, our exploratory study has shown that different thalamic nuclei are involved at different stages of the degenerative process in both SCA1 and SCA2. It is therefore possible that thalamic alterations might significantly contribute to the progression of the disease years before overt clinical manifestations occur.

Nucleus accumbens degeneration in spinocerebellar ataxia type 2: a preliminary study.

BACKGROUND: Spinocerebellar ataxia type 2 (SCA2) exhibits mainly cerebellar and oculomotor dysfunctions but also, frequently, cognitive impairment and neuropsychological symptoms. The mechanism of the progression of SCA2 remains unclear. This study aimed to evaluate longitudinal structural changes in the brains of SCA2 patients based on atrophy rate. METHODS: The OpenNeuro Dataset ds001378 was used. It comprises the demographic data and two magnetic resonance images each of nine SCA2 patients and 16 healthy controls. All structural images were preprocessed using FreeSurfer software, and each region's bilateral volume was summed. Atrophy rates were calculated based on the concept of symmetrised percent change and compared between SCA2 patients and healthy controls using non-parametric statistics. As post hoc analysis, correlation analysis was performed between infratentorial volume ratio and the accumbens area atrophy rates in SCA2 patients. RESULTS: There were no significant differences between groups for age, gender, and the time between scans. Statistical analysis indicated a significantly larger atrophy rate of the accumbens area in SCA2 patients than in controls. Additionally, the infratentorial volume ratio and accumbens area atrophy rates showed moderate negative correlation. CONCLUSIONS: This study found that nucleus accumbens (NAc) atrophy was significantly accelerated in SCA2 patients. Anatomically, the NAc is densely connected with infratentorial brain regions, so it is reasonable to posit that degeneration propagates from the cerebellum and brainstem to the NAc and other supratentorial areas. Functionally, the NAc is essential for appropriate behaviour, so NAc degeneration might contribute to neuropsychological symptoms in SCA2 patients.

A Case of Coexistent Spinocerebellar Ataxia Type 2 and Primary Progressive Multiple Sclerosis-Coincidental or Associated?

Spinocerebellar ataxia type 2 (SCA2) is a dominantly inherited ataxia primarily characterised by progressive cerebellar syndrome, which is developed due to the expansion of the CAG trinucleotide repeat within the first exon of the ATXN2 gene. We report a rare case of a 41-year-old woman with coexistent genetically verified SCA2 and primary progressive multiple sclerosis (MS). Considering our case and a few others reported in the literature, as well as a possible genetic association between ATXN2 and MS susceptibility, we suggest that the coexistence of SCA and MS may not be coincidental, especially in patients with a progressive MS course.

The Frequency of Intermediate Alleles in Patients with Cerebellar Phenotypes.

Cerebellar syndromes are clinically and etiologically heterogeneous and can be classified as hereditary, neurodegenerative non-hereditary, or acquired. Few data are available on the frequency of each form in the clinical setting. Growing interest is emerging regarding the genetic forms caused by triplet repeat expansions. Alleles with repeat expansion lower than the pathological threshold, termed intermediate alleles (IAs), have been found to be associated with disease manifestation. In order to assess the relevance of IAs as a cause of cerebellar syndromes, we enrolled 66 unrelated Italian ataxic patients and described the distribution of the different etiology of their syndromes and the frequency of IAs. Each patient underwent complete clinical, hematological, and neurophysiological assessments, neuroimaging evaluations, and genetic tests for autosomal dominant cerebellar ataxia (SCA) and fragile X-associated tremor/ataxia syndrome (FXTAS). We identified the following diagnostic categories: 28% sporadic adult-onset ataxia, 18% cerebellar variant of multiple system atrophy, 9% acquired forms, 9% genetic forms with full-range expansion, and 12% cases with intermediate-range expansion. The IAs were six in the FMR1 gene, two in the gene responsible for SCA8, and one in the ATXN2 gene. The clinical phenotype of patients carrying the IAs resembles, in most of the cases, the one associated with full-range expansion. Our study provides an exhaustive description of the causes of cerebellar ataxia, estimating for the first time the frequency of IAs in SCAs- and FXTAS-associated genes. The high percentage of cases with IAs supports further screening among patients with cerebellar syndromes.

