Free-Water Imaging in Friedreich Ataxia Using Multi-Compartment Models.

BACKGROUND: The neurological phenotype of Friedreich ataxia (FRDA) is characterized by neurodegeneration and neuroinflammation in the cerebellum and brainstem. Novel neuroimaging approaches quantifying brain free-water using diffusion magnetic resonance imaging (dMRI) are potentially more sensitive to these processes than standard imaging markers. OBJECTIVES: To quantify the extent of free-water and microstructural change in FRDA-relevant brain regions using neurite orientation dispersion and density imaging (NODDI), and bitensor diffusion tensor imaging (btDTI). METHOD: Multi-shell dMRI was acquired from 14 individuals with FRDA and 14 controls. Free-water measures from NODDI (FISO) and btDTI (FW) were compared between groups in the cerebellar cortex, dentate nuclei, cerebellar peduncles, and brainstem. The relative sensitivity of the free-water measures to group differences was compared to microstructural measures of NODDI intracellular volume, free-water corrected fractional anisotropy, and conventional uncorrected fractional anisotropy. RESULTS: In individuals with FRDA, FW was elevated in the cerebellar cortex, peduncles (excluding middle), dentate, and brainstem (P < 0.005). FISO was elevated primarily in the cerebellar lobules (P < 0.001). On average, FW effect sizes were larger than all other markers (mean ηρ 2 = 0.43), although microstructural measures also had very large effects in the superior and inferior cerebellar peduncles and brainstem (ηρ 2 > 0.37). Across all regions and metrics, effect sizes were largest in the superior cerebellar peduncles (ηρ 2 > 0.46). CONCLUSIONS: Multi-compartment diffusion measures of free-water and neurite integrity distinguish FRDA from controls with large effects. Free-water magnitude in the brainstem and cerebellum provided the greatest distinction between groups. This study supports further applications of multi-compartment diffusion modeling, and investigations of free-water as a measure of disease expression and progression in FRDA. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Localized Changes in Dentate Nucleus Shape and Magnetic Susceptibility in Friedreich Ataxia.

BACKGROUND: The dentate nuclei of the cerebellum are key sites of neuropathology in Friedreich ataxia (FRDA). Reduced dentate nucleus volume and increased mean magnetic susceptibility, a proxy of iron concentration, have been reported by magnetic resonance imaging studies in people with FRDA. Here, we investigate whether these changes are regionally heterogeneous. METHODS: Quantitative susceptibility mapping data were acquired from 49 people with FRDA and 46 healthy controls. The dentate nuclei were manually segmented and analyzed using three dimensional vertex-based shape modeling and voxel-based assessments to identify regional changes in morphometry and susceptibility, respectively. RESULTS: Individuals with FRDA, relative to healthy controls, showed significant bilateral surface contraction most strongly at the rostral and caudal boundaries of the dentate nuclei. The magnitude of this surface contraction correlated with disease duration, and to a lesser extent, ataxia severity. Significantly greater susceptibility was also evident in the FRDA cohort relative to controls, but was instead localized to bilateral dorsomedial areas, and also correlated with disease duration and ataxia severity. CONCLUSIONS: Changes in the structure of the dentate nuclei in FRDA are not spatially uniform. Atrophy is greatest in areas with high gray matter density, whereas increases in susceptibility-reflecting iron concentration, demyelination, and/or gliosis-predominate in the medial white matter. These findings converge with established histological reports and indicate that regional measures of dentate nucleus substructure are more sensitive measures of disease expression than full-structure averages. Biomarker development and therapeutic strategies that directly target the dentate nuclei, such as gene therapies, may be optimized by targeting these areas of maximal pathology. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The Role of Verbal Fluency in the Cerebellar Cognitive Affective Syndrome Scale in Friedreich Ataxia.

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.

Progressive Spinal Cord Degeneration in Friedreich's Ataxia: Results from ENIGMA-Ataxia.

