Friedreich Ataxia Rating Scale Research Articles

Development and Validation of SCACOMS, a Composite Scale for Assessing Disease Progression and Treatment Effects in Spinocerebellar Ataxia.

Spinocerebellar ataxias (SCA) are rare inherited neurodegenerative disorders characterized by a progressive impairment of gait, balance, limb coordination, and speech. There is currently no composite scale that includes multiple aspects of the SCA experience to assess disease progression and treatment effects. Applying the method of partial least squares (PLS) regression, we developed the Spinocerebellar Ataxia Composite Scale (SCACOMS) from two SCA natural history datasets (NCT01060371, NCT02440763). PLS regression selected items based on their ability to detect clinical decline, with optimized weights based on the item's degree of progression. Following model validation, SCACOMS was leveraged to examine disease progression and treatment effects in a 48-week SCA clinical trial cohort (NCT03701399). Items from the Clinical Global Impression-Global Improvement Scale (CGI-I), the Friedreich Ataxia Rating Scale (FARS) - functional stage, and the Modified Functional Scale for the Assessment and Rating of Ataxia (f-SARA) were objectively selected with weightings based on their sensitivity to clinical decline. The resulting SCACOMS exhibited improved sensitivity to disease progression and greater treatment effects (compared to the original scales from which they were derived) in a 48-week clinical trial of a novel therapeutic agent. The trial analyses also provided a SCACOMS-derived estimate of the temporal delay in SCA disease progression. SCACOMS is a useful composite measure, effectively capturing disease progression and highlighting treatment effects in patients with SCA. SCACOMS will be a powerful tool in future studies given its sensitivity to clinical decline and ability to detect a meaningful clinical impact of disease-modifying treatments.

Cardiopulmonary exercise testing on adaptive equipment in children and adults with Friedreich ataxia.

Traditional exercise is often difficult for individuals with Friedreich ataxia (FRDA), and evidence is limited regarding how to measure exercise performance in this population. We evaluated the feasibility, reliability, and natural history of adaptive cardiopulmonary exercise test (CPET) performance in children and adults with FRDA. Participants underwent CPET on either an arm cycle ergometer (ACE) or recumbent leg cycle ergometer (RLCE) at up to four visits (baseline, 2 weeks, 4 weeks, and 1 year). Maximum work, oxygen consumption (peak VO2), oxygen (O2) pulse, and anaerobic threshold (AT) were measured in those who reached maximal volition. Test-retest reliability was assessed with intraclass coefficients, and longitudinal change was assessed using regression analysis. In our cohort (N = 23), median age was 18 years (interquartile range [IQR], 14-23), median age of FRDA onset was 8 years (IQR 6-13), median Friedreich Ataxia Rating Scale score was 58 (IQR 54-62), and GAA repeat length on the shorter FXN allele (GAA1) was 766 (IQR, 650-900). Twenty-one (91%) completed a maximal CPET (n = 8, ACE and n = 13, RLCE). Age, sex, and GAA1 repeat length were each associated with peak VO2. Preliminary estimates demonstrated reasonable agreement between visits 2 and 3 for peak work by both ACE and RLCE, and for peak VO2, O2 pulse, and AT by RLCE. We did not detect significant performance changes over 1 year. Adaptive CPET is feasible in FRDA, a relevant clinical trial outcome for interventions that impact exercise performance and will increase access to participation as well as generalizability of findings.

FARS-ADL across Ataxias: Construct Validity, Sensitivity to Change, and Minimal Important Change.