The Relationships Between Ataxia and Cognition in Spinocerebellar Ataxia Type 2.

The clinical spectrum of spinocerebellar ataxia type 2 includes motor manifestations and cognitive disturbances in executive functions, memory, and visuoconstructive skills. The relationships between severity of motor disturbances and altered cognition are poorly known. In this study, we assessed patients with spinocerebellar ataxia type 2 and age- and sex-matched healthy control subjects by a test battery including the Mini-mental State Examination, the Wisconsin Card Sorting test, and the Wechsler Memory Scale-Revised. The correlation between severity of motor ataxia (as assessed by a validated and widely used severity scale, the SARA scale, and by an objective automated computerized system of gait analysis) and altered cognition was then evaluated by Spearman correlation analysis. Patients performed worse than healthy controls in almost all administered neuropsychological tests. Nevertheless, only global intellectual abilities and executive functions significantly correlated with the overall severity of ataxia as assessed by the SARA scale, and impaired executive functions alone correlated with performance on several spatio-temporal gait analysis parameters. Our findings would probably suggest a prominent influence of executive functions on motor abilities in patients with spinocerebellar ataxia type 2 and raise the possibility that cognitive pharmaceutical or rehabilitative interventions may be of benefit in the management of motor problems in these patients.

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.

Mid-Gestation lethality of Atxn2l-Ablated Mice.

Depletion of yeast/fly Ataxin-2 rescues TDP-43 overexpression toxicity. In mouse models of Amyotrophic Lateral Sclerosis via TDP-43 overexpression, depletion of its ortholog ATXN2 mitigated motor neuron degeneration and extended lifespan from 25 days to >300 days. There is another ortholog in mammals, named ATXN2L (Ataxin-2-like), which is almost uncharacterized but also functions in RNA surveillance at stress granules. We generated mice with Crispr/Cas9-mediated deletion of Atxn2l exons 5-8, studying homozygotes prenatally and heterozygotes during aging. Our novel findings indicate that ATXN2L absence triggers mid-gestational embryonic lethality, affecting female animals more strongly. Weight and development stages of homozygous mutants were reduced. Placenta phenotypes were not apparent, but brain histology showed lamination defects and apoptosis. Aged heterozygotes showed no locomotor deficits or weight loss over 12 months. Null mutants in vivo displayed compensatory efforts to maximize Atxn2l expression, which were prevented upon nutrient abundance in vitro. Mouse embryonal fibroblast cells revealed more multinucleated giant cells upon ATXN2L deficiency. In addition, in human neural cells, transcript levels of ATXN2L were induced upon starvation and glucose and amino acids exposure, but this induction was partially prevented by serum or low cholesterol administration. Neither ATXN2L depletion triggered dysregulation of ATXN2, nor a converse effect was observed. Overall, this essential role of ATXN2L for embryogenesis raises questions about its role in neurodegenerative diseases and neuroprotective therapies.

Selective Forces Related to Spinocerebellar Ataxia Type 2.

Spinocerebellar ataxia type 2 (SCA2) is caused by an unstable expanded CAG repeat tract (CAGexp) at ATXN2. Although prone to selective forces such as anticipation, SCA2 frequency seems to be stable in populations. Our aim was to estimate reproductive success, segregation patterns, and role of anticipation in SCA2. Adult subjects from families with molecular diagnosis provided data about all his/her relatives. Affected and unaffected sibs older than 65.7 years of age were used to estimate reproductive success and segregation patterns. Twenty-one SCA2 families were studied, including 1017 individuals (164 affected) who were born from 1840 to 2012. The median number of children of the non-carriers and carriers, among 99 subjects included in the reproductive success analysis, were 2 and 3 (p < 0.025), respectively. Therefore, the reproductive success of carriers was 1.5. There were 137 non-carriers (59.6%) and 93 carriers (40.4%) (p = 0.04), among subjects included in the segregation analysis. Age at onset across generations pointed to anticipation as a frequent phenomenon. We raised evidence in favor of increased reproductive success related to the carrier state at ATXN2, and segregation distortion favoring normal alleles. Since majority of normal alleles analyzed carried 22 repeats, we propose that this distortion segregation can be related to the high frequency of this allele in human chromosomes.