BACKGROUND: Spinal cord damage is a hallmark of Friedreich's ataxia (FRDA), but its progression and clinical correlates remain unclear. OBJECTIVE: The objective of this study was to perform a characterization of cervical spinal cord structural damage in a large multisite FRDA cohort. METHODS: We performed a cross-sectional analysis of cervical spinal cord (C1-C4) cross-sectional area (CSA) and eccentricity using magnetic resonance imaging data from eight sites within the ENIGMA-Ataxia initiative, including 256 individuals with FRDA and 223 age- and sex-matched control subjects. Correlations and subgroup analyses within the FRDA cohort were undertaken based on disease duration, ataxia severity, and onset age. RESULTS: Individuals with FRDA, relative to control subjects, had significantly reduced CSA at all examined levels, with large effect sizes (d > 2.1) and significant correlations with disease severity (r < -0.4). Similarly, we found significantly increased eccentricity (d > 1.2), but without significant clinical correlations. Subgroup analyses showed that CSA and eccentricity are abnormal at all disease stages. However, although CSA appears to decrease progressively, eccentricity remains stable over time. CONCLUSIONS: Previous research has shown that increased eccentricity reflects dorsal column (DC) damage, while decreased CSA reflects either DC or corticospinal tract (CST) damage, or both. Hence our data support the hypothesis that damage to the DC and damage to CST follow distinct courses in FRDA: developmental abnormalities likely define the DC, while CST alterations may be both developmental and degenerative. These results provide new insights about FRDA pathogenesis and indicate that CSA of the cervical spinal cord should be investigated further as a potential biomarker of disease progression. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Interrater Reliability of the Scale for the Assessment and Rating of Ataxia, Berg Balance Scale, and Functional Independence Measure Motor Domain in Individuals With Hereditary Cerebellar Ataxia.

OBJECTIVE: To determine the interrater reliability of the Scale for the Assessment and Rating of Ataxia (SARA), Berg Balance Scale (BBS), and motor domain of the FIM (m-FIM) administered by physiotherapists in individuals with a hereditary cerebellar ataxia (HCA). DESIGN: Participants were assessed by 1 of 4 physiotherapists. Assessments were video-recorded and the remaining 3 physiotherapists scored the scales for each participant. Raters were blinded to each other's scores. SETTING: Assessments were administered at 3 clinical locations in separate states in Australia. PARTICIPANTS: Twenty-one individuals (mean age=47.63 years; SD=18.42; 13 male and 8 female) living in the community with an HCA were recruited (N=21). MAIN OUTCOME MEASURES: Total and single-item scores of the SARA, BBS, and m-FIM were examined. The m-FIM was conducted by interview. RESULTS: Intraclass coefficients (2,1) for the total scores of the m-FIM (0.92; 95% confidence interval [CI], 0.85-0.96), SARA (0.92; 95% CI, 0.86-0.96), and BBS (0.99; 95% CI, 0.98-0.99) indicated excellent interrater reliability. However, there was inconsistent agreement with the individual items, with SARA item 5 (right side) and item 7 (both sides) demonstrating poor interrater reliability and items 1 and 2 demonstrating excellent reliability. CONCLUSIONS: The m-FIM (by interview), SARA, and BBS have excellent interrater reliability for use when assessing individuals with an HCA. Physiotherapists could be considered for administration of the SARA in clinical trials. However, further work is required to improve the agreement of the single-item scores and to examine the other psychometric properties of these scales.

Brain Structure and Degeneration Staging in Friedreich Ataxia: Magnetic Resonance Imaging Volumetrics from the ENIGMA-Ataxia Working Group.

OBJECTIVE: Friedreich ataxia (FRDA) is an inherited neurological disease defined by progressive movement incoordination. We undertook a comprehensive characterization of the spatial profile and progressive evolution of structural brain abnormalities in people with FRDA. METHODS: A coordinated international analysis of regional brain volume using magnetic resonance imaging data charted the whole-brain profile, interindividual variability, and temporal staging of structural brain differences in 248 individuals with FRDA and 262 healthy controls. RESULTS: The brainstem, dentate nucleus region, and superior and inferior cerebellar peduncles showed the greatest reductions in volume relative to controls (Cohen d = 1.5-2.6). Cerebellar gray matter alterations were most pronounced in lobules I-VI (d = 0.8), whereas cerebral differences occurred most prominently in precentral gyri (d = 0.6) and corticospinal tracts (d = 1.4). Earlier onset age predicted less volume in the motor cerebellum (rmax  = 0.35) and peduncles (rmax  = 0.36). Disease duration and severity correlated with volume deficits in the dentate nucleus region, brainstem, and superior/inferior cerebellar peduncles (rmax  = -0.49); subgrouping showed these to be robust and early features of FRDA, and strong candidates for further biomarker validation. Cerebral white matter abnormalities, particularly in corticospinal pathways, emerge as intermediate disease features. Cerebellar and cerebral gray matter loss, principally targeting motor and sensory systems, preferentially manifests later in the disease course. INTERPRETATION: FRDA is defined by an evolving spatial profile of neuroanatomical changes beyond primary pathology in the cerebellum and spinal cord, in line with its progressive clinical course. The design, interpretation, and generalization of research studies and clinical trials must consider neuroanatomical staging and associated interindividual variability in brain measures. ANN NEUROL 2021;90:570-583.

