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.

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.

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.

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.

A gyrification analysis approach based on Laplace Beltrami eigenfunction level sets.

An accurate measure of the complexity of patterns of cortical folding or gyrification is necessary for understanding normal brain development and neurodevelopmental disorders. Conventional gyrification indices (GIs) are calculated based on surface curvature (curvature-based GI) or an outer hull surface of the cortex (outer surface-based GI). The latter is dependent on the definition of the outer hull surface and a corresponding function between surfaces. In the present study, we propose the Laplace Beltrami-based gyrification index (LB-GI). This is a new curvature-based local GI computed using the first three Laplace Beltrami eigenfunction level sets. As with outer surface-based GI methods, this method is based on the hypothesis that gyrification stems from a flat surface during development. However, instead of quantifying gyrification with reference to corresponding points on an outer hull surface, LB-GI quantifies the gyrification at each point on the cortical surface with reference to their surrounding gyral points, overcoming several shortcomings of existing methods. The LB-GI was applied to investigate the cortical maturation profile of the human brain from preschool to early adulthood using the PING database. The results revealed more detail in patterns of cortical folding than conventional curvature-based methods, especially on frontal and posterior tips of the brain, such as the frontal pole, lateral occipital, lateral cuneus, and lingual. Negative associations of cortical folding with age were observed at cortical regions, including bilateral lingual, lateral occipital, precentral gyrus, postcentral gyrus, and superior frontal gyrus. The results also indicated positive significant associations between age and the LB-GI of bilateral insula, the medial orbitofrontal, frontal pole and rostral anterior cingulate regions. It is anticipated that the LB-GI will be advantageous in providing further insights in the understanding of brain development and degeneration in large clinical neuroimaging studies.

Robust Markers and Sample Sizes for Multicenter Trials of Huntington Disease.

OBJECTIVE: The identification of sensitive biomarkers is essential to validate therapeutics for Huntington disease (HD). We directly compare structural imaging markers across the largest collective imaging HD dataset to identify a set of imaging markers robust to multicenter variation and to derive upper estimates on sample sizes for clinical trials in HD. METHODS: We used 1 postprocessing pipeline to retrospectively analyze T1-weighted magnetic resonance imaging (MRI) scans from 624 participants at 3 time points, from the PREDICT-HD, TRACK-HD, and IMAGE-HD studies. We used mixed effects models to adjust regional brain volumes for covariates, calculate effect sizes, and simulate possible treatment effects in disease-affected anatomical regions. We used our model to estimate the statistical power of possible treatment effects for anatomical regions and clinical markers. RESULTS: We identified a set of common anatomical regions that have similarly large standardized effect sizes (>0.5) between healthy control and premanifest HD (PreHD) groups. These included subcortical, white matter, and cortical regions and nonventricular cerebrospinal fluid (CSF). We also observed a consistent spatial distribution of effect size by region across the whole brain. We found that multicenter studies were necessary to capture treatment effect variance; for a 20% treatment effect, power of >80% was achieved for the caudate (n = 661), pallidum (n = 687), and nonventricular CSF (n = 939), and, crucially, these imaging markers provided greater power than standard clinical markers. INTERPRETATION: Our findings provide the first cross-study validation of structural imaging markers in HD, supporting the use of these measurements as endpoints for both observational studies and clinical trials. ANN NEUROL 2020;87:751-762.

Early white matter pathology in the fornix of the limbic system in Huntington disease.

Huntington disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene. The typical motor symptoms have been associated with basal ganglia pathology. However, psychiatric and cognitive symptoms often precede the motor component and may be due to changes in the limbic system. Recent work has indicated pathology in the hypothalamus in HD but other parts of the limbic system have not been extensively studied. Emerging evidence suggests that changes in HD also include white matter pathology. Here we investigated if the main white matter tract of the limbic system, the fornix, is affected in HD. We demonstrate that the fornix is 34% smaller already in prodromal HD and 41% smaller in manifest HD compared to controls using volumetric analyses of MRI of the IMAGE-HD study. In post-mortem fornix tissue from HD cases, we confirm the smaller fornix volume in HD which is accompanied by signs of myelin breakdown and reduced levels of the transcription factor myelin regulating factor but detect no loss of oligodendrocytes. Further analyses using RNA-sequencing demonstrate downregulation of oligodendrocyte identity markers in the fornix of HD cases. Analysis of differentially expressed genes based on transcription-factor/target-gene interactions also revealed enrichment for binding sites of SUZ12 and EZH2, components of the Polycomb Repressive Complex 2, as well as RE1 Regulation Transcription Factor. Taken together, our data show that there is early white matter pathology of the fornix in the limbic system in HD likely due to a combination of reduction in oligodendrocyte genes and myelin break down.

