SARA captures disparate progression and responsiveness in spinocerebellar ataxias.

BACKGROUND: The Scale for Assessment and Rating of Ataxia (SARA) is a widely used clinical scale to assess cerebellar ataxia but faces some criticisms about the relevancy of all its items. OBJECTIVES: To prepare for future clinical trials, we analyzed the progression of SARA and its items in several polyQ spinocerebellar ataxias (SCA) from various cohorts. METHODS: We included data from patients with SCA1, SCA2, SCA3, and SCA6 from four cohorts (EUROSCA, RISCA, CRC-SCA, and SPATAX) for a total of 850 carriers and 3431 observations. Longitudinal progression of the SARA and its items was measured. Cohort, stage and genetic effects were tested. We looked at the respective contribution of each item to the total scale. Sensitivity to change of the scale and the impact of item removal was evaluated by calculating sample sizes needed in various scenarios. RESULTS: Longitudinal progression was significantly different between cohorts in SCA1, SCA2 and SCA3, the EUROSCA cohort having the fastest progression. Advanced-stage patients were progressing slower in SCA2 and SCA6. Items were not contributing equally to the full scale through ataxia severity: gait, stance, hand movement, and heel-shin contributed the most in the early stage, and finger-chase, nose-finger, and sitting in later stages. Few items drove the sensitivity to the change of SARA, but changes in the scale structure could not improve its sensitivity in all populations. CONCLUSION: SARA and its item's progression pace showed high heterogeneity across cohorts and SCAs. However, no combinations of items improved the responsiveness in all SCAs or populations taken separately.

Long non-coding RNA TUG1 is downregulated in Friedreich's ataxia.

Friedreich's ataxia is a neurodegenerative disorder caused by reduced frataxin levels. It leads to motor and sensory impairments and has a median life expectancy of around 35 years. As the most common inherited form of ataxia, Friedreich's ataxia lacks reliable, non-invasive biomarkers, prolonging and inflating the cost of clinical trials. This study proposes TUG1, a long non-coding RNA, as a promising blood-based biomarker for Friedreich's ataxia, which is known to regulate various cellular processes. In a previous study using a frataxin knockdown mouse model, we observed several hallmark Friedreich's ataxia symptoms. Building on this, we hypothesized that a dual-source approach-comparing the data from peripheral blood samples from Friedreich's ataxia patients with tissue samples from affected areas in Friedreich's ataxia knockdown mice, tissues usually unattainable from patients-would effectively identify robust biomarkers. A comprehensive reanalysis was conducted on gene expression data from 183 age- and sex-matched peripheral blood samples of Friedreich's ataxia patients, carriers and controls and 192 tissue data sets from Friedreich's ataxia knockdown mice. Blood and tissue samples underwent RNA isolation and quantitative reverse transcription polymerase chain reaction, and frataxin knockdown was confirmed through enzyme-linked immunosorbent assays. Tug1 RNA interaction was explored via RNA pull-down assays. Validation was performed in serum samples on an independent set of 45 controls and 45 Friedreich's ataxia patients and in blood samples from 66 heterozygous carriers and 72 Friedreich's ataxia patients. Tug1 and Slc40a1 emerged as potential blood-based biomarkers, confirmed in the Friedreich's ataxia knockdown mouse model (one-way ANOVA, P ≤ 0.05). Tug1 was consistently downregulated after Fxn knockdown and correlated strongly with Fxn levels (R 2 = 0.71 during depletion, R 2 = 0.74 during rescue). Slc40a1 showed a similar but tissue-specific pattern. Further validation of Tug1's downstream targets strengthened its biomarker candidacy. In additional human samples, TUG1 levels were significantly downregulated in both whole blood and serum of Friedreich's ataxia patients compared with controls (Wilcoxon signed-rank test, P < 0.05). Regression analyses revealed a negative correlation between TUG1 fold-change and disease onset (P < 0.0037) and positive correlations with disease duration and functional disability stage score (P < 0.04). This suggests that elevated TUG1 levels correlate with earlier onset and more severe cases. This study identifies TUG1 as a potential blood-based biomarker for Friedreich's ataxia, showing consistent expression variance in human and mouse tissues related to disease severity and key Friedreich's ataxia pathways. It correlates with frataxin levels, indicating its promise as an early, non-invasive marker. TUG1 holds potential for Friedreich's ataxia monitoring and therapeutic development, meriting additional research.

