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.

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.

Associations of inflammatory cytokines and cortisol with nonmotor features of Huntington's disease.

OBJECTIVE: Huntington's disease (HD) is an inherited neurodegenerative disease involving progressive motor abnormalities, cognitive decline, and psychiatric disturbances. Depression and cognitive difficulties are among the most impactful symptoms of HD, yet the pathogenesis of these symptoms is not fully understood. HD involves low-level chronic inflammation and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which are linked to depression and cognitive impairment in non-HD populations. However, previous research on the relationships of these pathologies with depression and cognition in HD is limited and inconsistent. METHODS: Fifty-three adults with the HD gene expansion (30 premanifest and 23 manifest) completed measures of depression and cognitive functioning. Forty-eight out of 53 participants provided hair samples for quantification of cortisol, and 34 participants provided blood samples for quantification of peripheral inflammatory cytokines. We examined the associations of four cytokines (interleukin [IL]-6, IL-10, IL-1ß, and tumor necrosis factor [TNF]-α) and cortisol levels with depression and cognitive scores. RESULTS: In unadjusted models, higher levels of plasma IL-6, IL-10, and TNF-α correlated with higher depression scores, and higher levels of IL-10 and TNF-α correlated with poorer cognitive performance. After controlling for age, sex, and body mass index, only the correlations of IL-10 with depression and cognitive performance remained significant. No correlations were evident with hair cortisol. INTERPRETATIONS: Peripheral inflammation is associated with depression symptoms and cognitive impairment in HD. Our findings suggest that interactions between the immune and nervous systems are important in HD, and highlight the potential of chronic inflammation as a therapeutic target in early stages of HD.

Genotype-specific spinal cord damage in spinocerebellar ataxias: an ENIGMA-Ataxia study.

BACKGROUND: Spinal cord damage is a feature of many spinocerebellar ataxias (SCAs), but well-powered in vivo studies are lacking and links with disease severity and progression remain unclear. Here we characterise cervical spinal cord morphometric abnormalities in SCA1, SCA2, SCA3 and SCA6 using a large multisite MRI dataset. METHODS: Upper spinal cord (vertebrae C1-C4) cross-sectional area (CSA) and eccentricity (flattening) were assessed using MRI data from nine sites within the ENIGMA-Ataxia consortium, including 364 people with ataxic SCA, 56 individuals with preataxic SCA and 394 nonataxic controls. Correlations and subgroup analyses within the SCA cohorts were undertaken based on disease duration and ataxia severity. RESULTS: Individuals in the ataxic stage of SCA1, SCA2 and SCA3, relative to non-ataxic controls, had significantly reduced CSA and increased eccentricity at all examined levels. CSA showed large effect sizes (d>2.0) and correlated with ataxia severity (r<-0.43) and disease duration (r<-0.21). Eccentricity correlated only with ataxia severity in SCA2 (r=0.28). No significant spinal cord differences were evident in SCA6. In preataxic individuals, CSA was significantly reduced in SCA2 (d=1.6) and SCA3 (d=1.7), and the SCA2 group also showed increased eccentricity (d=1.1) relative to nonataxic controls. Subgroup analyses confirmed that CSA and eccentricity are abnormal in early disease stages in SCA1, SCA2 and SCA3. CSA declined with disease progression in all, whereas eccentricity progressed only in SCA2. CONCLUSIONS: Spinal cord abnormalities are an early and progressive feature of SCA1, SCA2 and SCA3, but not SCA6, which can be captured using quantitative MRI.

Monash-Alfred protocol for assessment of atypical parkinsonian syndromes (MAP-APS).