Abnormal Findings in Polysomnographic Recordings of Patients with Spinocerebellar Ataxia Type 2 (SCA2).

Spinocerebellar ataxia type 2 (SCA2) is characterized by a progressive cerebellar syndrome, and additionally saccadic slowing, cognitive dysfunction, and sleep disorders. The aim of this study was to assess the frequency of abnormal findings in sleep recordings of patients with SCA2. Seventeen patients with genetically confirmed SCA2 from the Movement Disorders Outpatient group of the Hospital de Clínicas da UFPR were evaluated with a structured medical interview and the Scale for the Assessment and Rating of Ataxia (SARA). Polysomnographic recordings were performed and sleep stages were scored according to standard criteria. There were 10 male subjects and 7 females, aged 24-66 years (mean 47.44). A sex- and age-matched control group of healthy subjects was used for comparison. There was a reduction of rapid eye movement (REM) sleep in 12 (70.58%), increased REM latency in 9 (52.94%), increased obstructive sleep apnea-index in 14 (82.35%), absent REM density (REM density was calculated as the total number of 3-s miniepochs of REM sleep with at least 1 REM per minute) in 13 (76.47%), and markedly reduced REM density in 4 (23.52%). There was an indirect correlation according to the SARA scale and the REM density decrease (r = - 0.6; P = < 0.001); and with a disease progression correlating with a reduction in the REM density (r = - 0.52, P = 0.03). In SCA2, changes occur mainly REM sleep. The absence/decrease of REM sleep density, even in oligosymptomatic patients, and the correlation of this finding with disease time and with the SARA scale were the main findings of the study.

Long-Term Suppression of Disabling Tremor by Thalamic Stimulation in a Patient with Spinocerebellar Ataxia Type 2.

The beneficial effect of thalamic deep brain stimulation (DBS) on action tremor has been reported in a few cases of spinocerebellar ataxia (SCA); however, several factors should be taken into account regarding the indication for DBS in advanced cases. We performed DBS of the ventral intermediate nucleus (Vim) of the thalamus for treatment of coarse action tremor in a patient with SCA2 (spinocerebellar ataxia type 2) in the wheelchair-bound stage. Although improvement of the tremor of the proximal part was incomplete, the patient regained substantial parts of daily functioning. The effect lasted for more than 6 years, and the suppression of tremor significantly contributed to maintaining the level of the patient's expression into the bedridden stage. Vim DBS can be a treatment option for tremor in SCA patients, even in the advanced stage, as long as the tremor is depriving the patient of behavioral expression. As residual proximal tremor may hamper functional recovery, DBS of other targets or multi-targets should be further explored to attain a better outcome.

Role of Sca2 and RickA in the Dissemination of Rickettsia parkeri in Amblyomma maculatum.