Video-Based Kinematic Analysis of Movement Quality in a Phase 3 Clinical Trial of Troriluzole in Adults with Spinocerebellar Ataxia: A Post Hoc Analysis.

INTRODUCTION: Traditional methods for assessing movement quality rely on subjective standardized scales and clinical expertise. This limitation creates challenges for assessing patients with spinocerebellar ataxia (SCA), in whom changes in mobility can be subtle and varied. We hypothesized that a machine learning analytic system might complement traditional clinician-rated measures of gait. Our objective was to use a video-based assessment of gait dispersion to compare the effects of troriluzole with placebo on gait quality in adults with SCA. METHODS: Participants with SCA underwent gait assessment in a phase 3, double-blind, placebo-controlled trial of troriluzole (NCT03701399). Videos were processed through a deep learning pose extraction algorithm, followed by the estimation of a novel gait stability measure, the Pose Dispersion Index, quantifying the frame-by-frame symmetry, balance, and stability during natural and tandem walk tasks. The effects of troriluzole treatment were assessed in mixed linear models, participant-level grouping, and treatment group-by-visit week interaction adjusted for age, sex, baseline modified Functional Scale for the Assessment and Rating of Ataxia (f-SARA), and time since diagnosis. RESULTS: From 218 randomized participants, 67 and 56 participants had interpretable videos of a tandem and natural walk attempt, respectively. At Week 48, individuals assigned to troriluzole exhibited significant (p = 0.010) improvement in tandem walk Pose Dispersion Index versus placebo {adjusted interaction coefficient: 0.584 [95% confidence interval (CI) 0.137 to 1.031]}. A similar, nonsignificant trend was observed in the natural walk assessment [coefficient: 1.198 (95% CI - 1.067 to 3.462)]. Further, lower baseline Pose Dispersion Index during the natural walk was significantly (p = 0.041) associated with a higher risk of subsequent falls [adjusted Poisson coefficient: - 0.356 [95% CI - 0.697 to - 0.014)]. CONCLUSION: Using this novel approach, troriluzole-treated subjects demonstrated improvement in gait as compared to placebo for the tandem walk. Machine learning applied to video-captured gait parameters can complement clinician-reported motor assessment in adults with SCA. The Pose Dispersion Index may enhance assessment in future research. TRIAL REGISTRATION-CLINICALTRIALS. GOV IDENTIFIER: NCT03701399.

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.

Content Validity of the Modified Functional Scale for the Assessment and Rating of Ataxia (f-SARA) Instrument in Spinocerebellar Ataxia.

The functional Scale for the Assessment and Rating of Ataxia (f-SARA) assesses Gait, Stance, Sitting, and Speech. It was developed as a potentially clinically meaningful measure of spinocerebellar ataxia (SCA) progression for clinical trial use. Here, we evaluated content validity of the f-SARA. Qualitative interviews were conducted among individuals with SCA1 (n = 1) and SCA3 (n = 6) and healthcare professionals (HCPs) with SCA expertise (USA, n = 5; Europe, n = 3). Interviews evaluated symptoms and signs of SCA and relevance of f-SARA concepts for SCA. HCP cognitive debriefing was conducted. Interviews were recorded, transcribed, coded, and analyzed by ATLAS.TI software. Individuals with SCA1 and 3 reported 85 symptoms, signs, and impacts of SCA. All indicated difficulties with walking, stance, balance, speech, fatigue, emotions, and work. All individuals with SCA1 and 3 considered Gait, Stance, and Speech relevant f-SARA concepts; 3 considered Sitting relevant (42.9%). All HCPs considered Gait and Speech relevant; 5 (62.5%) indicated Stance was relevant. Sitting was considered a late-stage disease indicator. Most HCPs suggested inclusion of appendicular items would enhance clinical relevance. Cognitive debriefing supported clarity and comprehension of f-SARA. Maintaining current abilities on f-SARA items for 1 year was considered meaningful for most individuals with SCA1 and 3. All HCPs considered meaningful changes as stability in f-SARA score over 1-2 years, 1-2-point change in total f-SARA score, and deviation from natural history. These results support content validity of f-SARA for assessing SCA disease progression in clinical trials.

CRPD frontiers in movement disorders Therapeutics: From evidence to treatment and applications: Addressing Patients' Needs in the Management of the Ataxias.