Introduction: Atypical parkinsonian syndromes (APS) are rare neurodegenerative syndromes for which parkinsonism is one significant feature. APS includes progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and corticobasal syndrome (CBS). The diagnosis of APS remains reliant on clinical features with no available diagnostic or prognostic biomarker. Clinical scales remain the gold standard assessment measures in clinical trials and research. The lack of standardised approach for research cohorts has contributed to shortcomings in disease understanding and limits collaboration between researchers. The primary objectives of this study are to (1) establish an assessment protocol for parkinsonian syndromes and (2) to implement it at a single site to establish the viability and utility of populating a clinical and biological databank of patients with APS. Methods: The Monash Alfred Protocol for Assessment of APS was devised by expert consensus within a broad multidisciplinary team. Eligible patients are diagnosed as possible or probable PSP, MSA or CBS by a consultant neurologist with expertise in movement disorders. Participants will be assessed at recruitment and then annually for up to 3 years; individuals within 5 years of index symptom onset will also undergo a once-off 6-month assessment. Ethics and dissemination: Each participant or their legally authorised representative will provide informed written consent prior to commencement of the study. Data will be stored on a locally hosted Research Electronic Data Capture database. Trial registration number: Australian New Zealand Clinical Trials Registry (ANZCTN 12622000923763).

The relationship between disease-specific psychosocial stressors and depressive symptoms in Huntington's disease.

BACKGROUND: Huntington's disease (HD) is an inherited neurodegenerative disease involving motor abnormalities, cognitive decline, and psychological difficulties. Depression is among the most common psychological difficulties in HD. People with HD encounter numerous stressors related to their diagnosis and the impact of HD on their daily lives. Understanding the relationship between HD-specific psychosocial stressors and depression symptoms is critical for optimising treatment and developing a holistic, disease-specific model of depression in HD. METHODS: Fifty-seven adults with the HD gene expansion (33 pre-symptomatic, 24 symptomatic) completed a self-report depression questionnaire and rated how much stress they experienced in relation to 20 psychosocial challenges commonly associated with HD. We examined associations between depression symptoms and each stressor individually, and after clustering using principal components analysis. RESULTS: Depression symptoms were significantly associated with most of the psychosocial stressors assessed. Clustering with principal components analysis revealed that higher depression scores had significant independent associations with greater stress related to the future implications of HD (ß = .44, p = .001) and sleep and psychological difficulties (ß = .28, p = .005), but not with stress related to functional limitations (ß = .11, p = .33) or interpersonal issues caused by HD (ß = .15, p = .21). CONCLUSIONS: Stressful experiences associated with HD constitute an important risk factor for depression in HD. Our findings support the use of more psychologically informed models of depression in HD and necessitate further research on tailored psychosocial interventions for HD patients with depression.

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.

Imaging the neurovascular unit in health and neurodegeneration: a scoping review of interdependencies between MRI measures.

The neurovascular unit (NVU) is a complex structure that facilitates nutrient delivery and metabolic waste clearance, forms the blood-brain barrier (BBB), and supports fluid homeostasis in the brain. The integrity of NVU subcomponents can be measured in vivo using magnetic resonance imaging (MRI), including quantification of enlarged perivascular spaces (ePVS), BBB permeability, cerebral perfusion and extracellular free water. The breakdown of NVU subparts is individually associated with aging, pathology, and cognition. However, how these subcomponents interact as a system, and how interdependencies are impacted by pathology remains unclear. This systematic scoping review identified 26 studies that investigated the inter-relationships between multiple subcomponents of the NVU in nonclinical and neurodegenerative populations using MRI. A further 112 studies investigated associations between the NVU and white matter hyperintensities (WMH). We identify two putative clusters of NVU interdependencies: a 'vascular' cluster comprising BBB permeability, perfusion and basal ganglia ePVS; and a 'fluid' cluster comprising ePVS, free water and WMH. Emerging evidence suggests that subcomponent coupling within these clusters may be differentially related to aging, neurovascular injury or neurodegenerative pathology.

Multimodal Analysis of Secondary Cerebellar Alterations After Pediatric Traumatic Brain Injury.