The Gram-negative obligate intracellular bacterium Rickettsia parkeri is an emerging tick-borne human pathogen. Recently, R. parkeri Sca2 and RickA have been implicated in adherence and actin-based motility in vertebrate host cell infection models; however, the rickettsia-derived factors essential to tick infection are unknown. Using R. parkeri mutants lacking functional Sca2 or RickA to compare actin polymerization, replication, and cell-to-cell spread in vitro, similar phenotypes in tick and mammalian cells were observed. Specifically, actin polymerization in cultured tick cells is controlled by the two separate proteins in a time-dependent manner. To assess the role of Sca2 and RickA in dissemination in the tick host, Rickettsia-free Amblyomma maculatum, the natural vector of R. parkeri, was exposed to wild-type, R. parkeri rickA::tn, or R. parkeri sca2::tn bacteria, and individual tick tissues, including salivary glands, midguts, ovaries, and hemolymph, were analyzed at 12 h and after continued bloodmeal acquisition for 3 or 7 days postexposure. Initially, ticks exposed to wild-type R. parkeri had the highest rickettsial load across all organs; however, rickettsial loads decreased and wild-type rickettsiae were cleared from the ovaries at 7 days postexposure. In contrast, ticks exposed to R. parkeririckA::tn or R. parkerisca2::tn had comparatively lower rickettsial loads, but bacteria persisted in all organs for 7 days. These data suggest that while RickA and Sca2 function in actin polymerization in tick cells, the absence of these proteins did not change dissemination patterns within the tick vector.

Predictors of survival in spinocerebellar ataxia type 2 population from Southern Italy.

One hundred-eighteen spinocerebellar ataxia type 2 patients from 35 distinct families personally observed between 1973 and 2016 were retrospectively reviewed. The time point of data collection was 1 January 2017. Thirty-one patients were confined to wheelchair. The median time to wheelchair was 21 years (95% CI, 17.5-24.6). Thirty-seven patients were deceased. The median time to death was 25 years (95% CI, 22.9-27.1). CAG repeat number and ataxia score at first visit influenced the time to wheelchair and death.

Peripheral markers of autophagy in polyglutamine diseases.

Polyglutamine disorders are neurodegenerative diseases that share a CAG repeat expansion in the coding region, resulting in aggregated proteins that can be only degraded through aggrephagy. We measured the expression of autophagy genes in peripheral blood mononuclear cells of 20 patients with Huntington's disease (HD), 20 with spinocerebellar ataxia type 2 (SCA2), and 20 healthy individuals. HD patients showed increased expression of MAP1LC3B (+ 43%; p = 0.048), SQSTM1 (+ 49%; p = 0.002), and WDFY3 (+ 89%; p < 0.001). SCA2 patients had increased expression of WDFY3 (+ 69%; p < 0.001). We show that peripheral markers of autophagy are elevated in polyQ diseases, and this is particularly evident in HD.

Prodromal spinocerebellar ataxia type 2: Prospects for early interventions and ethical challenges.

The characterization of prodromal stages in neurodegenerative disorders is becoming increasingly important because of the need for early neuroprotective therapies. Research during the past 3 decades in spinocerebellar ataxia type 2 has revealed a large body of evidence suggesting that many disease features precede the manifest cerebellar syndrome, which delineates the prodromal stage of this disorder. This stage is defined by clinical, imaging, and functional criteria, which are supported by early molecular events demonstrated in animal models. Knowledge regarding prodromal spinocerebellar ataxia type 2 provides insight into the mechanisms underlying neurodegeneration from the early stages, which enables the design of promising disease-modifying clinical trials through the identification of the optimum moment to begin the therapies, the appropriate selection of individuals, and the identification of sensitive outcome measures. The management of patients in prodromal spinocerebellar ataxia type 2 may raise ethical dilemmas related to predictive diagnosis and early interventions, which impose new challenges to clinical and therapeutic research. © 2017 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.

Non-motor and Extracerebellar Features in Spinocerebellar Ataxia Type 2.

