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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. [ABSTRACT FROM AUTHOR]

Upper limb function for people with Friedreich ataxia determines capacity to participate in daily activities. Current upper limb measures available do not fully capture impairments related to Friedreich ataxia. We have developed an objective measure, the Ataxia Instrumented Measure–Spoon (AIM-S), which consists of a spoon equipped with a BioKin wireless motion capture device, and algorithms that analyse these signals, to measure ataxia of the upper limb during the pre-oral phase of eating. The aim of this study was to evaluate the AIM-S as a sensitive and functionally relevant clinical outcome for use in clinical trials. A prospective longitudinal study evaluated the capacity of the AIM-S to detect change in upper limb function over 48 weeks. Friedreich ataxia clinical severity, performance on the Nine-Hole Peg Test and Box and Block Test and responses to a purpose-designed questionnaire regarding acceptability of AIM-S were recorded. Forty individuals with Friedreich ataxia and 20 control participants completed the baseline assessment. Thirty individuals with Friedreich ataxia completed the second assessment. The sensitivity of the AIM-S to detect deterioration in upper limb function was greater than other measures. Patient-reported outcomes indicated the AIM-S reflected a daily activity and was more enjoyable to complete than other assessments. The AIM-S is a more accurate, less variable measure of upper limb function in Friedreich ataxia than existing measures. The AIM-S is perceived by individuals with Friedreich ataxia to be related to everyday life and will permit individuals who are non-ambulant to be included in future clinical trials. [ABSTRACT FROM AUTHOR]

Friedreich ataxia (FRDA) has been associated with functional abnormalities in cerebral and cerebellar networks, particularly in the ventral attention network. However, how functional alterations change with disease progression remains largely unknown. Longitudinal changes in brain activation, associated with working memory performance (N-back task), and grey matter volume were assessed over 24 months in 21 individuals with FRDA and 28 healthy controls using functional and structural magnetic resonance imaging, respectively. Participants also completed a neurocognitive battery assessing working memory (digit span), executive function (Stroop, Haylings), and set-shifting (Trail Making Test). Individuals with FRDA displayed significantly increased brain activation over 24 months in ventral attention brain regions, including bilateral insula and inferior frontal gyrus (pars triangularis and pars opercularis), compared with controls, but there was no difference in working memory (N-back) performance between groups. Moreover, there were no significant differences in grey matter volume changes between groups. Significant correlations between brain activations and both clinical severity and age at disease onset were observed in FRDA individuals only at 24 months. There was significant longitudinal decline in Trail Making Test (TMT) difference score (B-A) in individuals with FRDA, compared with controls. These findings provide the first evidence of increased longitudinal activation over time in the cerebral cortex in FRDA, compared with controls, despite comparable working memory performance. This finding represents a possible compensatory response in the ventral attention network to help sustain working memory performance in individuals with FRDA. [ABSTRACT FROM AUTHOR]

Friedreich ataxia (FRDA) is the most common genetic cause of ataxia with a prevalence of approximately 1 in 29,000. Ocular motor abnormalities are common in FRDA and include fixation instability, saccadic dysmetria, and vestibular dysfunction. It has not yet been determined whether aspects of spatial attention, which are closely coupled to eye movements, are similarly compromised in FRDA. This study examined attentional engagement and disengagement of eye movements in FRDA using a gap overlap task. Thirteen individuals with genetically confirmed FRDA and 12 age-matched unaffected controls participated in the experiment. The gap overlap paradigm was used to examine the effect of early (gap condition), simultaneous (null condition), or late (overlap condition) removal of a central fixation on saccadic latency to a peripheral target stimulus. Although the FRDA group showed a larger gap effect (i.e., difference in saccadic latencies between the overlap and gap condition), these participants demonstrated a greater difference in latencies in the overlap relative to the null condition, suggestive of deficits within the disengagement process of attentional orienting. We propose a role for the cerebellum in these deficits in the disengagement of spatial attention based on evidence of cerebellar connectivity with regions involved in exogenous shifts of attention. The significant correlations between saccadic latency and disease severity as measured by the Friedreich Ataxia Rating Scale further support the proposal that saccadic latency might be useful as a surrogate marker of disease severity and progression in future clinical trials in FRDA. [ABSTRACT FROM AUTHOR]

Cerebellar pathology engenders the disturbance of movement that characterizes Friedreich ataxia (FRDA), yet the impact of cerebellar pathology on cognition in FRDA remains unclear. Numerous studies have unequivocally demonstrated the role of the cerebellar pathology in disturbed cognitive, language and affective regulation, referred to as Cerebellar Cognitive Affective Syndrome (CCAS), and quantified by the CCAS-Scale (CCAS-S). The presence of dysarthria in many individuals with ataxia, particularly FRDA, may confound results on some items of the CCAS-S resulting in false-positive scores. This study explored the relationship between performance on the CCAS-S and clinical metrics of disease severity in 57 adults with FRDA. In addition, this study explored the relationship between measures of intelligibility and naturalness of speech and scores on the CCAS-S in a subgroup of 39 individuals with FRDA. We demonstrated a significant relationship between clinical metrics and performance on the CCAS-S. In addition, we confirmed the items that returned the greatest rate of failure were based on Verbal Fluency Tasks, revealing a significant relationship between these items and measures of speech. Measures of speech explained over half of the variance in the CCAS-S score suggesting the role of dysarthria in the performance on the CCAS-S is not clear. Further work is required prior to adopting the CCAS-S as a cognitive screening tool for individuals with FRDA. [ABSTRACT FROM AUTHOR]