Importance: Traumatic brain injury (TBI) is known to cause widespread neural disruption in the cerebrum. However, less is known about the association of TBI with cerebellar structure and how such changes may alter executive functioning. Objective: To investigate alterations in subregional cerebellum volume and cerebral white matter microstructure after pediatric TBI and examine subsequent changes in executive function. Design, Setting, and Participants: This retrospective cohort study combined 12 data sets (collected between 2006 and 2020) from 9 sites in the Enhancing Neuroimaging Genetics Through Meta-Analysis Consortium Pediatric TBI working group in a mega-analysis of cerebellar structure. Participants with TBI or healthy controls (some with orthopedic injury) were recruited from trauma centers, clinics, and institutional trauma registries, some of which were followed longitudinally over a period of 0.7 to 1.9 years. Healthy controls were recruited from the surrounding community. Data analysis occurred from October to December 2022. Exposure: Accidental mild complicated-severe TBI (msTBI) for those in the TBI group. Some controls received a diagnosis of orthopedic injury. Main Outcomes and Measures: Volume of 18 cerebellar lobules and vermal regions were estimated from 3-dimensional T1-weighted magnetic resonance imaging (MRI) scans. White matter organization in 28 regions of interest was assessed with diffusion tensor MRI. Executive function was measured by parent-reported scores from the Behavior Rating Inventory of Executive Functioning. Results: A total of 598 children and adolescents (mean [SD] age, 14.05 [3.06] years; range, 5.45-19.70 years; 386 male participants [64.5%]; 212 female participants [35.5%]) were included in the study, with 314 participants in the msTBI group, and 284 participants in the non-TBI group (133 healthy individuals and 151 orthopedically injured individuals). Significantly smaller total cerebellum volume (d = -0.37; 95% CI, -0.52 to -0.22; P < .001) and subregional cerebellum volumes (eg, corpus medullare; d = -0.43; 95% CI, -0.58 to -0.28; P < .001) were observed in the msTBI group. These alterations were primarily seen in participants in the chronic phase (ie, >6 months postinjury) of injury (total cerebellar volume, d = -0.55; 95% CI, -0.75 to -0.35; P < .001). Smaller cerebellum volumes were associated with higher scores on the Behavior Rating Inventory of Executive Functioning Global Executive Composite score (ß = -208.9 mm3; 95% CI, -319.0 to -98.0 mm3; P = .008) and Metacognition Index score (ß = -202.5 mm3; 95% CI, -319.0 to -85.0 mm3; P = .02). In a subset of 185 participants with longitudinal data, younger msTBI participants exhibited cerebellum volume reductions (ß = 0.0052 mm3; 95% CI, 0.0013 to 0.0090 mm3; P = .01), and older participants slower growth rates. Poorer white matter organization in the first months postinjury was associated with decreases in cerebellum volume over time (ß=0.52 mm3; 95% CI, 0.19 to 0.84 mm3; P = .005). Conclusions and Relevance: In this cohort study of pediatric msTBI, our results demonstrated robust cerebellar volume alterations associated with pediatric TBI, localized to the posterior lobe. Furthermore, longitudinal cerebellum changes were associated with baseline diffusion tensor MRI metrics, suggesting secondary cerebellar atrophy. These results provide further understanding of secondary injury mechanisms and may point to new opportunities for intervention.

Brain Networks Involved in Sensory Perception in Parkinson's Disease: A Scoping Review.

Parkinson's Disease (PD) has historically been considered a disorder of motor dysfunction. However, a growing number of studies have demonstrated sensory abnormalities in PD across the modalities of proprioceptive, tactile, visual, auditory and temporal perception. A better understanding of these may inform future drug and neuromodulation therapy. We analysed these studies using a scoping review. In total, 101 studies comprising 2853 human participants (88 studies) and 125 animals (13 studies), published between 1982 and 2022, were included. These highlighted the importance of the basal ganglia in sensory perception across all modalities, with an additional role for the integration of multiple simultaneous sensation types. Numerous studies concluded that sensory abnormalities in PD result from increased noise in the basal ganglia and increased neuronal receptive field size. There is evidence that sensory changes in PD and impaired sensorimotor integration may contribute to motor abnormalities.

