Somatic CAG repeat expansion in blood associates with biomarkers of neurodegeneration in Huntington's disease decades before clinical motor diagnosis.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease with the age at which characteristic symptoms manifest strongly influenced by inherited HTT CAG length. Somatic CAG expansion occurs throughout life and understanding the impact of somatic expansion on neurodegeneration is key to developing therapeutic targets. In 57 HD gene expanded (HDGE) individuals, ~23 years before their predicted clinical motor diagnosis, no significant decline in clinical, cognitive or neuropsychiatric function was observed over 4.

Neuroimaging to Facilitate Clinical Trials in Huntington's Disease: Current Opinion from the EHDN Imaging Working Group.

 Neuroimaging is increasingly being included in clinical trials of Huntington's disease (HD) for a wide range of purposes from participant selection and safety monitoring, through to demonstration of disease modification. Selection of the appropriate modality and associated analysis tools requires careful consideration. On behalf of the EHDN Imaging Working Group, we present current opinion on the utility and future prospects for inclusion of neuroimaging in HD trials.

Assessment of Perivascular Space Morphometry Across the White Matter in Huntington's Disease Using MRI.

Background: Perivascular spaces (PVS) are fluid-filled cavities surrounding small cerebral blood vessels. There are limited reports of enlarged PVS across the grey matter in manifest Huntington's disease (HD). Little is known about how PVS morphometry in the white matter may contribute to HD.

Freesurfer Software Update Significantly Impacts Striatal Volumes in the Huntington's Disease Young Adult Study and Will Influence HD-ISS Staging.

Background: The Huntington's Disease Integrated Staging System (HD-ISS) defined disease onset using volumetric cut-offs for caudate and putamen derived from FreeSurfer 6 (FS6). The impact of the latest software update (FS7) on volumes remains unknown. The Huntington's Disease Young Adult Study (HD-YAS) is appropriately positioned to explore differences in FS bias when detecting early atrophy.

Progressive alterations in white matter microstructure across the timecourse of Huntington's disease.

Background: Whole-brain longitudinal diffusion studies are crucial to examine changes in structural connectivity in neurodegeneration. Here, we investigated the longitudinal alterations in white matter (WM) microstructure across the timecourse of Huntington's disease (HD).

Methods: We examined changes in WM microstructure from premanifest to early manifest disease, using data from two cohorts with different disease burden.

Validating Automated Segmentation Tools in the Assessment of Caudate Atrophy in Huntington's Disease.

Neuroimaging shows considerable promise in generating sensitive and objective outcome measures for therapeutic trials across a range of neurodegenerative conditions. For volumetric measures the current gold standard is manual delineation, which is unfeasible for samples sizes required for large clinical trials. Using a cohort of early Huntington's disease (HD) patients ( = 46) and controls ( = 35), we compared the performance of four automated segmentation tools (FIRST, FreeSurfer, STEPS, MALP-EM) with manual delineation for generating cross-sectional caudate volume, a region known to be vulnerable in HD.

Cerebrospinal fluid flow dynamics in Huntington's disease evaluated by phase contrast MRI.

Multiple targeted therapeutics for Huntington's disease are now in clinical trials, including intrathecally delivered compounds. Previous research suggests that CSF dynamics may be altered in Huntington's disease, which could be of paramount relevance to intrathecal drug delivery to the brain. To test this hypothesis, we conducted a prospective cross-sectional study comparing people with early stage Huntington's disease with age- and gender-matched healthy controls.

Longitudinal Diffusion Tensor Imaging Shows Progressive Changes in White Matter in Huntington's Disease.

Background: Huntington's disease is marked by progressive neuroanatomical changes, assumed to underlie the development of the disease's characteristic symptoms. Previous work has demonstrated longitudinal macrostructural white-matter atrophy, with some evidence of microstructural change focused in the corpus callosum.

Objective: To more accurately characterise longitudinal patterns, we examined white matter microstructural change using Diffusion Tensor Imaging (DTI) data from three timepoints over a 15 month period.

Short-interval observational data to inform clinical trial design in Huntington's disease.

Objectives: To evaluate candidate outcomes for disease-modifying trials in Huntington's disease (HD) over 6-month, 9-month and 15-month intervals, across multiple domains. To present guidelines on rapid efficacy readouts for disease-modifying trials.

Methods: 40 controls and 61 patients with HD, recruited from four EU sites, underwent 3 T MRI and standard clinical and cognitive assessments at baseline, 6 and 15 months.

Inconsistent emotion recognition deficits across stimulus modalities in Huntington׳s disease.

Background: Recognition of negative emotions is impaired in Huntington׳s Disease (HD). It is unclear whether these emotion-specific problems are driven by dissociable cognitive deficits, emotion complexity, test cue difficulty, or visuoperceptual impairments. This study set out to further characterise emotion recognition in HD by comparing patterns of deficits across stimulus modalities; notably including for the first time in HD, the more ecologically and clinically relevant modality of film clips portraying dynamic facial expressions.

Impact of the control for corrupted diffusion tensor imaging data in comparisons at the group level: an application in Huntington disease.

Background: Corrupted gradient directions (GD) in diffusion weighted images may seriously affect reliability of diffusion tensor imaging (DTI)-based comparisons at the group level. In the present study we employed a quality control (QC) algorithm to eliminate corrupted gradient directions from DTI data. We then assessed effects of this procedure on comparisons between Huntington disease (HD) subjects and controls at the group level.

Cerebellar abnormalities in Huntington's disease: a role in motor and psychiatric impairment?