Patient-focused outcomes present a central need for trial-readiness across all ataxias. The Activities of Daily Living part of the Friedreich Ataxia Rating Scale (FARS-ADL) captures functional impairment and longitudinal change but is only validated in Friedreich Ataxia. Validation of FARS-ADL regarding disease severity and patient-meaningful impairment, and its sensitivity to change across genetic ataxias. Real-world registry data of FARS-ADL in 298 ataxia patients across genotypes were analyzed, including (1) cross-correlation with FARS-stage, Scale for the Assessment and Rating of Ataxia (SARA), Patient-Reported Outcome Measure (PROM)-ataxia, and European Quality of Life 5 Dimensions visual analogue scale (EQ5D-VAS); (2) sensitivity to change within a trial-relevant 1-year median follow-up, anchored in Patient Global Impression of Change (PGI-C); and (3) general linear modeling of factors age, sex, and depression (nine-item Patient Health Questionnaire [PHQ-9]). FARS-ADL correlated with overall disability (rhoFARS-stage = 0.79), clinical disease severity (rhoSARA = 0.80), and patient-reported impairment (rhoPROM-ataxia = 0.69, rhoEQ5D-VAS = -0.37), indicating comprehensive construct validity. Also at item level, and validated within genotype (SCA3, RFC1), FARS-ADL correlated with the corresponding SARA effector domains; and all items correlated to EQ5D-VAS quality of life. FARS-ADL was sensitive to change at a 1-year interval, progressing only in patients with worsening PGI-C. Minimal important change was 1.1. points based on intraindividual variability in patients with stable PGI-C. Depression was captured using FARS-ADL (+0.3 points/PHQ-9 count) and EQ5D-VAS, but not FARS-stage or SARA. FARS-ADL reflects both disease severity and patient-meaningful impairment across genetic ataxias, with sensitivity to change in trial-relevant timescales in patients perceiving change. It thus presents a promising patient-focused outcome for upcoming ataxia trials. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Standing Balance Conditions and Digital Sway Measures for Clinical Trials of Friedreich's Ataxia.

Progressive loss of standing balance is a feature of Friedreich's ataxia (FRDA). This study aimed to identify standing balance conditions and digital postural sway measures that best discriminate between FRDA and healthy controls (HC). We assessed test-retest reliability and correlations between sway measures and clinical scores. Twenty-eight subjects with FRDA and 20 HC completed six standing conditions: feet apart, feet together, and feet tandem, both with eyes opened (EO) and eyes closed. Sway was measured using a wearable sensor on the lumbar spine for 30 seconds. Test completion rate, test-retest reliability with intraclass correlation coefficients, and areas under the receiver operating characteristic curves (AUCs) for each measure were compared to identify distinguishable FRDA sway characteristics from HC. Pearson correlations were used to evaluate the relationships between discriminative measures and clinical scores. Three of the six standing conditions had completion rates over 70%. Of these three conditions, natural stance and feet together with EO showed the greatest completion rates. All six of the sway measures' mean values were significantly different between FRDA and HC. Four of these six measures discriminated between groups with >0.9 AUC in all three conditions. The Friedreich Ataxia Rating Scale Upright Stability and Total scores correlated with sway measures with P-values <0.05 and r-values (0.63-0.86) and (0.65-0.81), respectively. Digital postural sway measures using wearable sensors are discriminative and reliable for assessing standing balance in individuals with FRDA. Natural stance and feet together stance with EO conditions suggest use in clinical trials for FRDA. © 2024 International Parkinson and Movement Disorder Society.

Effectiveness of rehabilitation intervention in persons with Friedreich ataxia.

