Apathy predicts rate of cognitive decline over 24 months in premanifest Huntington's disease

Background Cognitive impairment is a core feature of Huntington's disease (HD), however, the onset and rate of cognitive decline is highly variable. Apathy is the most common neuropsychiatric symptom of HD, and is associated with cognitive impairment. The aim of this study was to investigate apathy as a predictor of subsequent cognitive decline over 2 years in premanifest and early HD, using a prospective, longitudinal design. Methods A total of 118 premanifest HD gene carriers, 111 early HD and 118 healthy control participants from the multi-centre TRACK-HD study were included. Apathy symptoms were assessed at baseline using the apathy severity rating from the Short Problem Behaviours Assessment. A composite of 12 outcome measures from nine cognitive tasks was used to assess cognitive function at baseline and after 24 months. Results In the premanifest group, after controlling for age, depression and motor signs, more apathy symptoms predicted faster cognitive decline over 2 years. In contrast, in the early HD group, more motor signs, but not apathy, predicted faster subsequent cognitive decline. In the control group, only older age predicted cognitive decline. Conclusions Our findings indicate that in premanifest HD, apathy is a harbinger for cognitive decline. In contrast, after motor onset, in early diagnosed HD, motor symptom severity more strongly predicts the rate of cognitive decline.Neurological Motor Disorder

A genetic association study of glutamine-encoding DNA sequence structures, somatic CAG expansion, and DNA repair gene variants, with Huntington disease clinical outcomes

Background: Huntington disease (HD) is caused by an unstable CAG/CAA repeat expansion encoding a toxic polyglutamine tract. Here, we tested the hypotheses that HD outcomes are impacted by somatic expansion of, and polymorphisms within, the HTT CAG/CAA glutamine-encoding repeat, and DNA repair genes. Methods: The sequence of the glutamine-encoding repeat and the proportion of somatic CAG expansions in blood DNA from participants inheriting 40 to 50 CAG repeats within the TRACK-HD and Enroll-HD cohorts were determined using high-throughput ultra-deep-sequencing. Candidate gene polymorphisms were genotyped using kompetitive allele-specific PCR (KASP). Genotypic associations were assessed using time-to-event and regression analyses. Findings: Using data from 203 TRACK-HD and 531 Enroll-HD participants, we show that individuals with higher blood DNA somatic CAG repeat expansion scores have worse HD outcomes: a one-unit increase in somatic expansion score was associated with a Cox hazard ratio for motor onset of 3·05 (95% CI = 1·94 to 4·80, p = 1·3 × 10−6). We also show that individual-specific somatic expansion scores are associated with variants in FAN1 (pFDR = 4·8 × 10-6), MLH3 (pFDR = 8·0 × 10−4), MLH1 (pFDR = 0·004) and MSH3 (pFDR = 0·009). We also show that HD outcomes are best predicted by the number of pure CAGs rather than total encoded-glutamines. Interpretation: These data establish pure CAG length, rather than encoded-glutamine, as the key inherited determinant of downstream pathophysiology. These findings have implications for HD diagnostics, and support somatic expansion as a mechanistic link for genetic modifiers of clinical outcomes, a driver of disease, and potential therapeutic target in HD and related repeat expansion disorders

Composite UHDRS Correlates With Progression of Imaging Biomarkers in Huntington's Disease

Background The composite Unified Huntington's Disease Rating Scale (cUHDRS) is a multidimensional measure of progression in Huntington's disease (HD) being used as a primary outcome in clinical trials investigating potentially disease-modifying huntingtin-lowering therapies.Objective Evaluating volumetric and structural connectivity correlates of the cUHDRS.Methods One hundred and nineteen premanifest and 119 early-HD participants were included. Gray and white matter (WM) volumes were correlated with cUHDRS cross-sectionally and longitudinally using voxel-based morphometry. Correlations between baseline fractional anisotropy (FA); mean, radial, and axial diffusivity; and baseline cUHDRS were examined using tract-based spatial statistics.Results Worse performance in the cUHDRS over time correlated with longitudinal volume decreases in the occipito-parietal cortex and centrum semiovale, whereas lower baseline scores correlated with decreased volume in the basal ganglia and surrounding WM. Lower cUHDRS scores were also associated with reduced FA and increased diffusivity at baseline.Conclusion The cUHDRS correlates with imaging biomarkers and tracks atrophy progression in HD supporting its biological relevance. (c) 2021 International Parkinson and Movement Disorder SocietyNeurological Motor Disorder