Neuroinflammation in the Cerebellum and Brainstem in Friedreich Ataxia: An [18F]-FEMPA PET Study.

BACKGROUND: Neuroinflammation is proposed to accompany, or even contribute to, neuropathology in Friedreich ataxia (FRDA), with implications for disease treatment and tracking. OBJECTIVES: To examine brain glial activation and systemic immune dysfunction in people with FRDA and quantify their relationship with symptom severity, duration, and onset age. METHODS: Fifteen individuals with FRDA and 13 healthy controls underwent brain positron emission tomography using the translocator protein (TSPO) radioligand [18 F]-FEMPA, a marker of glial activation, together with the quantification of blood plasma inflammatory cytokines. RESULTS: [18 F]-FEMPA binding was significantly increased in the dentate nuclei (d = 0.67), superior cerebellar peduncles (d = 0.74), and midbrain (d = 0.87), alongside increased plasma interleukin-6 (IL-6) (d = 0.73), in individuals with FRDA compared to controls. Increased [18 F]-FEMPA binding in the dentate nuclei, brainstem, and cerebellar anterior lobe correlated with earlier age of symptom onset (controlling for the genetic triplet repeat expansion length; all r part < -0.6), and in the pons and anterior lobe with shorter disease duration (r = -0.66; -0.73). CONCLUSIONS: Neuroinflammation is evident in brain regions implicated in FRDA neuropathology. Increased neuroimmune activity may be related to earlier disease onset and attenuate over the course of the illness. © 2021 International Parkinson and Movement Disorder Society.

Consensus Paper: Novel Directions and Next Steps of Non-invasive Brain Stimulation of the Cerebellum in Health and Disease.

The cerebellum is involved in multiple closed-loops circuitry which connect the cerebellar modules with the motor cortex, prefrontal, temporal, and parietal cortical areas, and contribute to motor control, cognitive processes, emotional processing, and behavior. Among them, the cerebello-thalamo-cortical pathway represents the anatomical substratum of cerebellum-motor cortex inhibition (CBI). However, the cerebellum is also connected with basal ganglia by disynaptic pathways, and cerebellar involvement in disorders commonly associated with basal ganglia dysfunction (e.g., Parkinson's disease and dystonia) has been suggested. Lately, cerebellar activity has been targeted by non-invasive brain stimulation (NIBS) techniques including transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) to indirectly affect and tune dysfunctional circuitry in the brain. Although the results are promising, several questions remain still unsolved. Here, a panel of experts from different specialties (neurophysiology, neurology, neurosurgery, neuropsychology) reviews the current results on cerebellar NIBS with the aim to derive the future steps and directions needed. We discuss the effects of TMS in the field of cerebellar neurophysiology, the potentials of cerebellar tDCS, the role of animal models in cerebellar NIBS applications, and the possible application of cerebellar NIBS in motor learning, stroke recovery, speech and language functions, neuropsychiatric and movement disorders.

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.

The cognitive profile of Friedreich ataxia: a systematic review and meta-analysis.

BACKGROUND: Study the cognitive profile of individuals with Friedreich ataxia (FRDA) and seek evidence for correlations between clinical, genetic and imaging characteristics and neuropsychological impairments. METHODS: Based on PRISMA guidelines, a meta-analysis was realized using the Pubmed and Scopus databases to identify studies (1950-2021) reporting neuropsychological test results in genetically confirmed FRDA and control participants in at least one of the following cognitive domains: attention/executive, language, memory and visuo-spatial functions as well as emotion. Studies using identical outcomes in a minimum of two studies were pooled. Pooled effect sizes were calculated with Cohen's d. RESULTS: Eighteen studies were included. Individuals with FRDA displayed significantly lower performance than individuals without FRDA in most language, attention, executive function, memory visuospatial function, emotion regulation and social cognitive tasks. Among the included studies, thirteen studies examined the relationship between neuropsychological test results and clinical parameters and reported significant association with disease severity and six studies reviewed the relationship between neuroimaging measures and cognitive performance and mainly reported links between reduced cognitive performance and changes in cerebellar structure. CONCLUSIONS: Individuals with FRDA display significantly lower performances in many cognitive domains compared to control participants. The spectrum of the cognitive profile alterations in FRDA and its correlation with disease severity and cerebellar structural parameters suggest a cerebellar role in the pathophysiology of FRDA cognitive impairments.