The relevance of rehabilitation in progressive neurological disorders, such as Friedreich's Ataxia (FRDA), has yet to be convincingly proven. FRDA is characterized by ataxia, loss of gait, scoliosis, cardiomyopathy, dysarthria and dysphagia, with reduced life expectancy. The disease onset is usually in adolescence, leading to progressive disability. Omaveloxolone has been recently approved as the first pharmacological treatment for FRDA in adults and adolescents aged 16 years and older. Regarding non-pharmacological therapies, neurorehabilitation is a valuable aid in addressing the symptoms and in maintaining the residual functioning. We performed a prospective observational cohort study to evaluate the efficacy of inpatient rehabilitation (IR) for people with FRDA. A total of 42 individuals (29 adults and 13 children) with FRDA were recruited. There were 27 ambulant and 15 non-ambulant participants. The patients underwent IR of 3 and 4 weeks in children and adults, respectively. The IR treatment was designed to be applied within a multidisciplinary setting, so FRDA patients underwent, in addition to physiotherapy, also occupational therapy, practical manual activities and psychological support aiming to enhance transferable skills useful in the activities of daily living. The primary outcome was the Scale for the Assessment and Rating of Ataxia (SARA). Other measures were: Friedreich Ataxia Rating Scale (FARS) and Nine Hole Peg Test (NHPT). Furthermore, we used the 6 Minute Walk Test (6MWT), the Timed Up and Go (TUG) and the Berg Balance Scale (BBS) only on ambulant subjects. Outcomes were evaluated at baseline and at the end of the treatment. We report that the IR significantly improves motor performance and ataxia symptoms in patients with FRDA. Our study shows significant functional improvement in all the outcome measures used, except for NHPT bilaterally. FARS and SARA scores post-IR are significatively reduced when compared (p < 0.001). We demonstrate that IR programs in FRDA can provide a meaningful clinical improvement in terms of outcome measures. These findings could be useful when approaching progressive neurological disorders.

Propensity matched comparison of omaveloxolone treatment to Friedreich ataxia natural history data.

The natural history of Friedreich ataxia is being investigated in a multi-center longitudinal study designated the Friedreich ataxia Clinical Outcome Measures Study (FACOMS). To understand the utility of this study in analysis of clinical trials, we performed a propensity-matched comparison of data from the open-label MOXIe extension (omaveloxolone) to that from FACOMS. MOXIe extension patients were matched to FACOMS patients using logistic regression to estimate propensity scores based on multiple covariates: sex, baseline age, age of onset, baseline modified Friedreich Ataxia Rating scale (mFARS) score, and baseline gait score. The change from baseline in mFARS at Year 3 for the MOXIe extension patients compared to the matched FACOMS patients was analyzed as the primary efficacy endpoint using mixed model repeated measures analysis. Data from the MOXIe extension show that omaveloxolone provided persistent benefit over 3 years when compared to an untreated, matched cohort from FACOMS. At each year, in all analysis populations, patients in the MOXIe extension experienced a smaller change from baseline in mFARS score than matched FACOMS patients. In the primary pooled population (136 patients in each group) by Year 3, patients in the FACOMS matched set progressed 6.6 points whereas patients treated with omaveloxolone in MOXIe extension progressed 3 points (difference = -3.6; nominal p value = 0.0001). These results suggest a meaningful slowing of Friedreich ataxia progression with omaveloxolone, and consequently detail how propensity-matched analysis may contribute to understanding of effects of therapeutic agents. This demonstrates the direct value of natural history studies in clinical trial evaluations.

Differences in spontaneous speech fluency between Parkinson's disease and spinocerebellar ataxia type 3.

The basal ganglia and cerebellum both have a role in speech production although the effect of isolated involvement of these structures on speech fluency remains unclear. The study aimed to assess the differences in the articulatory pattern in patients with cerebellar vs. basal ganglia disorders. A total of 20 individuals with Parkinson's disease (PD), 20 with spinocerebellar ataxia type 3 (SCA3), and 40 controls (control group, CG) were included. Diadochokinesis (DDK) and monolog tasks were collected. The only variable that distinguished SCA3 carriers from the CG was the number of syllables in the monolog, with SCA3 patients of a significantly lower number. For patients with PD, the number of syllables, phonation time, DDK, and monolog were significantly lower than for CG. Patients with PD were significantly worse compared to patients with SCA3 in the number of syllables and phonation time in DDK, and phonation time in monolog. Additionally, there was a significant correlation between the number of syllables in the monolog and the MDS-UPDRS III for participants with PD, and the Friedreich Ataxia Rating Scale for participants with SCA3 suggesting a relationship between speech and general motor functioning. The monolog task is better at discriminating individuals with cerebellar vs. Parkinson's diseases as well as differentiating healthy control and was related to the severity of the disease.

Auditory neuropathy in mice and humans with Friedreich ataxia.

