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.

Longitudinal imaging highlights preferential basal ganglia circuit atrophy in Huntington's disease.

Huntington's disease is caused by a CAG repeat expansion in the Huntingtin gene (HTT), coding for polyglutamine in the Huntingtin protein, with longer CAG repeats causing earlier age of onset. The variable 'Age' × ('CAG'-L), where 'Age' is the current age of the individual, 'CAG' is the repeat length and L is a constant (reflecting an approximation of the threshold), termed the 'CAG Age Product' (CAP) enables the consideration of many individuals with different CAG repeat expansions at the same time for analysis of any variable and graphing using the CAG Age Product score as the X axis. Structural MRI studies have showed that progressive striatal atrophy begins many years prior to the onset of diagnosable motor Huntington's disease, confirmed by longitudinal multicentre studies on three continents, including PREDICT-HD, TRACK-HD and IMAGE-HD. However, previous studies have not clarified the relationship between striatal atrophy, atrophy of other basal ganglia structures, and atrophy of other brain regions. The present study has analysed all three longitudinal datasets together using a single image segmentation algorithm and combining data from a large number of subjects across a range of CAG Age Product score. In addition, we have used a strategy of normalizing regional atrophy to atrophy of the whole brain, in order to determine which regions may undergo preferential degeneration. This made possible the detailed characterization of regional brain atrophy in relation to CAG Age Product score. There is dramatic selective atrophy of regions involved in the basal ganglia circuit-caudate, putamen, nucleus accumbens, globus pallidus and substantia nigra. Most other regions of the brain appear to have slower but steady degeneration. These results support (but certainly do not prove) the hypothesis of circuit-based spread of pathology in Huntington's disease, possibly due to spread of mutant Htt protein, though other connection-based mechanisms are possible. Therapeutic targets related to prion-like spread of pathology or other mechanisms may be suggested. In addition, they have implications for current neurosurgical therapeutic approaches, since delivery of therapeutic agents solely to the caudate and putamen may miss other structures affected early, such as nucleus accumbens and output nuclei of the striatum, the substantia nigra and the globus pallidus.

The shape of things to come. Mapping spatiotemporal progression of striatal morphology in Huntington disease: The IMAGE-HD study.

Mapping the spatiotemporal progression of neuroanatomical change in Huntington's Disease (HD) is fundamental to the development of bio-measures for prognostication. Statistical shape analysis to measure the striatum has been performed in HD, however there have been a limited number of longitudinal studies. To address these limitations, we utilised the Spherical Harmonic Point Distribution Method (SPHARM-PDM) to generate point distribution models of the striatum in individuals, and used linear mixed models to test for localised shape change over time in pre-manifest HD (pre-HD), symp-HD (symp-HD) and control individuals. Longitudinal MRI scans from the IMAGE-HD study were used (baseline, 18 and 30 months). We found significant differences in the shape of the striatum between groups. Significant group-by-time interaction was observed for the putamen bilaterally, but not for caudate. A differential rate of shape change between groups over time was observed, with more significant deflation in the symp-HD group in comparison with the pre-HD and control groups. CAG repeats were correlated with bilateral striatal shape in pre-HD and symp-HD. Robust statistical analysis of the correlates of striatal shape change in HD has confirmed the suitability of striatal morphology as a potential biomarker correlated with CAG-repeat length, and potentially, an endophenotype.

Hippocampal morphology in Huntington's disease, implications for plasticity and pathogenesis: The IMAGE-HD study.

While striatal changes in Huntington's Disease (HD) are well established, few studies have investigated changes in the hippocampus, a key neuronal hub. Using MRI scans obtained from the IMAGE-HD study, hippocampi were manually traced and then analysed with the Spherical Harmonic Point Distribution Method (SPHARM-PDM) in 36 individuals with presymptomatic-HD, 37 with early symptomatic-HD, and 36 healthy matched controls. There were no significant differences in overall hippocampal volume between groups. Interestingly we found decreased bilateral hippocampal volume in people with symptomatic-HD who took selective serotonin reuptake inhibitors compared to those who did not, despite no significant differences in anxiety, depressive symptoms, or motor incapacity between the two groups. In symptomatic-HD, there was also significant shape deflation in the right hippocampal head, showing the utility of using manual tracing and SPHARM-PDM to characterise subtle shape changes which may be missed by other methods. This study confirms previous findings of the lack of hippocampal volumetric differentiation in presymptomatic-HD and symptomatic-HD compared to controls. We also find novel shape and volume findings in those with symptomatic-HD, especially in relation to decreased hippocampal volume in those treated with SSRIs.