Developing an Instrumented Measure of Upper Limb Function in Friedreich Ataxia.

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.

Multiple mechanisms underpin cerebral and cerebellar white matter deficits in Friedreich ataxia: The IMAGE-FRDA study.

Friedreich ataxia is a progressive neurodegenerative disorder with reported abnormalities in cerebellar, brainstem, and cerebral white matter. White matter structure can be measured using in vivo neuroimaging indices sensitive to different white matter features. For the first time, we examined the relative sensitivity and relationship between multiple white matter indices in Friedreich ataxia to more richly characterize disease expression and infer possible mechanisms underlying the observed white matter abnormalities. Diffusion-tensor, magnetization transfer, and T1-weighted structural images were acquired from 31 individuals with Friedreich ataxia and 36 controls. Six white matter indices were extracted: fractional anisotropy, diffusivity (mean, axial, radial), magnetization transfer ratio (microstructure), and volume (macrostructure). For each index, whole-brain voxel-wise between-group comparisons and correlations with disease severity, onset age, and gene triplet-repeat length were undertaken. Correlations between pairs of indices were assessed in the Friedreich ataxia cohort. Spatial similarities in the voxel-level pattern of between-group differences across the indices were also assessed. Microstructural abnormalities were maximal in cerebellar and brainstem regions, but evident throughout the brain, while macroscopic abnormalities were restricted to the brainstem. Poorer microstructure and reduced macrostructural volume correlated with greater disease severity and earlier onset, particularly in peri-dentate nuclei and brainstem regions. Microstructural and macrostructural abnormalities were largely independent. Reduced fractional anisotropy was most strongly associated with axial diffusivity in cerebral tracts, and magnetization transfer in cerebellar tracts. Multiple mechanisms likely underpin white matter abnormalities in Friedreich ataxia, with differential impacts in cerebellar and cerebral pathways.

Longitudinal Increases in Cerebral Brain Activation During Working Memory Performance in Friedreich Ataxia: 24-Month Data from IMAGE-FRDA.

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.

Longitudinal evaluation of iron concentration and atrophy in the dentate nuclei in friedreich ataxia.

BACKGROUND: Friedreich ataxia is a recessively inherited, progressive neurological disease characterized by impaired mitochondrial iron metabolism. The dentate nuclei of the cerebellum are characteristic sites of neurodegeneration in the disease, but little is known of the longitudinal progression of abnormalities in these structures. METHODS: Using in vivo magnetic resonance imaging, including quantitative susceptibility mapping, we investigated changes in iron concentration and volume in the dentate nuclei in individuals with Friedreich ataxia (n = 20) and healthy controls (n = 18) over a 2-year period. RESULTS: The longitudinal rate of iron concentration was significantly elevated bilaterally in participants with Friedreich ataxia relative to healthy controls. Atrophy rates did not differ significantly between groups. Change in iron concentration and atrophy both correlated with baseline disease severity or duration, indicating sensitivity of these measures to disease stage. Specifically, atrophy was maximal in individuals early in the disease course, whereas the rate of iron concentration increased with disease progression. CONCLUSIONS: Progressive dentate nucleus abnormalities are evident in vivo in Friedreich ataxia, and the rates of change of iron concentration and atrophy in these structures are sensitive to the disease stage. The findings are consistent with an increased rate of iron concentration and atrophy early in the disease, followed by iron accumulation and stable volume in later stages. This pattern suggests that iron dysregulation persists after loss of the vulnerable neurons in the dentate. The significant changes observed over a 2-year period highlight the utility of quantitative susceptibility mapping as a longitudinal biomarker and staging tool. © 2019 International Parkinson and Movement Disorder Society.

Can rehabilitation improve the health and well-being in Friedreich's ataxia: a randomized controlled trial?

