OBJECTIVE: To evaluate the reliability, responsiveness, and validity of the Scale for the Assessment and Rating of Ataxia (SARA) in patients with lysosomal storage disorders (LSDs) who present with neurological symptoms, and quantify the threshold for a clinically meaningful change.
METHODS: We analyzed data from three clinical trial cohorts (IB1001-201, IB1001-202, and IB1001-301) of patients with Niemann-Pick disease type C (NPC) and GM2 Gangliosidoses (Tay-Sachs and Sandhoff disease) comprising 122 patients and 703 visits. Reproducibility was described as re-test reliability between repeat baseline visits or baseline and post-treatment washout visits. Responsiveness was determined in relation to the Investigator\'s, Caregiver\'s, and Patient\'s Clinical Global Impression of Improvement (CGI-I). The CGI-I data was also used to quantify a threshold for a clinically meaningful improvement on the SARA scale. Using a qualitative methods approach, patient/caregiver interviews from the IB1001-301 trial were further used to assess a threshold of meaningful change as well as the breadth of neurological signs and symptoms captured and evaluated by the SARA scale.
RESULTS: The Inter-Class Correlation (ICC) was 0.95 or greater for all three trials, indicating a high internal consistency/reliability. The mean change in SARA between repeat baseline and post-treatment washout visit assessments in all trials was -0.05, SD 1.98, i.e., minimal, indicating no significant differences, learning effects or other systematic biases. For the CGI-I responses and change in SARA scores, Area Under the Curve (AUC) values were 0.82, 0.71, and 0.77 for the Investigator\'s, Caregiver\'s, and Patient\'s CGI-I respectively, indicating strong agreement. Further qualitative analyses of the patient/caregiver interviews demonstrated a 1-point or greater change on SARA to be a clinically meaningful improvement which is directly relevant to the patient\'s everyday functioning and quality of life. Changes captured by the SARA were also paralleled by improvement in a broad range of neurological signs and symptoms and beyond cerebellar ataxia.
CONCLUSIONS: Qualitative and quantitative data demonstrate the reliability and responsiveness of the SARA score as a valid measure of neurological signs and symptoms in LSDs with CNS involvement, such as NPC and GM2 Gangliosidoses. A 1-point change represents a clinically meaningful transition reflecting the gain or loss of complex function.

BACKGROUND: Spinocerebellar ataxia type 3 (SCA3) is an inherited, autosomal, and rare neurodegenerative disease. Serum/plasma biomarkers or functional magnetic resonance imaging used to assess progression, except for neurological examinations, is either inconvenient or expensive. Handgrip strength (HGS) may be considered as a biomarker to predict the progress of SCA3 and align with the alteration of plasma neurofilament light chain (NfL) and Scale for the Assessment and Rating of Ataxia (SARA).
METHODS: Patients with SCA3 and healthy subjects were recruited from Changhua Christian Hospital. SARA, body mass index (BMI), and NfL were obtained for both groups. HGS was measured using a Jamar Plus + hand dynamometer.
RESULTS: This study recruited 31 patients and 36 controls. HGS in the SCA3 group revealed a profound decrease (P < 0.001) compared with normal subjects. HGS also had a negative correlation with SARA (r =  - 0.548, P = 0.001), NfL (r =  - 0.359, P = 0.048), and a positive correlation with BMI (r = 0.680, P < 0.001). Moreover, HGS/BMI ratio correlated with SARA (r =  - 0.441, P = 0.013). Controlling for gender and age, HGS still correlated with the above clinical items. The initial hypothesis was also proved in SCA3 84Q transgenic mice, showing grip strength weakness compared to normal mice.
CONCLUSIONS: HGS can be an alternative tool to assess the clinical severity of SCA3. Further research is needed to investigate the underlying mechanisms.

UNASSIGNED: Video recordings of neurological examinations are often used in clinical trials. The Scale for Assessment and Rating of Ataxia (SARA) is a widely used clinical scale for ataxic patients. Despite several advantages of video ratings, correlation between live ratings and remote video-ratings has not been systematically investigated.
UNASSIGNED: To compare live and remote video assessment of SARA.
UNASSIGNED: Full SARA examinations of 69 patients with cerebellar ataxia were recorded on video. Live rating from site investigators were compared with remote video rating of three experienced ataxia clinicians using Bland-Altman analysis.
UNASSIGNED: Live and remote video ratings showed a high level of agreement for the complete score (bias = 0.09, with standard deviation = 2.00) and all single SARA items (bias <0.20 for all items).
UNASSIGNED: Remote video ratings of SARA are a reliable means to assess severity of ataxia.

