Natural variation in sensory-motor white matter organization influences manifestations of Huntington's disease.

While the HTT CAG-repeat expansion mutation causing Huntington's disease (HD) is highly correlated with the rate of pathogenesis leading to disease onset, considerable variance in age-at-onset remains unexplained. Therefore, other factors must influence the pathogenic process. We asked whether these factors were related to natural biological variation in the sensory-motor system. In 243 participants (96 premanifest and 35 manifest HD; 112 controls), sensory-motor structural MRI, tractography, resting-state fMRI, electrophysiology (including SEP amplitudes), motor score ratings, and grip force as sensory-motor performance were measured. Following individual modality analyses, we used principal component analysis (PCA) to identify patterns associated with sensory-motor performance, and manifest versus premanifest HD discrimination. We did not detect longitudinal differences over 12 months. PCA showed a pattern of loss of caudate, grey and white matter volume, cortical thickness in premotor and sensory cortex, and disturbed diffusivity in sensory-motor white matter tracts that was connected to CAG repeat length. Two further major principal components appeared in controls and HD individuals indicating that they represent natural biological variation unconnected to the HD mutation. One of these components did not influence HD while the other non-CAG-driven component of axial versus radial diffusivity contrast in white matter tracts were associated with sensory-motor performance and manifest HD. The first component reflects the expected CAG expansion effects on HD pathogenesis. One non-CAG-driven component reveals an independent influence on pathogenesis of biological variation in white matter tracts and merits further investigation to delineate the underlying mechanism and the potential it offers for disease modification. Hum Brain Mapp 37:4615-4628, 2016. © 2016 Wiley Periodicals, Inc.

Biological and clinical manifestations of Huntington's disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data.

BACKGROUND: Huntington's disease (HD) is an autosomal dominant, fully penetrant, neurodegenerative disease that most commonly affects adults in mid-life. Our aim was to identify sensitive and reliable biomarkers in premanifest carriers of mutated HTT and in individuals with early HD that could provide essential methodology for the assessment of therapeutic interventions. METHODS: This multicentre study uses an extensive battery of novel assessments, including multi-site 3T MRI, clinical, cognitive, quantitative motor, oculomotor, and neuropsychiatric measures. Blinded analyses were done on the baseline cross-sectional data from 366 individuals: 123 controls, 120 premanifest (pre-HD) individuals, and 123 patients with early HD. FINDINGS: The first participant was enrolled in January, 2008, and all assessments were completed by August, 2008. Cross-sectional analyses identified significant changes in whole-brain volume, regional grey and white matter differences, impairment in a range of voluntary neurophysiological motor, and oculomotor tasks, and cognitive and neuropsychiatric dysfunction in premanifest HD gene carriers with normal motor scores through to early clinical stage 2 disease. INTERPRETATION: We show the feasibility of rapid data acquisition and the use of multi-site 3T MRI and neurophysiological motor measures in a large multicentre study. Our results provide evidence for quantifiable biological and clinical alterations in HTT expansion carriers compared with age-matched controls. Many parameters differ from age-matched controls in a graded fashion and show changes of increasing magnitude across our cohort, who range from about 16 years from predicted disease diagnosis to early HD. These findings might help to define novel quantifiable endpoints and methods for rapid and reliable data acquisition, which could aid the design of therapeutic trials.

Topological length of white matter connections predicts their rate of atrophy in premanifest Huntington's disease.

We lack a mechanistic explanation for the stereotyped pattern of white matter loss seen in Huntington's disease (HD). While the earliest white matter changes are seen around the striatum, within the corpus callosum, and in the posterior white matter tracts, the order in which these changes occur and why these white matter connections are specifically vulnerable is unclear. Here, we use diffusion tractography in a longitudinal cohort of individuals yet to develop clinical symptoms of HD to identify a hierarchy of vulnerability, where the topological length of white matter connections between a brain area and its neighbors predicts the rate of atrophy over 24 months. This demonstrates a new principle underlying neurodegeneration in HD, whereby brain connections with the greatest topological length are the first to suffer damage that can account for the stereotyped pattern of white matter loss observed in premanifest HD.

Therapeutic strategies for circadian rhythm and sleep disturbances in Huntington disease.