OBJECTIVE: To determine the effectiveness of a six-week rehabilitation programme followed by a home exercise programme for Friedreich's ataxia. DESIGN: Randomized, delayed-start control single-blind trial. SETTING: Outpatient rehabilitation centre. SUBJECTS: Ambulant or non-ambulant individuals with Friedreich's ataxia. INTERVENTION: Participants were randomized to a six-week outpatient rehabilitation programme, immediately (intervention group) or after a six-week delayed-start (control group). The rehabilitation was followed by a six-week home exercise programme. MAIN MEASURES: The primary outcome was the Functional Independence Measure. Other measures included the Friedreich Ataxia Impact Scale and the Friedreich Ataxia Rating Scale. Outcomes were administered at baseline, 6, 12 and 18 weeks. RESULTS: Of 159 individuals screened, 92 were excluded and 48 declined to participate. A total of 19 participants were enrolled in the study. There was no significant difference in Functional Independence Measure change from baseline to six weeks in the intervention group (mean ± standard deviation, 2.00 ± 3.16) as compared to the control group (0.56 ± 4.06). Change in the Friedreich Ataxia Impact Scale body movement subscale indicated a significant improvement in health and well-being in the intervention group compared to the control group ( P = 0.003). Significant within-group improvements in the Friedreich Ataxia Impact Scale and the motor domain of the Functional Independence Measure post-rehabilitation were not sustained post-home exercise programme. CONCLUSION: Our study indicates that rehabilitation can improve health and well-being in individuals with Friedreich's ataxia; however, a larger study is required to have sufficient power to detect a significant change in the most sensitive measure of function, the motor domain of the Functional Independence Measure.

Progress in the treatment of Friedreich ataxia.

Friedreich ataxia (FRDA) is a progressive neurological disorder affecting approximately 1 in 29,000 individuals of European descent. At present, there is no approved pharmacological treatment for this condition however research into treatment of FRDA has advanced considerably over the last two decades since the genetic cause was identified. Current proposed treatment strategies include decreasing oxidative stress, increasing cellular frataxin, improving mitochondrial function as well as modulating frataxin controlled metabolic pathways. Genetic and cell based therapies also hold great promise. Finally, physical therapies are being explored as a means of maximising function in those affected by FRDA.

Compound heterozygous FXN mutations and clinical outcome in friedreich ataxia.

OBJECTIVE: Friedreich ataxia (FRDA) is an inherited neurodegenerative disease characterized by ataxia and cardiomyopathy. Homozygous GAA trinucleotide repeat expansions in the first intron of FXN occur in 96% of affected individuals and reduce frataxin expression. Remaining individuals are compound heterozygous for a GAA expansion and a FXN point/insertion/deletion mutation. We examined disease-causing mutations and the impact on frataxin structure/function and clinical outcome in FRDA. METHODS: We compared clinical information from 111 compound heterozygotes and 131 individuals with homozygous expansions. Frataxin mutations were examined using structural modeling, stability analyses and systematic literature review, and categorized into four groups: (1) homozygous expansions, and three compound heterozygote groups; (2) null (no frataxin produced); (3) moderate/strong impact; and (4) minimal impact. Mean age of onset and the presence of cardiomyopathy and diabetes mellitus were compared using regression analyses. RESULTS: Mutations in the hydrophobic core of frataxin affected stability whereas surface residue mutations affected interactions with iron sulfur cluster assembly and heme biosynthetic proteins. The null group of compound heterozygotes had significantly earlier age of onset and increased diabetes mellitus, compared to the homozygous expansion group. There were no significant differences in mean age of onset between homozygotes and the minimal and moderate/strong impact groups. INTERPRETATION: In compound heterozygotes, expression of partially functional mutant frataxin delays age of onset and reduces diabetes mellitus, compared to those with no frataxin expression from the non-expanded allele. This integrated analysis of categorized frataxin mutations and their correlation with clinical outcome provide a definitive resource for investigating disease pathogenesis in FRDA.

Cerebral compensation during motor function in Friedreich ataxia: The IMAGE-FRDA study.