BACKGROUND: Clinical decision-making in spinocerebellar ataxia spectrum diseases (SCAs) has mainly been based on genetic tests, not considering the SCAs\' imaging and clinical heterogenicity.
OBJECTIVE: To identify SCAs phenogroups by analysis and hierarchical clustering of infratentorial morphological MRI for unveiling pathophysiological differences among common SCA subtypes.
METHODS: We prospectively enrolled 119 (62 women; mean age 37 years) genetically diagnosed SCAs (SCA1 n = 21, SCA2 n = 10, symptomatic SCA3 n = 59, presymptomatic SCA3 n = 22, SCA6 n = 7) and 35 healthy controls (HCs). All patients underwent MRI and detailed neurological and neuropsychology examinations. The width of each cerebellar peduncle (CP) and anteroposterior diameter of the spinal cord and pontine were measured. Twenty-five SCAs patients (15 women; mean age 35 years) were followed for at least a year (17 (15, 24) months), whose MRI and the Scale for the Assessment and Rating of Ataxia (SARA) were collected.
RESULTS: Infratentorial morphological MRI measurements could significantly discriminate SCAs from HCs, even among SCA subtypes. Two mutually exclusive and clinically distinct phenogroups were identified. Despite similar (CAG)n, phenogroup 1 (n = 66, 55.5%) presented more atrophied infratentorial brain structures and more severe clinical symptoms with older age and earlier age of onset when compared with phenogroup 2. More importantly, all SCA2, most of SCA1 (76%), and symptomatic SCA3 (68%) were classified into phenogroup 1, whereas all SCA6 and all presymptomatic SCA3 were in phenogroup 2. The right middle CP had the highest diagnostic value in predicting phenogroup 2 (AUC = 0.99; P < 0.01) with high specificity (95%). Consistent with the significantly increased SARA (7.5 vs 10, P = 0.021), the bilateral inferior CP, spinal cord, and pontine tegmentum were more atrophy during the follow-up (P < 0.05).
CONCLUSIONS: SCAs were with significant infratentorial brain atrophy than HCs. We identified two different SCAs phenogroups associated with substantial differences in infratentorial brain atrophy, clinical presentation, and may reflect the underlying molecular profiles to some extent, paving the way for a more personalized diagnostic and treatment approach.

UNASSIGNED: Spinocerebellar ataxia type 3 (SCA3) is a common autosomal dominant hereditary ataxia, which is caused by a cytosine-adenine-guanine (CAG) repeat expansion on the causative gene ATXN3, usually with lower extremity ataxia as the first symptom, and effective treatment is scarce. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique that regulates the cerebellum and the neural network connected to it.
UNASSIGNED: Herein, we report familial cases of SCA3 in two nephews and their aunt, each of whom was treated with high-frequency (5 Hz) rTMS. The rTMS treatment lasted 2 weeks, once daily for 5 consecutive days a week, about 20 minutes each session. The Scale for the Assessment and Rating of Ataxia (SARA), the International Cooperative Ataxia Rating Scale (ICARS), and proton magnetic resonance spectroscopy (1H-MRS) examination were evaluated before and after rTMS treatment.
UNASSIGNED: We found that the ICARS scores improved significantly (p = 0.04), and the NAA/Cr values were elevated in vermis and both cerebellar hemispheres after rTMS treatment.
UNASSIGNED: Our study suggested that high-frequency rTMS therapy can contribute to the improvement of cerebellar NAA/Cr value of SCA3 patients, and improve posture and gait as well as limb kinetic function in SCA3 patients.

The study presents a novel approach to objectively assessing the upper-extremity motor symptoms in spinocerebellar ataxia (SCA) using data collected via a wearable sensor worn on the patient\'s wrist during upper-extremity tasks associated with the Assessment and Rating of Ataxia (SARA). First, we developed an algorithm for detecting/extracting the cycles of the finger-to-nose test (FNT). We extracted multiple features from the detected cycles and identified features and parameters correlated with the SARA scores. Additionally, we developed models to predict the severity of symptoms based on the FNT. The proposed technique was validated on a dataset comprising the seventeen (n = 17) participants\' assessments. The cycle detection technique showed an accuracy of 97.6% in a Bland-Altman analysis and a 94% accuracy (F1-score of 0.93) in predicting the severity of the FNT. Furthermore, the dependency of the upper-extremity tests was investigated through statistical analysis, and the results confirm dependency and potential redundancies in the upper-extremity SARA assessments. Our findings pave the way to enhance the utility of objective measures of SCA assessments. The proposed wearable-based platform has the potential to eliminate subjectivity and inter-rater variabilities in assessing ataxia.