Recent studies have found that human Friedreich ataxia patients have dysfunction of transmission in the auditory neural pathways. Here, we characterize hearing deficits in a mouse model of Friedreich ataxia and compare these to a clinical population. Sixteen mice with a C57BL/6 background were evaluated. Eight were YG8Pook/J animals (Friedreich ataxia phenotype) and eight wild-type mice served as controls. Auditory function was assessed between ages 6 and 12 months using otoacoustic emissions and auditory steady-state responses. At study end, motor deficit was assessed using Rotorod testing and inner ear tissue was examined. Thirty-seven individuals with Friedreich ataxia underwent auditory steady-state evoked potential assessment and response amplitudes were compared with functional hearing ability (speech perception-in-noise) and disease status was measured by the Friedreich Ataxia Rating Scale. The YG8Pook/J mice showed anatomic and functional abnormality. While otoacoustic emission responses from the cochlear hair cells were mildly affected, auditory steady-state responses showed exaggerated amplitude reductions as the animals aged with Friedreich ataxia mice showing a 50-60% decrease compared to controls who showed only a 20-25% reduction (F(2,94) = 17.90, p < 0.00). Furthermore, the YG8Pook/J mice had fewer surviving spiral ganglion neurons, indicating greater degeneration of the auditory nerve. Neuronal density was 20-25% lower depending on cochlear region (F(1, 30) = 45.02, p < 0.001). In human participants, auditory steady-state response amplitudes were correlated with both Consonant-Nucleus-Consonant word scores and Friedreich Ataxia Rating Scale score. This study found degenerative changes in auditory structure and function in YG8Pook/J mice, indicating that auditory measures in these animals may provide a model for testing Friedreich ataxia treatments. In addition, auditory steady-state response findings in a clinical population suggested that these scalp-recorded potentials may serve as an objective biomarker for disease progress in affected individuals.

Harmonizing results of ataxia rating scales: mFARS, SARA, and ICARS.

The ever-increasing body of ataxia research provides opportunities for large-scale meta-analyses, systematic reviews, and data aggregation. Because multiple standardized scales are used to quantify ataxia severity, harmonization of these measures is necessary for quantitative data pooling. We applied the modified Friedreich Ataxia Rating Scale (mFARS), the Scale for the Assessment and Rating of Ataxia (SARA), and the International Cooperative Ataxia Rating Scale (ICARS) to a large cohort of people with Friedreich's ataxia. We provide regression coefficients for scale interconversion and discuss the reliability of this approach, together with insights into the differential sensitivities of mFARS and SARA to disease progression.

Spinal cord magnetic resonance imaging and spectroscopy detect early-stage alterations and disease progression in Friedreich ataxia.