The cerebellum has received limited attention in Huntington's disease (HD), despite signs of possible cerebellar dysfunction, including motor incoordination and impaired gait, which are currently attributed to basal ganglia atrophy and disrupted fronto-striatal circuits. This study is the first to investigate a potential contribution of macro- and microstructural cerebellar damage to clinical manifestations of HD. T1- and diffusion-weighted 3T magnetic resonance imaging (MRI) scans were obtained from 12 controls and 22 early-stage HD participants.

Effectiveness of dietary interventions among adults of retirement age: a systematic review and meta-analysis of randomized controlled trials.

Background: Retirement from work involves significant lifestyle changes and may represent an opportunity to promote healthier eating patterns in later life. However, the effectiveness of dietary interventions during this period has not been evaluated.

Methods: We undertook a systematic review of dietary interventions among adults of retirement transition age (54 to 70 years).

Test-Retest Reliability of Diffusion Tensor Imaging in Huntington's Disease.

Diffusion tensor imaging (DTI) has shown microstructural abnormalities in patients with Huntington's Disease (HD) and work is underway to characterise how these abnormalities change with disease progression. Using methods that will be applied in longitudinal research, we sought to establish the reliability of DTI in early HD patients and controls. Test-retest reliability, quantified using the intraclass correlation coefficient (ICC), was assessed using region-of-interest (ROI)-based white matter atlas and voxelwise approaches on repeat scan data from 22 participants (10 early HD, 12 controls).

White matter integrity in premanifest and early Huntington's disease is related to caudate loss and disease progression.

Introduction: Huntington's disease (HD) is associated with progressive loss of caudate and white matter volume and integrity. Our aim was to systematically assess interactions between these changes and genetic markers of disease progression; we are not aware of previous studies in which this has been explicitly tested.

Methods: Tract-based spatial statistics were used to assess: (a) differences between the white matter diffusion metrics (fractional anisotropy and mean diffusivity) of 17 premanifest and 19 early manifest HD gene carriers and 21 controls, and (b) the relationships between diffusion metrics, caudate and total white matter volume, and disease burden score and CAG repeat length.

Evaluating multicenter DTI data in Huntington's disease on site specific effects: An ex post facto approach.

Purpose: Assessment of the feasibility to average diffusion tensor imaging (DTI) metrics of MRI data acquired in the course of a multicenter study.

Materials And Methods: Sixty-one early stage Huntington's disease patients and forty healthy controls were studied using four different MR scanners at four European sites with acquisition protocols as close as possible to a given standard protocol. The potential and feasibility of averaging data acquired at different sites was evaluated quantitatively by region-of-interest (ROI) based statistical comparisons of coefficients of variation (CV) across centers, as well as by testing for significant group-by-center differences on averaged fractional anisotropy (FA) values between patients and controls.

Are behavioral interventions effective in increasing physical activity at 12 to 36 months in adults aged 55 to 70 years? A systematic review and meta-analysis.

Background: Retirement represents a major transitional life stage in middle to older age. Changes in physical activity typically accompany this transition, which has significant consequences for health and well-being. The aim of this systematic review was to evaluate the evidence for the effect of interventions to promote physical activity in adults aged 55 to 70 years, focusing on studies that reported long-term effectiveness.

Longitudinal neuroimaging biomarkers in Huntington's Disease.

Identifying markers able to characterise the progression of Huntington's Disease (HD) is of great importance to the HD research community, as such markers may provide valuable outcome measures in future clinical trials. Neuroimaging measures are obvious candidates because of their clear relevance to the neuropathology of the disease. Many also show improved precision and sensitivity compared with standard functional scales.

Corpus callosal atrophy in premanifest and early Huntington's disease.

Background: Volumetric MRI studies have highlighted the pronounced loss of white matter in premanifest and early Huntington's Disease (HD). The current study focussed on the corpus callosum (CC) since it provides interhemispheric connections to vulnerable cortical areas.

Objectives: To investigate cross-sectional and longitudinal group differences in CC volume and hypothesis-driven associations with three cognitive tasks.

Can the theory of planned behaviour predict the physical activity behaviour of individuals?

The theory of planned behaviour (TPB) can identify cognitions that predict differences in behaviour between individuals. However, it is not clear whether the TPB can predict the behaviour of an individual person. This study employs a series of n-of-1 studies and time series analyses to examine the ability of the TPB to predict physical activity (PA) behaviours of six individuals.

Testing self-regulation interventions to increase walking using factorial randomized N-of-1 trials.

Objective: To investigate the suitability of N-of-1 randomized controlled trials (RCTs) as a means of testing the effectiveness of behavior change techniques based on self-regulation theory (goal setting and self-monitoring) for promoting walking in healthy adult volunteers.

Method: A series of N-of-1 RCTs in 10 normal and overweight adults ages 19-67 (M = 36.9 years).

An event-based model for disease progression and its application in familial Alzheimer's disease and Huntington's disease.

Understanding the progression of neurological diseases is vital for accurate and early diagnosis and treatment planning. We introduce a new characterization of disease progression, which describes the disease as a series of events, each comprising a significant change in patient state. We provide novel algorithms to learn the event ordering from heterogeneous measurements over a whole patient cohort and demonstrate using combined imaging and clinical data from familial Alzheimer's and Huntington's disease cohorts.

Evaluation of multi-modal, multi-site neuroimaging measures in Huntington's disease: Baseline results from the PADDINGTON study.

Background: Macro- and micro-structural neuroimaging measures provide valuable information on the pathophysiology of Huntington's disease (HD) and are proposed as biomarkers. Despite theoretical advantages of microstructural measures in terms of sensitivity to pathology, there is little evidence directly comparing the two.

Methods: 40 controls and 61 early HD subjects underwent 3 T MRI (T1- and diffusion-weighted), as part of the PADDINGTON study.