Aside from the well-known motor, cognitive and psychiatric signs and symptoms, Huntington disease (HD) is also frequently complicated by circadian rhythm and sleep disturbances. Despite the observation that these disturbances often precede motor onset and have a high prevalence, no studies are available in HD patients which assess potential treatments. In this review, we will briefly outline the nature of circadian rhythm and sleep disturbances in HD and subsequently focus on potential treatments based on findings in other neurodegenerative diseases with similarities to HD, such as Parkinson and Alzheimer disease. The most promising treatment options to date for circadian rhythm and sleep disruption in HD include melatonin (agonists) and bright light therapy, although further corroboration in clinical trials is warranted.

Making (anti-) sense out of huntingtin levels in Huntington disease.

BACKGROUND: Huntington disease (HD) is an autosomal dominant neurodegenerative disorder, characterized by motor, psychiatric and cognitive symptoms. HD is caused by a CAG repeat expansion in the first exon of the HTT gene, resulting in an expanded polyglutamine tract at the N-terminus of the huntingtin protein. Typical disease onset is around mid-life (adult-onset HD) whereas onset below 21 years is classified as juvenile HD. While much research has been done on the underlying HD disease mechanisms, little is known about regulation and expression levels of huntingtin RNA and protein. RESULTS: In this study we used 15 human post-mortem HD brain samples to investigate the expression of wild-type and mutant huntingtin mRNA and protein. In adult-onset HD brain samples, there was a small but significantly lower expression of mutant huntingtin mRNA compared to wild-type huntingtin mRNA, while wild-type and mutant huntingtin protein expression levels did not differ significantly. Juvenile HD subjects did show a lower expression of mutant huntingtin protein compared to wild-type huntingtin protein. Our results in HD brain and fibroblasts suggest that protein aggregation does not affect levels of huntingtin RNA and protein. Additionally, we did not find any evidence for a reduced expression of huntingtin antisense in fibroblasts derived from a homozygous HD patient. CONCLUSIONS: We found small differences in allelic huntingtin mRNA levels in adult-onset HD brain, with significantly lower mutant huntingtin mRNA levels. Wild-type and mutant huntingtin protein were not significantly different in adult-onset HD brain samples. Conversely, in juvenile HD brain samples mutant huntingtin protein levels were lower compared with wild-type huntingtin, showing subtle differences between juvenile HD and adult-onset HD. Since most HD model systems harbor juvenile repeat expansions, our results suggest caution with the interpretation of huntingtin mRNA and protein studies using HD cell and animal models with such long repeats. Furthermore, our huntingtin antisense results in homozygous HD cells do not support reduced huntingtin antisense expression due to an expanded CAG repeat.

High prevalence of vitamin D deficiency and insufficiency in patients with manifest Huntington disease: An explorative study.

Vitamin D deficiency and insufficiency are common in older institutionalized people and known to be associated with muscle weakness, impaired balance and increased fall risk. Falls and balance problems are common in people with Huntington disease (HD). Despite this, the prevalence of vitamin D deficiency in patients with manifest HD has never been investigated. Serum 25(OH)D levels were measured in routinely drawn blood samples from 28 Dutch institutionalized patients with manifest Huntington disease. Mean serum 25(OH)D level was 33 nmol/l (SD 15). Twenty-five subjects (89%) were vitamin D deficient or insufficient (25(OH)D < 50 nmol/L). A positive association was found between serum 25(OH)D levels and Functional Ambulation Classification (FAC) scores (p = 0.023).

Genetic diagnosis of hyperkinetic movement disorders.

INTRODUCTION: People with hyperkinetic movements have always attracted the attention of the public and professionals. Alert colleagues noticed families in which a disease passed from generation to generation around Lake Maracaibo in Venezuela. This study led in 1993 to the localization of the gene for Huntington disease on chromosome 4. The genetic basis of many other familial and sporadic diseases has been identified on human DNA. AREAS COVERED: The clinical presentation of hyperkinesias remains the starting point for diagnosis, but differential diagnosis is a long, difficult process, the first step being to differentiate between inherited and non-inherited forms. The need to know the diagnosis is of major importance for patient and family. Knowledge about the cause limits the number of extra diagnostics. This review of the literature presents the most frequently occurring genetically-determined forms of hyperkinesias, mainly chorea and dystonia and tries to give some practical guidelines. EXPERT OPINION: The final part of the review will offer some thoughts and views for future development in a world which probably has more knowledge than we can handle. The drive to find a diagnosis is rewarded by the patient but one also needs to reflect on the use of medical care.

