Premanifest Gene Carriers Research Articles

MRI measures of corpus callosum iron and myelin in early Huntington's disease.

Increased iron in subcortical gray matter (GM) structures of patients with Huntington's disease (HD) has been suggested as a causal factor in neuronal degeneration. But how iron content is related to white matter (WM) changes in HD is still unknown. For example, it is not clear whether WM changes share the same physiopathology (i.e. iron accumulation) with GM or whether there is a different mechanism. The present study used MRI to examine iron content in premanifest gene carriers (PreHD, n = 25) and in early HD patients (n = 25) compared with healthy controls (n = 50). 3T MRI acquisitions included high resolution 3D T1, EPI sequences for diffusion tensor imaging (DTI) as an indirect measure of tissue integrity, and T2*-weighted gradient echo-planar imaging for MR-based relaxometry (R2*), which provides an indirect measure of ferritin/iron deposition in the brain. Myelin breakdown starts in the PreHD stage, but there is no difference in iron content values. Iron content reduction manifests later, in the early HD stage, in which we found a lower R2* parameter value in the isthmus. The WM iron reduction in HD is temporally well-defined (no iron differences in PreHD subjects and iron differences only in early HD patients). Iron level in callosal WM may be regarded as a marker of disease state, as iron does not differentiate PreHD subjects from controls but distinguishes between PreHD and HD.

The Addenbrooke’s Cognitive Examination-Revised accurately detects cognitive decline in Huntington’s disease

Cognitive features, which begin before manifestation of the motor features, are an integral part of Huntington's disease and profoundly affect quality of life. A number of neuropsychological batteries have been used to assess this aspect of the condition, many of which are difficult to administer and time consuming, especially in advanced disease. We, therefore, investigated a simple and practical way to monitor cognition using the Addenbrooke's Cognitive Examination-Revised (ACE-R) in 126 manifest Huntington's disease patients, 28 premanifest gene carriers and 21 controls. Using this test, we demonstrated a selective decrease in phonemic, but not semantic, fluency in premanifest participants Cognitive decline in manifest Huntington's disease varied according to disease severity with extensive cognitive decline observed in early-stage Huntington's disease patients, indicating that this would be an optimal stage for interventions designed to halt cognitive decline, and lesser changes in the advanced cases. We next examined cognitive performance in patients prescribed antidopaminergic drugs as these drugs are known to decrease cognition when administered to healthy volunteers. We paradoxically found that these drugs may be beneficial, as early-stage Huntington's disease participants in receipt of them had improved attention and Mini-Mental State Examination scores. In conclusion, this is the first study to test the usefulness of the ACE-R in a Huntington's disease population and demonstrates that this is a brief, inexpensive and practical way to measure global cognitive performance in clinical practice with potential use in clinical trials.

Postural limits of stability in premanifest and manifest Huntington's disease.

Huntington's disease (HD) is associated with neuronal death in basal ganglia circuits important for postural control. Despite evidence of postural instability associated with HD, postural control at the limits of stability has not been investigated in this disease. To use computerized dynamic posturography to measure postural control at the limits of stability during the premanifest and manifest stages of HD. Patients with manifest HD, premanifest gene carriers, and matched controls stood on mechanically locked force plates while viewing a computer screen. The participant's estimated center of gravity was represented on the screen as a cursor along with eight target icons arranged in a circular pattern at the theoretical edge of limits of stability. On each trial, one of the eight targets was highlighted and the participant was instructed to control the cursor by rapidly shifting his/her weight in the direction of the target. Measures included reaction time, movement velocity, endpoint excursion, maximum excursion, and directional control. Analysis of variance revealed significant impairment on endpoint excursion, maximum excursion, and directional control (p≤0.001) in the Huntington's disease group, but not in the premanifest gene carrier group as compared to controls. No differences were found on reaction time or movement velocity measures. Group signal to noise ratios also were examined for the measures. HD patients, but not premanifest gene carriers, showed impaired postural control at the limits of stability. Impaired performance in HD patients has potential functional consequences including increased risk of falling during weight-shifting activities.

Reduced functional brain connectivity prior to and after disease onset in Huntington's disease

BackgroundHuntington's disease (HD) is characterised by both regional and generalised neuronal cell loss in the brain. Investigating functional brain connectivity patterns in rest in HD has the potential to broaden the understanding of brain functionality in relation to disease progression. This study aims to establish whether brain connectivity during rest is different in premanifest and manifest HD as compared to controls.MethodsAt the Leiden University Medical Centre study site of the TRACK-HD study, 20 early HD patients (disease stages 1 and 2), 28 premanifest gene carriers and 28 healthy controls underwent 3 T MRI scanning. Standard and high-resolution T1-weighted images and a resting state fMRI scan were acquired. Using FSL, group differences in resting state connectivity were examined for eight networks of interest using a dual regression method. With a voxelwise correction for localised atrophy, group differences in functional connectivity were examined.ResultsBrain connectivity of the left middle frontal and pre-central gyrus, and right post central gyrus with the medial visual network was reduced in premanifest and manifest HD as compared to controls (0.05 > p > 0.0001). In manifest HD connectivity of numerous widespread brain regions with the default mode network and the executive control network were reduced (0.05 > p > 0.0001).DiscussionBrain regions that show reduced intrinsic functional connectivity are present in premanifest gene carriers and to a much larger extent in manifest HD patients. These differences are present even when the potential influence of atrophy is taken into account. Resting state fMRI could potentially be used for early disease detection in the premanifest phase of HD and for monitoring of disease modifying compounds.