The Scale for the Assessment and Rating of Ataxia (SARA) is the reference clinical scale to assess the severity of cerebellar ataxia. In the context of upcoming therapeutic trials, a reliable clinical outcome is needed to assess the efficiency of treatments.
The aim is to precisely assess and compare temporal dynamics of SARA and a new f-SARA.
We analyzed data from four cohorts (EUROSCA, RISCA, CRC-SCA, and SPATAX) comprising 1210 participants and 4092 visits. The linearity of the progression and the variability were assessed using an ordinal Bayesian mixed-effect model (Leaspy). We performed sample size calculations for therapeutic trials with different scenarios to improve the responsiveness of the scale.
Seven of the eight different items had a nonlinear progression. The speed of progression was different between most of the items, with an average time for a one-point increase from 3.5 years [3.4; 3.6] (median, 95% credible interval) for the fastest item to 11.4 [10.9; 12.0] years. The total SARA score had a linear progression with an average time for a one-point increase of 0.95 [0.92; 0.98] years. After removing the four last items and rescaling all items from 0 to 4, variability increased and progression was slower and thus would require a larger sample size in a future therapeutic trial.
Despite a heterogeneous temporal dynamics at the item level, the global progression of SARA was linear. Changing the initial scale deteriorates the responsiveness. This new information about the temporal dynamics of the scale should help design the outcome of future clinical trials. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Spinocerebellar ataxias (SCAs) are progressive neurodegenerative disorders, but there is no metric that predicts disease severity over time. We hypothesized that by developing a new metric, the Severity Factor (S-Factor) using immutable disease parameters, it would be possible to capture disease severity independent of clinical rating scales. Extracting data from the CRC-SCA and READISCA natural history studies, we calculated the S-Factor for 438 participants with symptomatic SCA1, SCA2, SCA3, or SCA6, as follows: ((length of CAG repeat expansion - maximum normal repeat length) /maximum normal repeat length) × (current age - age at disease onset) × 10). Within each SCA type, the S-Factor at the first Scale for the Assessment and Rating of Ataxia (SARA) visit (baseline) was correlated against scores on SARA and other motor and cognitive assessments. In 281 participants with longitudinal data, the slope of the S-Factor over time was correlated against slopes of scores on SARA and other motor rating scales. At baseline, the S-Factor showed moderate-to-strong correlations with SARA and other motor rating scales at the group level, but not with cognitive performance. Longitudinally the S-Factor slope showed no consistent association with the slope of performance on motor scales. Approximately 30% of SARA slopes reflected a trend of non-progression in motor symptoms. The S-Factor is an observer-independent metric of disease burden in SCAs. It may be useful at the group level to compare cohorts at baseline in clinical studies. Derivation and examination of the S-factor highlighted challenges in the use of clinical rating scales in this population.

Disease severity in spinocerebellar ataxia type 3 (SCA3) is commonly defined by the Scale for the Assessment and Rating of Ataxia (SARA) sum score, but little is known about the contributions and progression patterns of individual items.
To investigate the temporal dynamics of SARA item scores in SCA3 patients and evaluate if clinical and demographic factors are differentially associated with evolution of axial and appendicular ataxia.
In a prospective, multinational cohort study involving 11 European and 2 US sites, SARA scores were determined longitudinally in 223 SCA3 patients with a follow-up assessment after 1 year.
An increase in SARA score from 10 to 20 points was mainly driven by axial and speech items, with a markedly smaller contribution of appendicular items. Finger chase and nose-finger test scores not only showed the lowest variability at baseline, but also the least deterioration at follow-up. Compared with the full set of SARA items, omission of both tests would result in lower sample size requirements for therapeutic trials. Sex was associated with change in SARA sum score and appendicular, but not axial, subscore, with a significantly faster progression in men. Despite considerable interindividual variability, the average annual progression rate of SARA score was approximately three times higher in subjects with a disease duration over 10 years than in those within 10 years from onset.
Our findings provide evidence for a difference in temporal dynamics between axial and appendicular ataxia in SCA3 patients, which will help inform the design of clinical trials and development of new (etiology-specific) outcome measures. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Repeated sessions of cerebellar anodal transcranial direct current stimulation (tDCS) have been suggested to modulate cerebellar-motor cortex (M1) connectivity and decrease ataxia severity. However, therapeutic trials involving etiologically homogeneous groups of ataxia patients are lacking. The objective of this study was to investigate if a two-week regimen of daily cerebellar tDCS sessions diminishes ataxia and non-motor symptom severity and alters cerebellar-M1 connectivity in individuals with spinocerebellar ataxia type 3 (SCA3). We conducted a randomized, double-blind, sham-controlled trial in which twenty mildly to moderately affected SCA3 patients received ten sessions of real or sham cerebellar tDCS (i.e., five days per week for two consecutive weeks). Effects were evaluated after two weeks, three months, six months, and twelve months. Change in Scale for the Assessment and Rating of Ataxia (SARA) score after two weeks was defined as the primary endpoint. Static posturography, SCA Functional Index tests, various patient-reported outcome measures, the cerebellar cognitive affective syndrome scale, and paired-pulse transcranial magnetic stimulation to examine cerebellar brain inhibition (CBI) served as secondary endpoints. Absolute change in SARA score did not differ between both trial arms at any of the time points. We observed significant short-term improvements in several motor, cognitive, and patient-reported outcomes after the last stimulation session in both groups but no treatment effects in favor of real tDCS. Nonetheless, some of the patients in the intervention arm showed a sustained reduction in SARA score lasting six or even twelve months, indicating interindividual variability in treatment response. CBI, which reflects the functional integrity of the cerebellothalamocortical tract, remained unchanged after ten tDCS sessions. Albeit exploratory, there was some indication for between-group differences in SARA speech score after six and twelve months and in the number of extracerebellar signs after three and six months. Taken together, our study does not provide evidence that a two-week treatment with daily cerebellar tDCS sessions reduces ataxia severity or restores cerebellar-M1 connectivity in early-to-middle-stage SCA3 patients at the group level. In order to potentially increase therapeutic efficacy, further research is warranted to identify individual predictors of symptomatic improvement.