The genetic ataxias have no cures and no proven ways to delay progression (no disease-modifying therapies). The acquired ataxias may have treatments that address the underlying cause and may slow or stop progression, but will not reverse damage already sustained. The idiopathic ataxias (of unknown genetic or acquired cause) also have no proven disease-modifying therapies. However, for all patients with ataxia of any cause, there is always something that can be done to improve quality of life-treat associated symptoms, provide information and resources, counsel patient and family, help with insurance and disability concerns, be available to listen and answer the many questions they will have.

Evaluating mFARS in pediatric Friedreich's ataxia: Insights from the FACHILD study.

OBJECTIVES: Friedreich ataxia (FRDA) is a rare genetic disorder caused by mutations in the FXN gene, leading to progressive coordination loss and other symptoms. The recently approved omaveloxolone targets this condition but is limited to patients over 16 years of age, highlighting the need for pediatric treatments due to the disorder's early onset and more rapid progression in children. This population also experiences increased non-neurological complications; the FACHILD study aimed to augment and expand the knowledge about the natural history of the disease and clinical outcome assessments for trials in children in FRDA. METHODS: The study enrolled 108 individuals aged 7-18 years with a confirmed FRDA diagnosis, with visits occurring from October 2017 to November 2022 across three institutions. Several measures were introduced to minimize the impact of the COVID-19 pandemic, including virtual visits. Outcome measures centered on the mFARS score and its subscores, and data were analyzed using mixed models for repeated measures. For context and to avoid misinterpretation, the analysis was augmented with data from patients enrolled in the Friedreich's Ataxia Clinical Outcome Measures Study. RESULTS: Results confirmed the general usefulness of the mFARS score in children, but also highlighted issues, particularly with the upper limb subscore (FARS B). Increased variability, limited homogeneity across study subgroups, and potential training effects might limit mFARS application in clinical trials in pediatric populations. INTERPRETATION: The FARS E (Upright Stability) score might be a preferred outcome measure in this patient population.

Characterization of Cardiac-Onset Initial Presentation in Friedreich Ataxia.

We examined the clinical features of Friedreich ataxia (FRDA) patients who present first with cardiac disease in order to understand the earliest features of the diagnostic journey in FRDA. We identified a group of subjects in the FACOMS natural history study whose first identified clinical feature was cardiac. Only 0.5% of the total cohort belonged to this group, which was younger on average at the time of presentation. Their cardiac symptoms ranged from asymptomatic features to heart failure with severe systolic dysfunction. Two of those individuals with severe dysfunction proceeded to heart transplantation, but others spontaneously recovered. In most cases, diagnosis of FRDA was not made until well after cardiac presentation. The present study shows that some FRDA patients present based on cardiac features, suggesting that earlier identification of FRDA might occur through enhancing awareness of FRDA among pediatric cardiologists who see such patients. This is important in the context of newly identified therapies for FRDA.

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

BACKGROUND: Progressive loss of standing balance is a feature of Friedreich's ataxia (FRDA). OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

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.

Irritability in Youths: A Critical Integrative Review.

Irritability, defined as proneness to anger that may impair an individual's functioning, is common in youths. There has been a recent upsurge in relevant research. The authors combine systematic and narrative review approaches to integrate the latest clinical and translational findings and provide suggestions for addressing research gaps. Clinicians and researchers should assess irritability routinely, and specific assessment tools are now available. Informant effects are prominent, are stable, and vary by age and gender. The prevalence of irritability is particularly high among individuals with attention deficit hyperactivity disorder, autism spectrum disorder, and mood and anxiety disorders. Irritability is associated with impairment and suicidality risk independent of co-occurring diagnoses. Developmental trajectories of irritability (which may begin early in life) have been identified and are differentially associated with clinical outcomes. Youth irritability is associated with increased risk of anxiety, depression, behavioral problems, and suicidality later in life. Irritability is moderately heritable, and genetic associations differ based on age and comorbid illnesses. Parent management training is effective for treating psychological problems related to irritability, but its efficacy in treating irritability should be tested rigorously, as should novel mechanism-informed interventions (e.g., those targeting exposure to frustration). Associations between irritability and suicidality and the impact of cultural context are important, underresearched topics. Analyses of large, diverse longitudinal samples that extend into adulthood are needed. Data from both animal and human research indicate that aberrant responses to frustration and threat are central to the pathophysiology of irritability, revealing important translational opportunities.

Digital Measures of Postural Sway Quantify Balance Deficits in Spinocerebellar Ataxia.