Friedreich ataxia is the most common hereditary ataxia. Atrophy of the spinal cord is one of the hallmarks of the disease. MRI and magnetic resonance spectroscopy are powerful and non-invasive tools to investigate pathological changes in the spinal cord. A handful of studies have reported cross-sectional alterations in Friedreich ataxia using MRI and diffusion MRI. However, to our knowledge no longitudinal MRI, diffusion MRI or MRS results have been reported in the spinal cord. Here, we investigated early-stage cross-sectional alterations and longitudinal changes in the cervical spinal cord in Friedreich ataxia, using a multimodal magnetic resonance protocol comprising morphometric (anatomical MRI), microstructural (diffusion MRI), and neurochemical (1H-MRS) assessments.We enrolled 28 early-stage individuals with Friedreich ataxia and 20 age- and gender-matched controls (cross-sectional study). Disease duration at baseline was 5.5 ± 4.0 years and Friedreich Ataxia Rating Scale total neurological score at baseline was 42.7 ± 13.6. Twenty-one Friedreich ataxia participants returned for 1-year follow-up, and 19 of those for 2-year follow-up (cohort study). Each visit consisted in clinical assessments and magnetic resonance scans. Controls were scanned at baseline only. At baseline, individuals with Friedreich ataxia had significantly lower spinal cord cross-sectional area (−31%, P = 8 × 10−17), higher eccentricity (+10%, P = 5 × 10−7), lower total N-acetyl-aspartate (tNAA) (−36%, P = 6 × 10−9) and higher myo-inositol (mIns) (+37%, P = 2 × 10−6) corresponding to a lower ratio tNAA/mIns (−52%, P = 2 × 10−13), lower fractional anisotropy (−24%, P = 10−9), as well as higher radial diffusivity (+56%, P = 2 × 10−9), mean diffusivity (+35%, P = 10−8) and axial diffusivity (+17%, P = 4 × 10−5) relative to controls. Longitudinally, spinal cord cross-sectional area decreased by 2.4% per year relative to baseline (P = 4 × 10−4), the ratio tNAA/mIns decreased by 5.8% per year (P = 0.03), and fractional anisotropy showed a trend to decrease (−3.2% per year, P = 0.08). Spinal cord cross-sectional area correlated strongly with clinical measures, with the strongest correlation coefficients found between cross-sectional area and Scale for the Assessment and Rating of Ataxia (R = −0.55, P = 7 × 10−6) and between cross-sectional area and Friedreich ataxia Rating Scale total neurological score (R = −0.60, P = 4 × 10−7). Less strong but still significant correlations were found for fractional anisotropy and tNAA/mIns. We report here the first quantitative longitudinal magnetic resonance results in the spinal cord in Friedreich ataxia. The largest longitudinal effect size was found for spinal cord cross-sectional area, followed by tNAA/mIns and fractional anisotropy. Our results provide direct evidence that abnormalities in the spinal cord result not solely from hypoplasia, but also from neurodegeneration, and show that disease progression can be monitored non-invasively in the spinal cord.

Paving the Way Toward Meaningful Trials in Ataxias: An Ataxia Global Initiative Perspective.

Paving the Way Toward Meaningful Trials in Ataxias: An Ataxia Global Initiative Perspective.

Clinical evidence of interventions assessed in Friedreich ataxia: a systematic review.

The rare inherited autosomal recessive disease Friedreich ataxia (FA) causes progressive neurodegenerative changes and disability in patients. A systematic literature review (SLR) was carried out to understand and summarize the published efficacy and safety of therapeutic interventions in this disease. Database searches were carried out in MEDLINE, Embase, and Cochrane by two independent reviewers. In addition, trial registries and conference proceedings were hand-searched. Thirty-two publications were deemed eligible according to PICOS criteria. Twenty-four publications detail randomized controlled trials. The most frequently identified therapeutic intervention was idebenone (n = 11), followed by recombinant erythropoietin (n = 6), omaveloxolone (n = 3), and amantadine hydrochloride (n = 2). Other therapeutic interventions were investigated in one publication: A0001, CoQ10, creatine, deferiprone, interferon-γ-1b, the L-carnitine levorotatory form of 5-hydroxytryptophan, luvadaxistat, resveratrol, RT001, and vatiquinone (EPI-743). These studies included patients from 8 to 73 years old, and disease duration varied from 4.7 to 19 years. Disease severity as per the mean GAA1 and GAA2 allele repeat length ranged from 350 to 930 and 620 to 987 nucleotides, respectively. Most frequently reported efficacy outcomes were the International Cooperative Ataxia Rating Scale (ICARS, n = 10), the Friedreich Ataxia Rating Scale (modified FARS and FARS-neuro, n = 12), the Scale for Assessment and Rating of Ataxia (SARA, n = 7), and the Activities of Daily Living scale (ADL, n = 8). Each of these assesses the severity of disability in FA patients. In many studies, patients with FA deteriorated according to these severity scales regardless of treatment, or inconclusive results were found. Generally, these therapeutic interventions were well-tolerated and safe. Serious adverse events were atrial fibrillation (n = 1), craniocerebral injury (n = 1), and ventricular tachycardia (n = 1). Identified literature showed a considerable unmet need for therapeutic interventions that halt or slow the deteriorating nature of FA. Novel efficacious drugs should be investigated that aim to improve symptoms or slow disease progression.