STAREE-Mind Imaging Study: a randomised placebo-controlled trial of atorvastatin for prevention of cerebrovascular decline and neurodegeneration in older individuals.

Introduction: Cerebrovascular disease and neurodegeneration are causes of cognitive decline and dementia, for which primary prevention options are currently lacking. Statins are well-tolerated and widely available medications that potentially have neuroprotective effects. The STAREE-Mind Imaging Study is a randomised, double-blind, placebo-controlled clinical trial that will investigate the impact of atorvastatin on markers of neurovascular health and brain atrophy in a healthy, older population using MRI. This is a nested substudy of the 'Statins for Reducing Events in the Elderly' (STAREE) primary prevention trial. Methods: Participants aged 70 years or older (n=340) will be randomised to atorvastatin or placebo. Comprehensive brain MRI assessment will be undertaken at baseline and up to 4 years follow-up, including structural, diffusion, perfusion and susceptibility imaging. The primary outcome measures will be change in brain free water fraction (a composite marker of vascular leakage, neuroinflammation and neurodegeneration) and white matter hyperintensity volume (small vessel disease). Secondary outcomes will include change in perivascular space volume (glymphatic drainage), cortical thickness, hippocampal volume, microbleeds and lacunae, prefrontal cerebral perfusion and white matter microstructure. Ethics and dissemination: Academic publications from this work will address the current uncertainty regarding the impact of statins on brain structure and vascular integrity. This study will inform the utility of repurposing these well-tolerated, inexpensive and widely available drugs for primary prevention of neurological outcomes in older individuals. Ethics approval was given by Monash University Human Research Ethics Committee, Protocol 12206. Trial registration number: ClinicalTrials.gov Identifier: NCT05586750.

MR Imaging in Ataxias: Consensus Recommendations by the Ataxia Global Initiative Working Group on MRI Biomarkers.

With many viable strategies in the therapeutic pipeline, upcoming clinical trials in hereditary and sporadic degenerative ataxias will benefit from non-invasive MRI biomarkers for patient stratification and the evaluation of therapies. The MRI Biomarkers Working Group of the Ataxia Global Initiative therefore devised guidelines to facilitate harmonized MRI data acquisition in clinical research and trials in ataxias. Recommendations are provided for a basic structural MRI protocol that can be used for clinical care and for an advanced multi-modal MRI protocol relevant for research and trial settings. The advanced protocol consists of modalities with demonstrated utility for tracking brain changes in degenerative ataxias and includes structural MRI, magnetic resonance spectroscopy, diffusion MRI, quantitative susceptibility mapping, and resting-state functional MRI. Acceptable ranges of acquisition parameters are provided to accommodate diverse scanner hardware in research and clinical contexts while maintaining a minimum standard of data quality. Important technical considerations in setting up an advanced multi-modal protocol are outlined, including the order of pulse sequences, and example software packages commonly used for data analysis are provided. Outcome measures most relevant for ataxias are highlighted with use cases from recent ataxia literature. Finally, to facilitate access to the recommendations by the ataxia clinical and research community, examples of datasets collected with the recommended parameters are provided and platform-specific protocols are shared via the Open Science Framework.

Reduced cerebello-cerebral functional connectivity correlates with disease severity and impaired white matter integrity in Friedreich ataxia.