BACKGROUND: Maintaining balance is crucial for independence and quality of life. Loss of balance is a hallmark of spinocerebellar ataxia (SCA). OBJECTIVE: The aim of this study was to identify which standing balance conditions and digital measures of body sway were most discriminative, reliable, and valid for quantifying balance in SCA. METHODS: Fifty-three people with SCA (13 SCA1, 13 SCA2, 14 SCA3, and 13 SCA6) and Scale for Assessment and Rating of Ataxia (SARA) scores 9.28 ± 4.36 and 31 healthy controls were recruited. Subjects stood in six test conditions (natural stance, feet together and tandem, each with eyes open [EO] and eyes closed [EC]) with an inertial sensor on their lower back for 30 seconds (×2). We compared test completion rate, test-retest reliability, and areas under the receiver operating characteristic curve (AUC) for seven digital sway measures. Pearson's correlations related sway with the SARA and the Patient-Reported Outcome Measure of Ataxia (PROM ataxia). RESULTS: Most individuals with SCA (85%-100%) could stand for 30 seconds with natural stance EO or EC, and with feet together EO. The most discriminative digital sway measures (path length, range, area, and root mean square) from the two most reliable and discriminative conditions (natural stance EC and feet together EO) showed intraclass correlation coefficients from 0.70 to 0.91 and AUCs from 0.83 to 0.93. Correlations of sway with SARA were significant (maximum r = 0.65 and 0.73). Correlations with PROM ataxia were mild to moderate (maximum r = 0.56 and 0.34). CONCLUSION: Inertial sensor measures of extent of postural sway in conditions of natural stance EC and feet together stance EO were discriminative, reliable, and valid for monitoring SCA. © 2024 International Parkinson and Movement Disorder Society.

Omaveloxolone for the treatment of Friedreich ataxia: clinical trial results and practical considerations.

INTRODUCTION: Omavaloxolone, an NRF2 activator, recently became the first drug approved specifically for the treatment of Friedreich ataxia (FRDA). This landmark achievement provides a background for a review of the detailed data leading to the approval. AREAS COVERED: The authors review the data from the 4 major articles on FRDA in the context of the authors' considerable (>1000 patients) experience in treating individuals with FRDA. The data is presented in the context not only of its scientific meaning but also in the practical context of therapy in FRDA. EXPERT OPINION: Omaveloxolone provides a significant advance in the treatment of FRDA that is likely to be beneficial in a majority of the FRDA population. The data suggesting a benefit is consistent, and adverse issues are relatively modest. The major remaining questions are the subgroups that are most responsive and how long the beneficial effects will remain significant in FRDA patients.

The Cerebellar Cognitive Affective/Schmahmann Syndrome Scale in Spinocerebellar Ataxias.

The Cerebellar Cognitive Affective/Schmahmann Syndrome (CCAS) manifests as impaired executive control, linguistic processing, visual spatial function, and affect regulation. The CCAS has been described in the spinocerebellar ataxias (SCAs), but its prevalence is unknown. We analyzed results of the CCAS/Schmahmann Scale (CCAS-S), developed to detect and quantify CCAS, in two natural history studies of 309 individuals Symptomatic for SCA1, SCA2, SCA3, SCA6, SCA7, or SCA8, 26 individuals Pre-symptomatic for SCA1 or SCA3, and 37 Controls. We compared total raw scores, domain scores, and total fail scores between Symptomatic, Pre-symptomatic, and Control cohorts, and between SCA types. We calculated scale sensitivity and selectivity based on CCAS category designation among Symptomatic individuals and Controls, and correlated CCAS-S performance against age and education, and in Symptomatic patients, against genetic repeat length, onset age, disease duration, motor ataxia, depression, and fatigue. Definite CCAS was identified in 46% of the Symptomatic group. False positive rate among Controls was 5.4%. Symptomatic individuals had poorer global CCAS-S performance than Controls, accounting for age and education. The domains of semantic fluency, phonemic fluency, and category switching that tap executive function and linguistic processing consistently separated Symptomatic individuals from Controls. CCAS-S scores correlated most closely with motor ataxia. Controls were similar to Pre-symptomatic individuals whose nearness to symptom onset was unknown. The use of the CCAS-S identifies a high CCAS prevalence in a large cohort of SCA patients, underscoring the utility of the scale and the notion that the CCAS is the third cornerstone of clinical ataxiology.

Quantitative Oculomotor Assessment in Hereditary Ataxia: Discriminatory Power, Correlation with Severity Measures, and Recommended Parameters for Specific Genotypes.