Tracking Huntington's Disease Progression Using Motor, Functional, Cognitive, and Imaging Markers.

BACKGROUND: Potential therapeutic targets and clinical trials for Huntington's disease have grown immensely in the last decade. However, to improve clinical trial outcomes, there is a need to better characterize profiles of signs and symptoms across different epochs of the disease to improve selection of participants. OBJECTIVE: The objective of the present study was to best distinguish longitudinal trajectories across different Huntington's disease progression groups. METHODS: Clinical and morphometric imaging data from 1082 participants across IMAGE-HD, TRACK-HD, and PREDICT-HD studies were combined, with longitudinal times ranging between 1 and 10 years. Participants were classified into 4 groups using CAG and age product. Using multivariate linear mixed modeling, 63 combinations of markers were tested for their sensitivity in differentiating CAG and age product groups. Next, multivariate linear mixed modeling was applied to define the best combination of markers to track progression across individual CAG and age product groups. RESULTS: Putamen and caudate volumes, individually and/or combined, were identified as the best variables to both differentiate CAG and age product groups and track progression within them. The model using only caudate volume best described advanced disease progression in the combined data set. Contrary to expectations, combining clinical markers and volumetric measures did not improve tracking longitudinal progression. CONCLUSIONS: Monitoring volumetric changes throughout a trial (alongside primary and secondary clinical end points) may provide a more comprehensive understanding of improvements in functional outcomes and help to improve the design of clinical trials. Alternatively, our results suggest that imaging deserves consideration as an end point in clinical trials because of the prospect of greater sensitivity. © 2021 International Parkinson and Movement Disorder Society.

Cortical morphometry and neural dysfunction in Huntington's disease: a review.

Numerous neuroimaging techniques have been used to identify biomarkers of disease progression in Huntington's disease (HD). To date, the earliest and most sensitive of these is caudate volume; however, it is becoming increasingly evident that numerous changes to cortical structures, and their interconnected networks, occur throughout the course of the disease. The mechanisms by which atrophy spreads from the caudate to these cortical regions remains unknown. In this review, the neuroimaging literature specific to T1-weighted and diffusion-weighted magnetic resonance imaging is summarized and new strategies for the investigation of cortical morphometry and the network spread of degeneration in HD are proposed. This new avenue of research may enable further characterization of disease pathology and could add to a suite of biomarker/s of disease progression for patient stratification that will help guide 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.

Accuracy of automated amygdala MRI segmentation approaches in Huntington's disease in the IMAGE-HD cohort.

Smaller manually-segmented amygdala volumes have been associated with poorer motor and cognitive function in Huntington's disease (HD). Manual segmentation is the gold standard in terms of accuracy; however, automated methods may be necessary in large samples. Automated segmentation accuracy has not been determined for the amygdala in HD. We aimed to determine which of three automated approaches would most accurately segment amygdalae in HD: FreeSurfer, FIRST, and ANTS nonlinear registration followed by FIRST segmentation. T1-weighted images for the IMAGE-HD cohort including 35 presymptomatic HD (pre-HD), 36 symptomatic HD (symp-HD), and 34 healthy controls were segmented using FreeSurfer and FIRST. For the third approach, images were nonlinearly registered to an MNI template using ANTS, then segmented using FIRST. All automated methods overestimated amygdala volumes compared with manual segmentation. Dice overlap scores, indicating segmentation accuracy, were not significantly different between automated approaches. Manually segmented volumes were most statistically differentiable between groups, followed by those segmented by FreeSurfer, then ANTS/FIRST. FIRST-segmented volumes did not differ between groups. All automated methods produced a bias where volume overestimation was more severe for smaller amygdalae. This bias was subtle for FreeSurfer, but marked for FIRST, and moderate for ANTS/FIRST. Further, FreeSurfer introduced a hemispheric bias not evident with manual segmentation, producing larger right amygdalae by 8%. To assist choice of segmentation approach, we provide sample size estimation graphs based on sample size and other factors. If automated segmentation is employed in samples of the current size, FreeSurfer may effectively distinguish amygdala volume between controls and HD.