Friedreich ataxia (FRDA) is a rare, inherited neurodegenerative disease characterised in most cases by progressive and debilitating motor dysfunction. Degeneration of cerebellar white matter pathways have been previously reported, alongside indications of cerebello-cerebral functional alterations. In this work, we examine resting-state functional connectivity changes within cerebello-cerebral circuits, and their associations with disease severity (Scale for the Assessment and Rating of Ataxia [SARA]), psychomotor function (speeded and paced finger tapping), and white matter integrity (diffusion tensor imaging) in 35 adults with FRDA and 45 age and sex-matched controls. Voxel-wise seed-based functional connectivity was assessed for three cerebellar cortical regions (anterior lobe, lobules I-V; superior posterior lobe, lobules VI-VIIB; inferior posterior lobe, lobules VIIIA-IX) and two dentate nucleus seeds (dorsal and ventral). Compared to controls, people with FRDA showed significantly reduced connectivity between the anterior cerebellum and bilateral pre/postcentral gyri, and between the superior posterior cerebellum and left dorsolateral PFC. Greater disease severity correlated with lower connectivity in these circuits. Lower anterior cerebellum-motor cortex functional connectivity also correlated with slower speeded finger tapping and less fractional anisotropy in the superior cerebellar peduncles, internal capsule, and precentral white matter in the FRDA cohort. There were no significant between-group differences in inferior posterior cerebellar or dentate nucleus connectivity. This study indicates that altered cerebello-cerebral functional connectivity is associated with functional status and white matter damage in cerebellar efferent pathways in people with FRDA, particularly in motor circuits.

The temporal dynamics of mood and their association with depressive symptoms in Huntington's disease.

BACKGROUND: Huntington's disease (HD) is an inherited neurodegenerative disorder characterised by progressive motor abnormalities, cognitive decline, and neuropsychiatric disturbances. Depression is among the most common neuropsychiatric syndromes in HD. Research in neurologically healthy samples has shown that depression is associated with distinct patterns of short-term fluctuations in mood, which may exacerbate negative effects on psychological wellbeing. The short-term dynamics of mood and their relationship with depression have not yet been investigated in HD. METHODS: Fifty-five adults with the HD CAG expansion (33 pre-manifest, 22 manifest) completed single timepoint measures of depression, demographic factors, and clinical disease outcomes on day 1, then rated their mood daily for 28 consecutive days. Average mood, mood variability, and mood inertia (auto-correlation) were calculated across the 28 days. RESULTS: Depression severity on day 1 was significantly associated with average mood across the 28 days, but not with day-to-day mood variability or inertia. Additionally, female HD CAG expansion carriers experienced more day-to-day variability in mood compared to males. LIMITATIONS: Our sample did not include HD CAG expansion carriers with severe depressive symptoms or advanced HD, which limits the generalisability of the findings. Additionally, findings may have been affected by antidepressant and antipsychotic medication use among many participants. CONCLUSIONS: In HD, short-term patterns of change in mood appear to be relatively independent of depression severity. Moreover, in female CAG-expansion carriers particularly, mood variability may warrant further clinical attention. These findings should be replicated in larger and more diverse samples, with different timescales and measures for assessing mood.

The association between sex hormones and the change in brain-predicted age difference in older women.

OBJECTIVE: The role of circulating sex hormones on structural brain ageing is yet to be established. This study explored whether concentrations of circulating sex hormones in older women are associated with the baseline and longitudinal changes in structural brain ageing, defined by the brain-predicted age difference (brain-PAD). DESIGN: Prospective cohort study using data from NEURO and Sex Hormones in Older Women; substudies of the ASPirin in Reducing Events in the Elderly clinical trial. PATIENTS: Community-dwelling older women (aged 70+ years). MEASUREMENTS: Oestrone, testosterone, dehydroepiandrosterone (DHEA), and sex-hormone binding globulin (SHBG) were quantified from plasma samples collected at baseline. T1-weighted magnetic resonance imaging was performed at baseline, 1 and 3 years. Brain age was derived from whole brain volume using a validated algorithm. RESULTS: The sample comprised of 207 women not taking medications known to influence sex hormone concentrations. A statistically higher baseline brain-PAD (older brain age relative to chronological age) was seen for women in the highest DHEA tertile compared with the lowest in the unadjusted analysis (p = .04). This was not significant when adjusted for chronological age, and potential confounding health and behavioural factors. Oestrone, testosterone and SHBG were not associated with brain-PAD cross-sectionally, nor were any of the examined sex hormones or SHBG associated with brain-PAD longitudinally. CONCLUSION: No strong evidence of an association between circulating sex hormones and brain-PAD. Given there is prior evidence to suggests sex hormones may be important for brain ageing, further studies of circulating sex hormones and brain health in postmenopausal women are warranted.