Characterizing bedside oculomotor deficits is a critical factor in defining the clinical presentation of hereditary ataxias. Quantitative assessments are increasingly available and have significant advantages, including comparability over time, reduced examiner dependency, and sensitivity to subtle changes. To delineate the potential of quantitative oculomotor assessments as digital-motor outcome measures for clinical trials in ataxia, we searched MEDLINE for articles reporting on quantitative eye movement recordings in genetically confirmed or suspected hereditary ataxias, asking which paradigms are most promising for capturing disease progression and treatment response. Eighty-nine manuscripts identified reported on 1541 patients, including spinocerebellar ataxias (SCA2, n = 421), SCA3 (n = 268), SCA6 (n = 117), other SCAs (n = 97), Friedreich ataxia (FRDA, n = 178), Niemann-Pick disease type C (NPC, n = 57), and ataxia-telangiectasia (n = 85) as largest cohorts. Whereas most studies reported discriminatory power of oculomotor assessments in diagnostics, few explored their value for monitoring genotype-specific disease progression (n = 2; SCA2) or treatment response (n = 8; SCA2, FRDA, NPC, ataxia-telangiectasia, episodic-ataxia 4). Oculomotor parameters correlated with disease severity measures including clinical scores (n = 18 studies (SARA: n = 9)), chronological measures (e.g., age, disease duration, time-to-symptom onset; n = 17), genetic stratification (n = 9), and imaging measures of atrophy (n = 5). Recurrent correlations across many ataxias (SCA2/3/17, FRDA, NPC) suggest saccadic eye movements as potentially generic quantitative oculomotor outcome. Recommendation of other paradigms was limited by the scarcity of cross-validating correlations, except saccadic intrusions (FRDA), pursuit eye movements (SCA17), and quantitative head-impulse testing (SCA3/6). This work aids in understanding the current knowledge of quantitative oculomotor parameters in hereditary ataxias, and identifies gaps for validation as potential trial outcome measures in specific ataxia genotypes.

Frataxin analysis using triple quadrupole mass spectrometry: application to a large heterogeneous clinical cohort.

BACKGROUND: Friedreich ataxia is a progressive multisystem disorder caused by deficiency of the protein frataxin; a small mitochondrial protein involved in iron sulfur cluster synthesis. Two types of frataxin exist: FXN-M, found in most cells, and FXN-E, found almost exclusively in red blood cells. Treatments in clinical trials include frataxin restoration by gene therapy, protein replacement, and epigenetic therapies, all of which necessitate sensitive assays for assessing frataxin levels. METHODS: In the present study, we have used a triple quadrupole mass spectrometry-based assay to examine the features of both types of frataxin levels in blood in a large heterogenous cohort of 106 patients with FRDA. RESULTS: Frataxin levels (FXN-E and FXN M) were predicted by GAA repeat length in regression models (R2 values = 0.51 and 0.27, respectively), and conversely frataxin levels predicted clinical status as determined by modified Friedreich Ataxia Rating scale scores and by disability status (R2 values = 0.13-0.16). There was no significant change in frataxin levels in individual subjects over time, and apart from start codon mutations, FXN-E and FXN-M levels were roughly equal. Accounting for hemoglobin levels in a smaller sub-cohort improved prediction of both FXN-E and FXN-M levels from R2 values of (0.3-0.38 to 0.20-0.51). CONCLUSION: The present data show that assay of FXN-M and FXN-E levels in blood provides an appropriate biofluid for assessing their repletion in particular clinical contexts.

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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). INTERPRETATION: 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.

A network approach to the investigation of childhood irritability: probing frustration using social stimuli.