Mixed longitudinal and cross-sectional analyses of deep gray matter and white matter using diffusion weighted images in premanifest and manifest Huntington's disease.

Changes in the brain of patients with Huntington's disease (HD) begin years before clinical onset, so it remains critical to identify biomarkers to track these early changes. Metrics derived from tensor modeling of diffusion-weighted MRIs (DTI), that indicate the microscopic brain structure, can add important information to regional volumetric measurements. This study uses two large-scale longitudinal, multicenter datasets, PREDICT-HD and IMAGE-HD, to trace changes in DTI of HD participants with a broad range of CAP scores (a product of CAG repeat expansion and age), including those with pre-manifest disease (i.e., prior to clinical onset). Utilizing a fully automated data-driven approach to study the whole brain divided in regions of interest, we traced changes in DTI metrics (diffusivity and fractional anisotropy) versus CAP scores, using sigmoidal and linear regression models. We identified points of inflection in the sigmoidal regression using change-point analysis. The deep gray matter showed more evident and earlier changes in DTI metrics over CAP scores, compared to the deep white matter. In the deep white matter, these changes were more evident and occurred earlier in superior and posterior areas, compared to anterior and inferior areas. The curves of mean diffusivity vs. age of HD participants within a fixed CAP score were different from those of controls, indicating that the disease has an additional effect to age on the microscopic brain structure. These results show the regional and temporal vulnerability of the white matter and deep gray matter in HD, with potential implications for experimental therapeutics.

Selective perforant-pathway atrophy in Huntington disease: MRI analysis of hippocampal subfields.

INTRODUCTION: While individuals with Huntington disease (HD) show memory impairment that indicates hippocampal dysfunction, the available literature does not consistently identify structural evidence for involvement of the whole hippocampus but rather suggests that hippocampal atrophy may be confined to certain hippocampal subregions. METHODS: We processed T1-weighted MRI from IMAGE-HD study using FreeSurfer 7.0 and compared the volumes of the hippocampal subfields among 36 early motor symptomatic (symp-HD), 40 pre-symptomatic (pre-HD), and 36 healthy control individuals across three timepoints over 36 months. RESULTS: Mixed-model analyses revealed significantly lower subfield volumes in symp-HD, compared with pre-HD and control groups, in the subicular regions of the perforant-pathway: presubiculum, subiculum, dentate gyrus, tail, and right molecular layer. These adjoining subfields aggregated into a single principal component, which demonstrated an accelerated rate of atrophy in the symp-HD. Volumes between pre-HD and controls did not show any significant difference. In the combined HD groups, CAG repeat length and disease burden score were associated with presubiculum, molecular layer, tail, and perforant-pathway subfield volumes. Hippocampal left tail and perforant-pathway subfields were associated with motor onset in the pre-HD group. CONCLUSIONS: Hippocampal subfields atrophy in early symptomatic HD affects key regions of the perforant-pathway, which may implicate the distinctive memory impairment at this stage of illness. Their volumetric associations with genetic and clinical markers suggest the selective susceptibility of these subfields to mutant Huntingtin and disease progression.

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.

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.

Cognition-oriented treatments and physical exercise on cognitive function in Huntington's disease: a systematic review.

