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.

Clinical Determinants of Dual Tasking in People With Premanifest Huntington Disease.

OBJECTIVE: Dual-tasking deficiencies are common in people with Huntington disease (HD) and contribute to reduced functional independence. To date, few studies have investigated the determinants of dual-tasking deficiencies in this population. The reliability of dual-tasking measures has also been poorly investigated in HD. The purpose of this study was to investigate the influence of clinical determinants on dual-tasking performance and to determine the association of disease burden outcomes on dual-tasking performance in individuals with premanifest HD. METHODS: Thirty-six individuals with premanifest HD and 28 age- and sex-matched healthy controls were recruited for this study. Participants performed 3 single-task (2 cognitive and 1 motor) and 2 dual-task assessments, comprising motor (postural stability) and cognitive (simple or complex mental arithmetic) components. In addition, participants performed a comprehensive clinical battery comprising motor, cognitive, mood, and sleep assessments as well as lifestyle and disease burden measures. RESULTS: Poorer sleep quality was associated with greater cognitive dual-task cost in individuals with premanifest HD. Compared with healthy controls, people with premanifest HD demonstrated an impaired capacity to dual task. Dual-task measures exhibited acceptable test-retest reliability in premanifest HD and healthy control groups. CONCLUSION: These results show that dual-tasking measures are sensitive and reliable in individuals with premanifest HD. Furthermore, poor sleep quality is associated with worse cognitive performance on dual tasks, which should be considered by rehabilitation specialists when examining and therapeutically managing dual-tasking problems in individuals with HD and other neurodegenerative populations in the future. IMPACT: This study adds important knowledge to the sparse literature on dual-tasking deficiencies in people with HD. When examining and therapeutically managing dual-tasking problems in this and other neurodegenerative populations, rehabilitation specialists should consider that people with premanifest HD may have an impaired capacity to dual task. Clinicians also should assess sleep quality, as poorer sleep quality is associated with worse cognitive performance on dual tasks in these individuals. LAY SUMMARY: If you have premanifest HD and poor quality of sleep, you may pay more attention to maintaining postural stability rather than performing arithmetic calculations to reduce the risk of falling.

Multimodal imaging biomarkers in premanifest and early Huntington's disease: 30-month IMAGE-HD data.

BACKGROUND: The discovery of potential disease-modifying therapies in a neurodegenerative condition like Huntington's disease depends on the availability of sensitive biomarkers that reflect decline across disease stages and that are functionally and clinically relevant. AIMS: To quantify macrostructural and microstructural changes in participants with premanifest and symptomatic Huntington's disease over 30 months, and to establish their functional and clinical relevance. METHOD: Multimodal magnetic resonance imaging study measuring changes in macrostructural (volume) and microstructural (diffusivity) measures in 40 patients with premanifest Huntington's disease, 36 patients with symptomatic Huntington's disease and 36 healthy control participants over three testing sessions spanning 30 months. RESULTS: Relative to controls, there was greater longitudinal atrophy in participants with symptomatic Huntington's disease in whole brain, grey matter, caudate and putamen, as well as increased caudate fractional anisotropy; caudate volume loss was the only measure to differ between premanifest Huntington's disease and control groups. Changes in caudate volume and fractional anisotropy correlated with each other and neurocognitive decline; caudate volume loss also correlated with clinical and disease severity. CONCLUSIONS: Caudate neurodegeneration, especially atrophy, may be the most suitable candidate surrogate biomarker for consideration in the development of upcoming clinical trials.