The Responsiveness of Gait and Balance Outcomes to Disease Progression in Friedreich Ataxia

To identify gait and balance measures that are responsive to change during the timeline of a clinical trial in Friedreich ataxia (FRDA), we administered a battery of potential measures three times over a 12-month period. Sixty-one ambulant individuals with FRDA underwent assessment of gait and balance at baseline, 6 months and 12 months. Outcomes included GAITRite® spatiotemporal gait parameters; Biodex Balance System Postural Stability Test (PST) and Limits of Stability; Berg Balance Scale (BBS); Timed 25-Foot Walk Test; Dynamic Gait Index (DGI); SenseWear MF Armband step and energy activity; and the Friedreich Ataxia Rating Scale Upright Stability Subscale (FARS USS). The standardised response mean (SRM) or correlation coefficients were reported as effect size indices for comparison of internal responsiveness. Internal responsiveness was also analysed in subgroups. SenseWear Armband daily step count had the largest effect size of all the variables over 6 months (SRM = -0.615), while the PST medial-lateral index had the largest effect size (SRM = 0.829) over 12 months. The FARS USS (SRM = 0.824) and BBS (SRM = -0.720) were the only outcomes able to detect change over 12 months in all subgroups. The DGI was the most responsive outcome in children, detecting a mean change of -2.59 (95% CI -3.52 to -1.66, p < 0.001, SRM = -1.429). In conclusion, the FARS USS and BBS are highly responsive and can detect change in a wide range of ambulant individuals with FRDA. However, therapeutic effects in children may be best measured by the DGI.

Body Mass Index and Height in the Friedreich Ataxia Clinical Outcome Measures Study.

Background and ObjectivesBody mass index (BMI) and height are important indices of health. We tested the association between these outcomes and clinical characteristics in Friedreich ataxia (FRDA), a progressive neuromuscular disorder.MethodsParticipants (N = 961) were enrolled in a prospective natural history study (Friedreich Ataxia Clinical Outcome Measure Study). Age- and sex-specific BMI and height Z-scores were calculated using CDC 2000 references for participants younger than 18 years. For adults aged 18 years or older, height Z-scores were also calculated, and absolute BMI was reported. Univariate and multivariate linear regression analyses tested the associations between exposures, covariates, and BMI or height measured at the baseline visit. In children, the superimposition by translation and rotation analysis method was used to compare linear growth trajectories between FRDA and a healthy reference cohort, the Bone Mineral Density in Childhood Study (n = 1,535 used for analysis).ResultsMedian age at the baseline was 20 years (IQR, 13–33 years); 49% (n = 475) were women. A substantial proportion of children (17%) were underweight (BMI-Z < fifth percentile), and female sex was associated with lower BMI-Z (β = −0.34, p < 0.05). In adults, older age was associated with higher BMI (β = 0.09, p < 0.05). Regarding height, in children, older age (β −0.06, p < 0.05) and worse modified Friedreich Ataxia Rating Scale (mFARS) scores (β = −1.05 for fourth quartile vs first quartile, p < 0.01) were associated with shorter stature. In girls, the magnitude of the pubertal growth spurt was less, and in boys, the pubertal growth spurt occurred later (p < 0.001 for both) than in a healthy reference cohort. In adults, in unadjusted analyses, both earlier age of FRDA symptom onset (=0.09, p < 0.05) and longer guanine-adenine-adenine repeat length (shorter of the 2 GAA repeats, β = −0.12, p < 0.01) were associated with shorter stature. Both adults and children with higher mFARS scores and/or who were nonambulatory were less likely to have height and weight measurements recorded at clinical visits.DiscussionFRDA affects both weight gain and linear growth. These insights will inform assessments of affected individuals in both research and clinical settings.

Digital endpoints for self-administered home-based functional assessment in pediatric Friedreich's ataxia.