Biological and clinical changes in premanifest and early stage Huntington's disease in the TRACK-HD study: the 12-month longitudinal analysis.

BACKGROUND: TRACK-HD is a prospective observational study of Huntington's disease (HD) that examines disease progression in premanifest individuals carrying the mutant HTT gene and those with early stage disease. We report 12-month longitudinal changes, building on baseline findings. METHODS: we did a 12-month follow-up of patients recruited from the four TRACK-HD study sites in Canada, France, the Netherlands, and the UK. Participants were premanifest individuals (preHD) carrying the mutant HTT gene, patients with early HD, and controls matched by age and sex with the combined preHD and early HD groups. Data were collected by use of 3T MRI and clinical, cognitive, quantitative motor, oculomotor, and neuropsychiatric measures. Statistical analysis assessed annualised change with the use of linear regression models to estimate differences between groups. FINDINGS: 116 preHD individuals, 114 early HD patients, and 115 people in the control group completed follow-up. Four preHD individuals, nine early HD patients, and eight people in the control group did not complete the follow-up. A further nine participants, who completed follow-up assessments, were unable to undergo MRI. After adjustment for demographics, annualised rates of generalised and regional brain atrophy were higher in preHD and early HD groups than in controls. Whole-brain atrophy rates were 0·20% (95% CI 0·05-0·34; p=0·0071) per year higher in preHD participants and 0·60% (0·44-0·76; p<0·0001) in early HD patients, and caudate atrophy rates were 1·37% (0·99-1·75; p<0·0001) per year higher in preHD and 2·86% (2·34-3·39; p<0·0001) in early HD. Voxel-based morphometry revealed grey-matter and white-matter atrophy, even in subjects furthest from predicted disease onset. Quantitative imaging showed statistically significant associations with disease burden, an indicator of disease pathology, and total functional capacity, a widely-used clinical measure of disease severity. Relative to controls, decline in cognition and quantitative motor function was detectable in both pre- and early HD, as was deterioration in oculomotor function in early HD. INTERPRETATION: quantitative imaging showed the greatest differentiation across the spectrum of disease and functional measures of decline were sensitive in early HD, with cognitive and quantitative motor impairment also detectable in preHD. We show longitudinal change over 12 months in generalised and regional brain volume, cognition, and quantitative motor tasks in individuals many years from predicted disease onset and show the feasibility of obtaining quantifiable endpoints for future trials.

Efficacy of community-based physiotherapy networks for patients with Parkinson's disease: a cluster-randomised trial.

BACKGROUND: Many patients with Parkinson's disease are treated with physiotherapy. We have developed a community-based professional network (ParkinsonNet) that involves training of a selected number of expert physiotherapists to work according to evidence-based recommendations, and structured referrals to these trained physiotherapists to increase the numbers of patients they treat. We aimed to assess the efficacy of this approach for improving health-care outcomes. METHODS: Between February, 2005, and August, 2007, we did a cluster-randomised trial with 16 clusters (defined as community hospitals and their catchment area). Clusters were randomly allocated by use of a variance minimisation algorithm to ParkinsonNet care (n=8) or usual care (n=8). Patients were assessed at baseline and at 8, 16, and 24 weeks of follow-up. The primary outcome was a patient preference disability score, the patient-specific index score, at 16 weeks. Health secondary outcomes were functional mobility, mobility-related quality of life, and total societal costs over 24 weeks. Analysis was by intention to treat. This trial is registered, number NCT00330694. FINDINGS: We included 699 patients. Baseline characteristics of the patients were comparable between the ParkinsonNet clusters (n=358) and usual-care clusters (n=341). The primary endpoint was similar for patients within the ParkinsonNet clusters (mean 47.7, SD 21.9) and control clusters (48.3, 22.4). Health secondary endpoints were also similar for patients in both study groups. Total costs over 24 weeks were lower in ParkinsonNet clusters compared with usual-care clusters (difference euro727; 95% CI 56-1399). INTERPRETATION: Implementation of ParkinsonNet networks did not change health outcomes for patients living in ParkinsonNet clusters. However, health-care costs were reduced in ParkinsonNet clusters compared with usual-care clusters. FUNDING: ZonMw; Netherlands Organisation for Scientific Research; Dutch Parkinson's Disease Society; National Parkinson Foundation; Stichting Robuust.