Cognitive impairment is prevalent in Huntington's disease (HD), with no treatments currently available. While cognition-oriented treatments and physical exercise have shown efficacy in improving cognition in other populations, they have not been systematically reviewed in HD. This systematic review aims to examine the effects of cognitive and exercise interventions on cognition in HD, along with effects on psychosocial function, functional independence, and neuroimaging outcomes. Seventeen studies (three cognitive, seven exercise, seven combining cognitive and physical exercise) were included. While there was generally low certainty of evidence, interventions that included cognitive training appeared to have larger effect sizes on cognition, while physical exercise (alone or combined with cognitive rehabilitation or stimulation) showed negligible effect sizes. On the other hand, combined interventions had larger effects on psychosocial function. Finally, effects on functional independence appeared negligible following exercise and combined interventions, and effects on neuroimaging outcomes were inconclusive. Larger studies should seek to confirm the benefits of cognitive and physical interventions, and further explore changes in functional independence and neural outcomes.

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.

Investigating longitudinal changes to frontal cortico-striatal tracts in Huntington's disease: the IMAGE-HD study.

The striatum is the principal site of disease pathology in Huntington's disease and contains neural connections to numerous cortical brain regions. Studies examining abnormalities to neural connections find that white matter integrity is compromised in HD; however, further regional, and longitudinal investigation is required. This paper is the first longitudinal investigation into region-based white-matter integrity changes in Huntington's Disease. The aim of this study was to better understand how disease progression impacts white matter tracts connecting the striatum to the prefrontal and motor cortical regions in HD. We used existing neuroimaging data from IMAGE-HD, comprised of 25 pre-symptomatic, 27 symptomatic, and 25 healthy controls at three separate time points (baseline, 18-months, 30-months). Fractional anisotropy, axial diffusivity and radial diffusivity were derived as measures of white matter microstructure. The anatomical regions of interest were identified using the Desikan-Killiany brain atlas. A Group by Time repeated measures ANCOVA was conducted for each tract of interest and for each measure. We found significantly lower fractional anisotropy and significantly higher radial diffusivity in the symptomatic group, compared to both the pre-symptomatic group and controls (the latter two groups did not differ from each other), in the rostral middle frontal and superior frontal tracts; as well as significantly higher axial diffusivity in the rostral middle tracts only. We did not find a Group by Time interaction for any of the white matter integrity measures. These findings demonstrate that whilst the microstructure of white matter tracts, extending from the striatum to these regions of interest, are compromised during the symptomatic stages of Huntington's disease, 36-month follow-up did not show progressive changes in these measures. Additionally, no correlations were found between clinical measures and tractography changes, indicating further investigations into the relationship between tractography changes and clinical symptoms in Huntington's disease are required.

Longitudinal mapping of cortical surface changes in Huntington's Disease.

This paper investigated cortical folding in Huntington's disease to understand how disease progression impacts the surface of the cortex. Cortical morphometry changes in eight gyral based regions of interest (i.e. the left and right hemispheres of the lateral occipital, precentral, superior frontal and rostral middle gyri) were examined. We used existing neuroimaging data from IMAGE-HD, comprising 26 pre-symptomatic, 26 symptomatic and 24 healthy control individuals at three separate time points (baseline, 18-month, 30-month). Local gyrification index and cortical thickness were derived as the measures of cortical morphometry using FreeSurfer 6.0's longitudinal pipeline. The gyral based regions of interest were identified using the Desikan-Killiany Atlas. A Group by Time repeated measures ANCOVA was conducted for each region of interest. We found significantly lower LGI at a group level in the right hemisphere lateral occipital region and both hemispheres of the precentral region; as well as significantly reduced cortical thickness at a group level in both hemispheres of the lateral occipital and precentral regions and the right hemisphere of the superior frontal region. We also found a Group by Time interaction for Local gyrification index in the right hemisphere lateral occipital region. This change was largely driven by a significant decrease in the symptomatic group between baseline and 18-months. Additionally, lower local gyrification index and cortical thickness were associated with higher disease burden score. These findings demonstrate that significant longitudinal decline in right hemisphere local gyrification index is evident during manifest disease in lateral occipital cortex and that these changes are more profound in individuals with greater disease burden score.

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.

Profiling Social Cognition in Premanifest Huntington's Disease.