BackgroundFriedreich’s ataxia is an inherited, progressive, neurodegenerative disease that typically begins in childhood. Disease severity is commonly assessed with rating scales, such as the modified Friedreich’s Ataxia Rating Scale, which are usually administered in the clinic by a neurology specialist.ObjectiveThis study evaluated the utility of home‐based, self‐administered digital endpoints in children with Friedreich’s ataxia and unaffected controls and their relationship to standard clinical rating scales.MethodsIn a cross‐sectional study with 25 participants (13 with Friedreich’s ataxia and 12 unaffected controls, aged 6–15 years), home‐based digital endpoints that reflect activities of daily living were recorded over 1 week. Domains analyzed were hand motor function with a digitized drawing, automated analysis of speech with a recorded oral diadochokinesis test, and gait and balance with wearable sensors.ResultsHand‐drawing and speech tests were easy to conduct and generated high‐quality data. The sensor‐based gait and balance tests suffered from technical limitations in this study setup. Several parameters discriminated between groups or correlated strongly with modified Friedreich’s Ataxia Rating Scale total score and activities of daily living total score in the Friedreich’s ataxia group. Hand‐drawing parameters also strongly correlated with standard 9‐hole peg test scores.InterpretationDeploying digital endpoints in home settings is feasible in this population, results in meaningful and robust data collection, and may allow for frequent sampling over longer periods of time to track disease progression. Care must be taken when training participants, and investigators should consider the complexity of the tasks and equipment used.

Determining the Validity of Conducting Rating Scales in Friedreich Ataxia through Video.

The Friedreich Ataxia Rating Scale (FARS) and the Scale for the Assessment and Rating of Ataxia (SARA) are commonly used neurological rating scales in Friedreich ataxia (FRDA). The modified Friedreich Ataxia Rating Scale (mFARS) has been accepted as an appropriate outcome measure for clinical trials in FRDA. The COVID-19 pandemic has resulted in limited face-to-face interactions with individuals involved in natural history studies and clinical trials. The aim of this study was to determine the validity of conducting the mFARS and SARA through video. Individuals who had the mFARS administered face-to-face in the previous 6 months were invited to participate. Participants were sent instructions and asked to have a carer present to assist. The mFARS and SARA were then administered by video. Differences between face-to-face and video scores and the reliability between scores obtained face-to-face and by video were examined. The mFARS and SARA were conducted by video with 19 individuals. Excellent test-retest reliability was seen in the mFARS lower limb coordination (ICC=0.96, 95% CI 0.90-0.98) and upright stability sections (ICC=0.97, 95% CI 0.93-0.99), total mFARS (ICC=0.97, 95% CI 0.92-0.99) and SARA scores (ICC=0.98, 95% CI 0.95-0.99). Excellent test-retest reliability was demonstrated in the majority of the mFARS sections, and in the total mFARS and SARA scores, suggesting that video is a valid method of conducting these scales. This method enables inclusion of participants who are unable to travel to study sites. A larger cohort will be required to further validate the use of video mFARS and SARA for future studies.

Objective Assessment of Progression and Disease Characterization of Friedreich Ataxia via an Instrumented Drinking Cup: Preliminary Results.

The monitoring of disease progression in certain neurodegenerative conditions can significantly be quantified with the help of objective assessments. The severity assessment of diseases like Friedreich ataxia (FRDA) are usually based on different subjective measures. The ability of a participant with FRDA to perform standard neurological tests is the most common way of assessing disease progression. In this feasibility study, an Ataxia Instrumented Measurement-Cup (AIM-C) is proposed to quantify the disease progression of 10 participants (mean age 39 years, onset of disease 16.3 years) in longitudinal timepoints. The device consists of a sensing system with the provision of extracting both kinetic and kinematic information while engaging in an activity closely associated with activities of daily living (ADL). A common functional task of simulated drinking was used to capture features that possesses disease progression information as well as certain other features which intrinsically correlate with commonly used clinical scales such as the modified Friedreich Ataxia Rating Scale (mFARS), the Functional Staging of Ataxia score and the ADL scale. Frequency and time-frequency domain features allowed the longitudinal assessment of participants with FRDA. Furthermore, both kinetic and kinematic measures captured clinically relevant features and correlated 85% with clinical assessments.