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.

A natural history study to track brain and spinal cord changes in individuals with Friedreich's ataxia: TRACK-FA study protocol.

INTRODUCTION: Drug development for neurodegenerative diseases such as Friedreich's ataxia (FRDA) is limited by a lack of validated, sensitive biomarkers of pharmacodynamic response in affected tissue and disease progression. Studies employing neuroimaging measures to track FRDA have thus far been limited by their small sample sizes and limited follow up. TRACK-FA, a longitudinal, multi-site, and multi-modal neuroimaging natural history study, aims to address these shortcomings by enabling better understanding of underlying pathology and identifying sensitive, clinical trial ready, neuroimaging biomarkers for FRDA. METHODS: 200 individuals with FRDA and 104 control participants will be recruited across seven international study sites. Inclusion criteria for participants with genetically confirmed FRDA involves, age of disease onset ≤ 25 years, Friedreich's Ataxia Rating Scale (FARS) functional staging score of ≤ 5, and a total modified FARS (mFARS) score of ≤ 65 upon enrolment. The control cohort is matched to the FRDA cohort for age, sex, handedness, and years of education. Participants will be evaluated at three study visits over two years. Each visit comprises of a harmonized multimodal Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS) scan of the brain and spinal cord; clinical, cognitive, mood and speech assessments and collection of a blood sample. Primary outcome measures, informed by previous neuroimaging studies, include measures of: spinal cord and brain morphometry, spinal cord and brain microstructure (measured using diffusion MRI), brain iron accumulation (using Quantitative Susceptibility Mapping) and spinal cord biochemistry (using MRS). Secondary and exploratory outcome measures include clinical, cognitive assessments and blood biomarkers. DISCUSSION: Prioritising immediate areas of need, TRACK-FA aims to deliver a set of sensitive, clinical trial-ready neuroimaging biomarkers to accelerate drug discovery efforts and better understand disease trajectory. Once validated, these potential pharmacodynamic biomarkers can be used to measure the efficacy of new therapeutics in forestalling disease progression. CLINICAL TRIAL REGISTRATION: ClinicalTrails.gov Identifier: NCT04349514.

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.

Overview of the Clinical Approach to Individuals With Cerebellar Ataxia and Neuropathy.

Increasingly, cerebellar syndromes are recognized as affecting multiple systems. Extracerebellar features include peripheral neuropathies affecting proprioception; cranial neuropathies such as auditory and vestibular; and neuronopathies, for example, dorsal root and vestibular. The presence of such features, which in and of themselves may cause ataxia, likely contribute to key disabilities such as gait instability and falls. Based on the evolving available literature and experience, we outline a clinical approach to the diagnosis of adult-onset ataxia where a combination of cerebellar and peripheral or cranial nerve pathology exists. Objective diagnostic modalities including electrophysiology, oculomotor, and vestibular function testing are invaluable in accurately defining an individual's phenotype. Advances in MRI techniques have led to an increased recognition of disease-specific patterns of cerebellar pathology, including those conditions where neuronopathies may be involved. Depending on availability, a stepwise approach to genetic testing is suggested. This is guided by factors such as pattern of inheritance and age at disease onset, and genetic testing may range from specific genetic panels through to whole-exome and whole-genome sequencing. Management is best performed with the involvement of a multidisciplinary team, aiming at minimization of complications such as falls and aspiration pneumonia and maximizing functional status.