OBJECTIVE: Discrepancies exist in reports of social cognition deficits in individuals with premanifest Huntington's disease (HD); however, the reason for this variability has not been investigated. The aims of this study were to (1) evaluate group- and individual-level social cognitive performance and (2) examine intra-individual variability (dispersion) across social cognitive domains in individuals with premanifest HD. METHOD: Theory of mind (ToM), social perception, empathy, and social connectedness were evaluated in 35 individuals with premanifest HD and 29 healthy controls. Cut-off values beneath the median and 1.5 × the interquartile range below the 25th percentile (P25 - 1.5 × IQR) of healthy controls for each variable were established for a profiling method. Dispersion between social cognitive domains was also calculated. RESULTS: Compared to healthy controls, individuals with premanifest HD performed worse on all social cognitive domains except empathy. Application of the profiling method revealed a large proportion of people with premanifest HD fell below healthy control median values across ToM (>80%), social perception (>57%), empathy (>54%), and social behaviour (>40%), with a percentage of these individuals displaying more pronounced impairments in empathy (20%) and ToM (22%). Social cognition dispersion did not differ between groups. No significant correlations were found between social cognitive domains and mood, sleep, and neurocognitive outcomes. CONCLUSIONS: Significant group-level social cognition deficits were observed in the premanifest HD cohort. However, our profiling method showed that only a small percentage of these individuals experienced marked difficulties in social cognition, indicating the importance of individual-level assessments, particularly regarding future personalised treatments.

Longitudinal investigation of brain activation during motor tasks in Friedreich ataxia: 24-month data from IMAGE-FRDA.

Friedreich ataxia (FRDA) is a progressive autosomal recessive disease. While motor dysfunction is the primary neurological hallmark, little is known about the underlying neurobiological changes associated with motor deficits over the course of disease. We investigated the hypothesis that progressive functional changes in both the cerebellum and cerebrum are related to longitudinal changes in performance on complex motor tasks in individuals with FRDA. Twenty-two individuals with FRDA and 28 controls participated over 24 months. The longitudinal investigation included finger tapping tasks with different levels of complexity (i.e., visually cued, multi-finger; self-paced, single finger), performed in conjunction with fMRI acquisitions, to interrogate changes in the neurobiology of motor and attentional brain networks including the cerebellum and cerebrum. We demonstrated evidence for significant longitudinal decreased cerebral fMRI activity over time in individuals with FRDA, relative to controls, during an attentionally-demanding motor task (visually cued tapping of multiple fingers) in six cerebral regions: right and left superior frontal gyri, right superior temporal gyrus, right primary somatosensory area, right anterior cingulate cortex, and right medial frontal gyrus. Importantly, longitudinal decreased activity was associated with more severe disease status at baseline, higher GAA1 repeat length and earlier age of onset. These findings suggest a dynamic pattern of neuronal activity in motor, attention and executive control networks over time in individuals with FRDA, which is associated with increased disease severity at baseline, increased GAA1 repeat length and earlier age at onset.

Recommendations to Optimize the Use of Volumetric MRI in Huntington's Disease Clinical Trials.

Volumetric magnetic resonance imaging (vMRI) has been widely studied in Huntington's disease (HD) and is commonly used to assess treatment effects on brain atrophy in interventional trials. Global and regional trajectories of brain atrophy in HD, with early involvement of striatal regions, are becoming increasingly understood. However, there remains heterogeneity in the methods used and a lack of widely-accessible multisite, longitudinal, normative datasets in HD. Consensus for standardized practices for data acquisition, analysis, sharing, and reporting will strengthen the interpretation of vMRI results and facilitate their adoption as part of a pathobiological disease staging system. The Huntington's Disease Regulatory Science Consortium (HD-RSC) currently comprises 37 member organizations and is dedicated to building a regulatory science strategy to expedite the approval of HD therapeutics. Here, we propose four recommendations to address vMRI standardization in HD research: (1) a checklist of standardized practices for the use of vMRI in clinical research and for reporting results; (2) targeted research projects to evaluate advanced vMRI methodologies in HD; (3) the definition of standard MRI-based anatomical boundaries for key brain structures in HD, plus the creation of a standard reference dataset to benchmark vMRI data analysis methods; and (4) broad access to raw images and derived data from both observational studies and interventional trials, coded to protect participant identity. In concert, these recommendations will enable a better understanding of disease progression and increase confidence in the use of vMRI for drug development.