BACKGROUND: Friedreich ataxia is characterized by progressive motor incoordination that is linked to peripheral, spinal, and cerebellar neuropathology. Cerebral abnormalities are also reported in Friedreich ataxia, but their role in disease expression remains unclear. METHODS: In this cross-sectional functional magnetic resonance imaging study, 25 individuals with Friedreich ataxia and 33 healthy controls performed simple (self-paced single-finger) and complex (visually cued multifinger) tapping tasks to respectively gauge basic and attentionally demanding motor behavior. For each task, whole brain functional activations were compared between groups and correlated with disease severity and offline measures of motor dexterity. RESULTS: During simple finger tapping, cerebral hyperactivation in individuals with Friedreich ataxia at the lower end of clinical severity and cerebral hypoactivation in those more severely affected was observed in premotor/ventral attention brain regions, including the supplementary motor area and anterior insula. Greater activation in this network correlated with greater offline finger tapping precision. Complex, attentionally demanding finger tapping was also associated with cerebral hyperactivation, but in this case within dorsolateral prefrontal regions of the executive control network and superior parietal regions of the dorsal attention system. Greater offline motor precision was associated with less activation in the dorsal attention network. DISCUSSION: Compensatory activity is evident in the cerebral cortex in individuals with Friedreich ataxia. Early compensation followed by later decline in premotor/ventral attention systems demonstrates capacity-limited neural reserve, while the additional engagement of higher order brain networks is indicative of compensatory task strategies. Network-level changes in cerebral brain function thus potentially serve to mitigate the impact of motor impairments in Friedreich ataxia. © 2017 International Parkinson and Movement Disorder Society.

Measuring Inhibition and Cognitive Flexibility in Friedreich Ataxia.

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder with subtle impact on cognition. Inhibitory processes and cognitive flexibility were examined in FRDA by assessing the ability to suppress a predictable verbal response. We administered the Hayling Sentence Completion Test (HSCT), the Trail Making Test, and the Stroop Test to 43 individuals with FRDA and 42 gender- and age-matched control participants. There were no significant group differences in performance on the Stroop or Trail Making Test whereas significant impairment in cognitive flexibility including the ability to predict and inhibit a pre-potent response as measured in the HSCT was evident in individuals with FRDA. These deficits did not correlate with clinical characteristics of FRDA (age of disease onset, disease duration, number of guanine-adenine-adenine repeats on the shorter or larger FXN allele, or Friedreich Ataxia Rating Scale score), suggesting that such impairment may not be related to the disease process in a straightforward way. The observed specific impairment of inhibition and predictive capacity in individuals with FRDA on the HSCT task, in the absence of impairment in associated executive functions, supports cerebellar dysfunction in conjunction with disturbance to cortico-thalamo-cerebellar connectivity, perhaps via inability to access frontal areas necessary for successful task completion.

Dysphagia in Friedreich Ataxia.

The objective of the study was to comprehensively characterise dysphagia in Friedreich ataxia (FRDA) and identify predictors of penetration/aspiration during swallowing. We also investigated the psychosocial impact of dysphagia on individuals with FRDA. Sixty participants with FRDA were screened for dysphagia using a swallowing quality of life questionnaire (Swal-QOL) and case history. Individuals reporting dysphagia underwent a standardised oromotor assessment (Frenchay Dysarthria Assessment, 2, FDA-2) and videofluoroscopic study of swallowing (VFSS). Data were correlated with disease parameters (age at symptom onset, age at assessment, disease duration, FXN intron 1 GAA repeat sizes, and Friedreich Ataxia Rating Scale (FARS) score). Predictors of airway penetration/aspiration were explored using logistic regression analysis. Ninety-eight percent (59/60) of participants reported dysphagia, of whom 35 (58.3%) underwent FDA-2 assessment, and 38 (63.3%) underwent VFSS. Laryngeal, respiratory, and tongue dysfunction was observed on the FDA-2. A Penetration-Aspiration Scale score above 3 (deemed significant airway compromise based on non-clinical groups) was observed on at least one consistency in 13/38 (34.2%) participants. All of those who aspirated (10/38, 26.3%) did so silently, with no overt signs of airway entry such as reflexive cough. Significant correlations were observed between dysphagic symptoms and disease duration and severity. No reliable predictors of penetration or aspiration were identified. Oropharyngeal dysphagia is commonly present in individuals with FRDA and worsens with disease duration and severity. Individuals with FRDA are at risk of aspiration at any stage of the disease and should be reviewed regularly. Instrumental analysis remains the only reliable method to detect aspiration in this population. Dysphagia significantly affects the quality of life of individuals with FRDA.