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.

Brain compensation during response inhibition in premanifest Huntington's disease.

Premanifest Huntington's disease (pre-HD) individuals typically show increased task-related functional magnetic resonance imaging (fMRI), suggested to reflect compensatory strategies. Despite the evidence, no study has attempted to understand the compensatory process in light of 'formal' models of compensation. We used a quantitative model of compensation - the Compensation-Related Utilization of Neural Circuits Hypothesis (CRUNCH), to characterise compensation in pre-HD using fMRI. Pre-HD individuals (n = 15) and controls (n = 15) performed a modified stop-signal task that incremented in four levels of stop difficulty. Our results did not support the critical assumption of the CRUNCH model - controls did not show increased fMRI activity with increased level of stop difficulty; however, controls showed decreased fMRI activity with increased stop difficulty in right inferior frontal gyrus and right caudate nucleus. Relative to controls, pre-HD individuals showed increased fMRI activity in right inferior frontal gyrus and in right caudate nucleus at higher levels of stop difficulty, which is the opposite effect to that predicted by the model. Our findings suggest a compensatory process of the response inhibition network in pre-HD; however, the pattern of fMRI activity was not in the manner expected by CRUNCH.

Network spread determines severity of degeneration and disconnection in Huntington's disease.

Trans-neuronal propagation of mutant huntingtin protein contributes to the organised spread of cortico-striatal degeneration and disconnection in Huntington's disease (HD). We investigated whether the network diffusion model, which models transneuronal spread as diffusion of pathological proteins via the brain connectome, can determine the severity of neural degeneration and disconnection in HD. We used structural magnetic resonance imaging (MRI) and high-angular resolution diffusion weighted imaging (DWI) data from symptomatic Huntington's disease (HD) (N = 26) and age-matched healthy controls (N = 26) to measure neural degeneration and disconnection in HD. The network diffusion model was used to test whether disease spread, via the human brain connectome, is a viable mechanism to explain the distribution of pathology across the brain. We found that an eigenmode identified in the healthy human brain connectome Laplacian matrix, accurately predicts the cortico-striatal spatial pattern of degeneration in HD. Furthermore, the spread of neural degeneration from sub-cortical brain regions, including the accumbens and thalamus, generates a spatial pattern which represents the typical neurodegenerative characteristics in HD. The white matter connections connecting the nodes with the highest amount of disease factors, when diffusion based disease spread is initiated from the striatum, were found to be most vulnerable to disconnection in HD. These findings suggest that trans-neuronal diffusion of mutant huntingtin protein across the human brain connectome may explain the pattern of gray matter degeneration and white matter disconnection that are hallmarks of HD.

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.

Emotion Recognition Correlates With Social-Neuropsychiatric Dysfunction in Huntington's Disease.

OBJECTIVES: People with Huntington's disease (HD) experience poor social quality of life, relationship breakdown, and social withdrawal, which are mediated to some extent by socially debilitating neuropsychiatric symptoms, such as apathy and disinhibition. Social cognitive symptoms, such as impaired emotion recognition, also occur in HD, however, the extent of their association with these socially debilitating neuropsychiatric symptoms is unknown. Our study examined the relationship between emotion recognition and symptom ratings of apathy and disinhibition in HD. METHODS: Thirty-two people with premanifest or symptomatic-HD completed Part 1 of The Awareness of Social Inference Test (TASIT), which is a facial emotion recognition task. In addition, we obtained severity ratings for apathy and disinhibition on the Frontal Systems Behavior Scale (FrSBe) from a close family member. Our analyses used motor symptom severity as a proxy for disease progression. RESULTS: Emotion recognition performance was significantly associated with family-ratings of apathy, above and beyond their shared association with disease severity. We found a similar pattern for disinhibition ratings, which fell short of statistical significance. As expected, worse emotion recognition performance was correlated with higher severity in FrSBe symptom ratings. CONCLUSIONS: Our findings suggest that emotion recognition abilities relate to key socially debilitating neuropsychiatric symptoms in HD. Our results help to understand the functional significance of emotion recognition impairments in HD, and may have implications for the development of remediation programs aimed at improving patients' social quality of life. (JINS, 2018, 24, 417-423).

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.