Volumetric MRI-Based Biomarkers in Huntington's Disease: An Evidentiary Review.

Huntington's disease (HD) is an autosomal-dominant inherited neurodegenerative disorder that is caused by expansion of a CAG-repeat tract in the huntingtin gene and characterized by motor impairment, cognitive decline, and neuropsychiatric disturbances. Neuropathological studies show that disease progression follows a characteristic pattern of brain atrophy, beginning in the basal ganglia structures. The HD Regulatory Science Consortium (HD-RSC) brings together diverse stakeholders in the HD community-biopharmaceutical industry, academia, nonprofit, and patient advocacy organizations-to define and address regulatory needs to accelerate HD therapeutic development. Here, the Biomarker Working Group of the HD-RSC summarizes the cross-sectional evidence indicating that regional brain volumes, as measured by volumetric magnetic resonance imaging, are reduced in HD and are correlated with disease characteristics. We also evaluate the relationship between imaging measures and clinical change, their longitudinal change characteristics, and within-individual longitudinal associations of imaging with disease progression. This analysis will be valuable in assessing pharmacodynamics in clinical trials and supporting clinical outcome assessments to evaluate treatment effects on neurodegeneration.

Utility of Huntington's Disease Assessments by Disease Stage: Floor/Ceiling Effects.

Introduction: An understanding of the clinimetric properties of clinical assessments, including their constraints, is critical to sound clinical study and trial design. Utilizing data from Enroll-HD-a global, prospective HD observational study and clinical research platform-we examined several well-established HD clinical assessments across all stages of disease for evidence of instrument constraints, specifically floor/ceiling effects, to inform selection of appropriate instruments for use in future studies/trials and identify gaps in instrument utility over the life-course of the disease. Material and Methods: Analyzing publicly available data from 6,614 HD gene-expansion carriers (HDGECs), we grouped participants into deciles based on baseline CAP score, which ranged from 26 to 229. We used descriptive statistics to characterize data distribution for 25 outcome measures (encompassing motor, function, cognition, and psychiatric/behavioral domains) in each CAP decile. A skewness statistic threshold of ±2 was defined a priori to indicate floor/ceiling effects. Results: We found evidence of floor/ceiling effects in the early premanifest stages of disease for most motor and function assessments (e.g., TMS, TFC) and select cognitive tasks (MMSE, Trail Making tests). Other cognitive assessments, and the HADS-SIS scales, performed well ubiquitously, with no evidence of floor/ceiling effects at any disease stage. Floor/ceiling effects were evident at every disease stage for certain assessments, including PBA-s measures. Ceiling effects were apparent for DCL from onset stages onwards, as expected. Discussion: Developing instruments sensitive to subtle differences in performance at the earlier stages of the disease spectrum, particularly in motor and function domains, is warranted.

A Multi-Study Model-Based Evaluation of the Sequence of Imaging and Clinical Biomarker Changes in Huntington's Disease.

Understanding the order and progression of change in biomarkers of neurodegeneration is essential to detect the effects of pharmacological interventions on these biomarkers. In Huntington's disease (HD), motor, cognitive and MRI biomarkers are currently used in clinical trials of drug efficacy. Here for the first time we use directly compare data from three large observational studies of HD (total N = 532) using a probabilistic event-based model (EBM) to characterise the order in which motor, cognitive and MRI biomarkers become abnormal. We also investigate the impact of the genetic cause of HD, cytosine-adenine-guanine (CAG) repeat length, on progression through these stages. We find that EBM uncovers a broadly consistent order of events across all three studies; that EBM stage reflects clinical stage; and that EBM stage is related to age and genetic burden. Our findings indicate that measures of subcortical and white matter volume become abnormal prior to clinical and cognitive biomarkers. Importantly, CAG repeat length has a large impact on the timing of onset of each stage and progression through the stages, with a longer repeat length resulting in earlier onset and faster progression. Our results can be used to help design clinical trials of treatments for Huntington's disease, influencing the choice of biomarkers and the recruitment of participants.