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant degenerative disease. Pathological studies have demonstrated not only cerebellar and brainstem atrophy, but substantia nigra, motoneurons, basal ganglia, thalamus, and peripheral nerves involvement. These findings may explain non-motor and extra-cerebellar features in SCA2. We accessed the non-motor symptoms and extra-cerebellar signs in SCA2 patients in order to provide a better understanding on pathophysiological mechanisms and natural history of brain degeneration in the disease. Thirty-three SCA2 patients were evaluated and compared with 26 healthy subjects. We investigated the following variables: sleep disorders, cognitive deficit, olfactory impairment, urinary dysfunction, psychiatric symptoms, cramps, pain, movement disorders, and weight loss. SCA2 had a high frequency of REM sleep behavior disorder (48.48 %, N = 16) as well as excessive daytime sleepiness (42.42 %, N = 14). Chorea was present in 15.15 % (N = 5), dystonia in 27.27 % (N = 9), and parkinsonism in 27.27 % (N = 9). Slow saccadic pursuit was present in 87.87 % (N = 29) and ophtalmoparesis in 78.78 % (N = 26) of patients. Regarding sleep disorders, 18.18 % (N = 6) of patients had restless leg syndrome. Dysphagia was present in 39.39 % (N = 13), weight loss 24.24 % (N = 8), and urinary dysfunction 27.27 % (N = 9). Cramps was present in only 6 % of patients (N = 2). This study highlighted the high frequency of non-motor symptoms and extra-cerebellar signs in SCA2. Our findings demonstrate the widespread of nervous system involvement in SCA2 patients and contribute to better understand the natural history of brain degeneration in this genetic condition.

NESSCA Validation and Responsiveness of Several Rating Scales in Spinocerebellar Ataxia Type 2.

Spinocerebellar ataxia type 2 (SCA2), caused by a CAG expansion (CAGexp) at ATXN2, has a complex clinical picture. While validated ataxia scales are available, comprehensive instruments to measure all SCA2 neurological manifestations are required. This study aims to validate the Neurological Examination Score for the assessment of Spinocerebellar Ataxias (NESSCA) to be used in SCA2 and to compare its responsiveness to those obtained with other instruments. NESSCA, SARA, SCAFI, and CCFS scales were applied in symptomatic SCA2 patients. Correlations were done with age at onset, disease duration, CAGexp, and between scales. Responsiveness was estimated by comparing deltas of stable to worse patients after 12 months, according to Patient Global Impression of change, and the area under the curve (AUC) of the Receiver Operating Characteristics curve of scores range. Eighty-eight evaluations (49 patients) were obtained. NESSCA had an even distribution and correlated with disease duration (r = 0.55), SARA (r = 0.63), and CAGexp (rho = 0.32): both explained 44% of NESSCA variance. Deltas (95% CI) after 1 year in stable and worse patients were only significantly different for SARA. NESSCA, SARA, SCAFI, and CCFS AUC were 0.63, 0.81, 0.49, and 0.48, respectively. NESSCA is valid to be used in SCA2. However, the only instrument that presented good responsiveness to change in 1 year was SARA. We suggest that NESSCA can be used as a secondary outcome in future trials in SCA2 due to the burden of neurological disabilities related to disease progression.

In vivo analysis of cerebellar Purkinje cell activity in SCA2 transgenic mouse model.

Cerebellar Purkinje cells (PCs) are primarily affected in many spinocerebellar ataxias (SCA). In this study we investigated functional activity of PCs in transgenic mouse model of SCA2, a polyglutamine neurodegenerative hereditary disorder. In our studies we used extracellular single-unit recording method to compare spontaneous activity of PCs in age-matched wild-type mice and SCA2-58Q transgenic mice. We discovered that the fraction of PCs with bursting and an irregular pattern of spontaneous activity dramatically increases in aged SCA2-58Q mice compared with wild-type littermates. Small-conductance calcium-activated potassium (SK) channels play an important role in determining firing rate of PCs. Indeed, we demonstrated that intraperitoneal (IP) injection of SK channel inhibitor NS8593 induces an irregular pattern of PC activity in wild-type mice. Furthermore, we demonstrated that IP injection of SK channel-positive modulator chlorzoxazone (CHZ) decreases spontaneous firing rate of cerebellar PCs. Finally, we have shown that IP injections with CHZ normalize firing activity of cerebellar PCs from aging SCA2-58Q mice. We propose that alterations in PC firing patterns is one of potential causes of ataxic symptoms in SCA2 and in other SCAs and that positive modulators of SK channels can be used to normalize activity of PCs and alleviate ataxic phenotype in patients with SCA.

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.