STRUCTURAL CONNECTIVITY IN HUNTINGTON'S DISEASE

Neurological Motor Disorder

DIFFUSION TENSOR IMAGING AND NEUROPSYCHIATRIC DISTURBANCE IN HUNTINGTON'S DISEASE

Neurological Motor Disorder

CORTICAL THINNING OF THE OCCIPITAL LOBE IN HUNTINGTON'S DISEASE AND ASSOCIATIONS WITH COGNITIVE PERFORMANCE

Neurological Motor Disorder

The impact of occipital lobe cortical thickness on cognitive task performance : An investigation in Huntington's Disease

Background: The occipital lobe is an important visual processing region of the brain. Following consistent findings of early neural changes in the occipital lobe in Huntington's Disease (HD), we examined cortical thickness across four occipital regions in premanifest (preHD) and early HD groups compared with controls. Associations between cortical thickness in gene positive individuals and performance on six cognitive tasks, each with a visual component, were examined. In addition, the association between cortical thickness in gene positive participants and one non-visual motor task was also examined for comparison. Methods: Cortical thickness was determined using FreeSurfer on T1-weighted 3T MR datasets from controls (N=97), preHD (N=109) and HD (N=69) from the TRACK-HD study. Regression models were fitted to assess between-group differences in cortical thickness, and relationships between performance on the cognitive tasks, the motor task and occipital thickness were examined in a subset of gene-positive participants (N=141). Results: Thickness of the occipital cortex in preHD and early HD participants was reduced compared with controls. Regionally-specific associations between reduced cortical thickness and poorer performance were found for five of the six cognitive tasks, with the strongest associations in lateral occipital and lingual regions. No associations were found with the cuneus. The non-visual motor task was not associated with thickness of any region. Conclusions: The heterogeneous pattern of associations found in the present study suggests that occipital thickness negatively impacts cognition, but only in regions that are linked to relatively advanced visual processing (e.g., lateral occipital, lingual regions), rather than in basic visual processing regions such as the cuneus. Our results show, for the first time, the functional implications of occipital atrophy highlighted in recent studies in HD

Early atrophy of pallidum and accumbens nucleus in Huntington's disease

In Huntington's disease (HD) atrophy of the caudate nucleus and putamen has been described many years before clinical manifestation. Volume changes of the pallidum, thalamus, brainstem, accumbens nucleus, hippocampus, and amygdala are less well investigated, or reported with contradicting results. The aim of our study is to provide a more precise view of the specific atrophy of the subcortical grey matter structures in different stages of Huntington's disease, and secondly to investigate how this influences the clinical manifestations. All TRACK-HD subjects underwent standardised T1-weighted 3T MRI scans encompassing 123 manifest HD (stage 1, n = 77; stage 2, n = 46), 120 premanifest HD (close to onset n = 58, far from onset n = 62) and 123 controls. Using FMRIB's FIRST and SIENAX tools the accumbens nucleus, amygdala, brainstem, caudate nucleus, hippocampus, pallidum, putamen, thalamus and whole brain volume were extracted. Results showed that volumes of the caudate nucleus and putamen were reduced in premanifest HD far from predicted onset (> 10.8 years). Atrophy of accumbens nucleus and pallidum was apparent in premanifest HD in the close to onset group (0-10.8 years). All other structures were affected to some degree in the manifest group, although brainstem, thalamus and amygdala were relatively spared. The accumbens nucleus, putamen, pallidum and hippocampus had a strong significant correlation with functional and motor scores. We conclude that volume changes may be a sensitive and reliable measure for early disease detection and in this way serve as a biomarker for Huntington's disease. Besides the caudate nucleus and putamen, the pallidum and the accumbens nucleus show great potential in this respect.Neurological Motor Disorder

Operationalizing compensation over time in neurodegenerative disease

Neurological Motor Disorder