BACKGROUND: Self-regulation in early childhood develops within a social context. Variations in such development can be attributed to inter-individual behavioral differences, which can be captured both as facets of temperament and across a normal:abnormal dimensional spectrum. With increasing emphasis on irritability as a robust early-life transdiagnostic indicator of broad psychopathological risk, linkage to neural mechanisms is imperative. Currently, there is inconsistency in the identification of neural circuits that underlie irritability in children, especially in social contexts. This study aimed to address this gap by utilizing a functional magnetic resonance imaging (fMRI) paradigm to investigate pediatric anger/frustration using social stimuli. METHODS: Seventy-three children (M = 6 years, SD = 0.565) were recruited from a larger longitudinal study on irritability development. Caregivers completed questionnaires assessing irritable temperament and clinical symptoms of irritability. Children participated in a frustration task during fMRI scanning that was designed to induce frustration through loss of a desired prize to an animated character. Data were analyzed using both general linear modeling (GLM) and independent components analysis (ICA) and examined from the temperament and clinical perspectives. RESULTS: ICA results uncovered an overarching network structure above and beyond what was revealed by traditional GLM analyses. Results showed that greater temperamental irritability was associated with significantly diminished spatial extent of activation and low-frequency power in a network comprised of the posterior superior temporal sulcus (pSTS) and the precuneus (p < .05, FDR-corrected). However, greater severity along the spectrum of clinical expression of irritability was associated with significantly increased extent and intensity of spatial activation as well as low- and high-frequency neural signal power in the right caudate (p < .05, FDR-corrected). CONCLUSIONS: Our findings point to specific neural circuitry underlying pediatric irritability in the context of frustration using social stimuli. Results suggest that a deliberate focus on the construction of network-based neurodevelopmental profiles and social interaction along the normal:abnormal irritability spectrum is warranted to further identify comprehensive transdiagnostic substrates of the irritability.

Using Smartphone Sensors for Ataxia Trials: Consensus Guidance by the Ataxia Global Initiative Working Group on Digital-Motor Biomarkers.

Smartphone sensors are used increasingly in the assessment of ataxias. To date, there is no specific consensus guidance regarding a priority set of smartphone sensor measurements, or standard assessment criteria that are appropriate for clinical trials. As part of the Ataxia Global Initiative Digital-Motor Biomarkers Working Group (AGI WG4), aimed at evaluating key ataxia clinical domains (gait/posture, upper limb, speech and oculomotor assessments), we provide consensus guidance for use of internal smartphone sensors to assess key domains. Guidance was developed by means of a literature review and a two stage Delphi study conducted by an Expert panel, which surveyed members of AGI WG4, representing clinical, research, industry and patient-led experts, and consensus meetings by the Expert panel to agree on standard criteria and map current literature to these criteria. Seven publications were identified that investigated ataxias using internal smartphone sensors. The Delphi 1 survey ascertained current practice, and systems in use or under development. Wide variations in smartphones sensor use for assessing ataxia were identified. The Delphi 2 survey identified seven measures that were strongly endorsed as priorities in assessing 3/4 domains, namely gait/posture, upper limb, and speech performance. The Expert panel recommended 15 standard criteria to be fulfilled in studies. Evaluation of current literature revealed that none of the studies met all criteria, with most being early-phase validation studies. Our guidance highlights the importance of consensus, identifies priority measures and standard criteria, and will encourage further research into the use of internal smartphone sensors to measure ataxia digital-motor biomarkers.

Disparities in Huntington Disease Severity: Analysis Using the ENROLL-HD Dataset.

Background and Objectives: Social and structural determinants of health (SDOH) have been associated with disability in neurologic diseases. However, the association between these factors and disability in Huntington disease (HD) has not been studied. This study aimed to evaluate the association of racial and sociodemographic factors with disease severity in patients with HD in North America. Methods: We conducted a cross-sectional study of genetically confirmed participants with HD (36+ CAG repeats) in the North American region using the ENROLL-HD 2020 periodic dataset. In this analysis, our exposure variable was the participant's race/ethnicity. The main outcome measure was disease severity, as measured by the Total Functional Capacity Score (TFC), which measures the level of disability of patients with HD. We used multivariate regression models to adjust for sociodemographic factors that may mediate or moderate a causal effect between race/ethnicity and disease severity. Results: Among 4,717 gene-positive participants in the North American region, 89.5% identified as White, 3.4% as Hispanic or Latino, and 2.3% as African American/Black. The average TFC score was 10.22 (SD 3.22); 48% of participants completed either secondary education (including college) or a professional degree, and 55% lived in a city and not in a town, village, or rural location. In multivariate regression models, we found that Black participants and those with less than a high school degree entered the ENROLL-HD study with lower TFC scores than White participants. We also found that compared with those with at least a high school degree, those who completed some form of higher education or professional degree had higher TFC scores (p < 0.001). This multivariate analysis did not find an association between geographic location and TFC score. Discussion: Our study found that Black participants in North America presented to ENROLL-HD with more advanced disease than White patients. We also found that higher education was associated with less advanced disease when entering the ENROLL-HD study. The role of race/ethnicity and education in HD symptom severity warrants further investigation. These findings underscore the importance of further studying the role of social and structural determinants of health in patients with HD, particularly those from historically marginalized communities.