Assessment of Ataxia Rating Scales and Cerebellar Functional Tests: Critique and Recommendations.

We assessed the clinimetric properties of ataxia rating scales and functional tests, and made recommendations regarding their use. A systematic literature search was conducted to identify the instruments used to rate ataxia symptoms. The identified rating scales and functional ability tests were reviewed and ranked by the panel as "recommended," "suggested," or "listed" for the assessment of patients with discrete cerebellar disorders, using previously established criteria. We reviewed 14 instruments (9 rating scales and 5 functional tests). "Recommended" rating scales for the assessment of symptoms severity were: for Friedreich's ataxia, the Friedreich's Ataxia Rating Scale, the International Cooperative Ataxia Rating Scale (ICARS), and the Scale for the Assessment and Rating of Ataxia (SARA); for spinocerebellar ataxias, ICARS and SARA; for ataxia telangiectasia: ICARS and SARA; for brain tumors, SARA; for congenital disorder of glycosylation-phosphomannomutase-2 deficiency, ICARS; for cerebellar symptoms in multiple sclerosis, ICARS; for cerebellar symptoms in multiple system atrophy: Unified Multiple System Atrophy Rating Scale and ICARS; and for fragile X-associated tremor ataxia syndrome, ICARS. "Recommended" functional tests were: for Friedreich's ataxia, Ataxia Functional Composite Score and Composite Cerebellar Functional Severity Score; and for spinocerebellar ataxias, Ataxia Functional Composite Score, Composite Cerebellar Functional Severity Score, and SCA Functional Index. We identified some "recommended" scales and functional tests for the assessment of patients with major hereditary ataxias and other cerebellar disorders. The main limitations of these instruments include the limited assessment of patients in the more severe end of the spectrum and children. Further research in these populations is warranted. © 2020 International Parkinson and Movement Disorder Society.

Test-retest reliability of the Friedreich's ataxia rating scale.

The modified Friedreich Ataxia Rating Scale (mFARS) is a disease specific, exam‐based neurological rating scale commonly used as a outcome measure in clinical trials. While extensive clinimetric testing indicates it’s validity in measuring disease progression, formal test–retest reliability was lacking. To fill this gap, we acquired results from screening and baseline visits of several large clinical trials and calculated intraclass correlation coefficients, coefficients of variance, standard error, and the minimally detectable changes. This study demonstrated excellent test–retest reliability of the mFARS, and it’s upright stability subscore.

Predictors of loss of ambulation in Friedreich's ataxia

BackgroundFriedreich's ataxia (FRDA) is a characterized by progressive loss of coordination and balance leading to loss of ambulation (LoA) in nearly all affected individuals. While transition to becoming fully wheelchair bound is a critical milestone in the disease course, it presents a particularly challenging prediction, mostly due to variability in inter- and intra-subject severity and progression. For these reasons, LoA or potential surrogates have been impractical as outcomes in clinical trials. MethodsWe studied progressive features leading to LoA in participants enrolled into the Friedreich's Ataxia Clinical Outcome Measures Study (FA-COMS), a natural history study with currently 4606 yearly follow up visits in 1021 patients. Loss of specific functions related to walking and standing of the neurological Friedreich Ataxia Rating Scale (FARS) exams were evaluated using time to event methods. To account for different severities, patients were stratified by age of disease onset. FindingsEarly onset FRDA patients (<15y of age) typically become fully wheelchair dependent at a median of 11.5y (25th, 75th percentiles 8.6y, 16.2y) after the onset of first symptoms. Further time to loss of function analyses revealed a unique pattern of function loss, in particular in stance/balance items of the FARS exam. Each step in this typical sequence predicts future risk of LoA and can be used to rank patients in their individual progression. InterpretationWe propose a stratification paradigm for time to LoA in FRDA. Concurrently, each step in a sequence of events represents a surrogate measure for future LoA. This will facilitate patient selection and stratification in clinical trials, and potentially enable study of LoA as a direct clinical outcome. FundingThis work was funded by the Friedreich's Ataxia Research alliance (FARA), www.curefa.org.