The effect of interference on temporal order memory in premanifest and manifest Huntington's disease.

Frontal-striatal dysfunction has been linked to cognitive impairment in Huntington's disease (HD). The frontal lobes play a role in memory for the temporal order in which items occur in a sequence. However, little is known about temporal order memory in HD or how it may be affected by interference. The study assessed temporal order memory in patients with manifest HD (n = 20), premanifest gene carriers for HD (Pre-HD; n = 18), and controls (n = 25) using a computerized radial 8-arm maze. On the sample phase of each trial, participants viewed a random sequence of circles appearing one at a time at the end of each arm. On the choice phase, participants viewed two sample phase circles and chose the circle occurring earliest in the sequence. Manipulations of the temporal lag (defined as the number of circles occurring in the sample phase sequence between the two choice phase circles) were conducted to systematically vary interference. Temporally proximal lags were hypothesized to generate more interference relative to temporally distal lags. The Pre-HD group was significantly impaired (p < 0.05) compared to controls on proximal temporal lags (high interference) but matched controls on distal lags (low interference). HD patients improved as a function of increased lag but demonstrated significant impairments (p < 0.05) across lags relative to controls. Temporal order memory is differentially affected by interference during the premanifest and manifest stages of HD. The study identifies a fundamental, yet relatively unexamined, deficit associated with HD.

OCULOMOTOR DEFICITS IN PREMANIFEST AND EARLY HUNTINGTON'S DISEASE AND THEIR STRUCTURAL BRAIN CORRELATES: THE LONGITUDINAL TRACK-HD STUDY

BackgroundOculomotor deficits are a potential predictor of Huntington's Disease (HD). Saccadic abnormalities include delayed initiation, low velocity and a lack of inhibition and can be partially explained by HD's stereotypical...

Huntington’s disease: Towards disease modification – Gaps and bridges, facts and opinions

Huntington’s disease (HD) is the most frequent autosomal dominant neurodegenerative disease with a known gene locus and product. HD likely affects a few hundred thousand subjects worldwide – either in its diagnosed or prodromal stage or by the burden to live with the knowledge of carrying the gene or being at risk. So far no disease modifying (neuroprotective) therapy is available. However, the availability of several transgenic or knock-in animal models, the rising clinical knowledge about the biology and phenotype of the disease in both manifest and pre-diagnosed stages through large observational and biomarker studies, and the progress in drug development and validation processes contributed to a considerable progress in the field. Several possible targets for a therapy based on identified mechanisms of action aiming at either delaying or preventing the progression of the disease are in preclinical or early clinical development. Selected approaches are discussed and the clinical infrastructure available to conduct clinical trials across the globe is outlined. Novel clinical trial endpoints such as quantitative motor (Q-Motor) assessments and further evidence for imaging measures as reliable endpoints for proof of concept studies are reviewed. Gaps and possible bridges for preclinical and clinical development are discussed and facts and opinions on areas needing further attention are presented. HD harbors unique opportunities: it is a promising model to establish a proof of concept for a disease modifying therapy in a neurodegenerative disease and the feasibility to treat premanifest gene carriers may even allow to delay or prevent the manifestation of the disease.

A2 TRACK-HD and TRACK-ON HD: yielding new insights in Huntington's disease

Professor Sarah Tabrizi is Professor of Clinical Neurology at UCL Institute of Neurology, and an Honorary Consultant Neurologist at the National Hospital for Neurology and Neurosurgery. After undergraduate degrees in Biochemistry and Medicine at the University of Edinburgh, Sarah undertook her PhD at UCL as an MRC Clinical Training Fellow studying the role of mitochondrial dysfunction in cellular neurodegeneration. After clinical training in Neurology, in 2002 she was awarded a 5-year MRC/DH National Clinician Scientist Fellowship, enabling her to establish her own research group, studying cellular mechanisms of neurodegeneration, concentrating on protein misfolding diseases, particularly prion disease and Huntington9s disease. In 2006, she was awarded one of the first HEFCE New Blood Senior Lectureships; in 2007 she was promoted to Reader and in 2009 to Professor at UCL. In addition to bench science which focuses on cellular mechanisms of neurodegeneration, Sarah also leads a large translational research programme in Huntington9s disease working towards finding treatments for this disease. Sarah is PI of TRACK-HD, a major international research initiative aimed at understanding the neurobiology of the neurodegenerative changes in premanifest and early stage HD gene carriers, which is essential for the development of disease-modifying therapies to treat this disorder. She also first described the role of the immune system as a modifier of Huntington9s disease pathogenesis, and has an ongoing research interest in this area. Professor Tabrizi has had funding from the MRC, Wellcome Trust, CHDI/High Q Foundation, EU Framework 7, UK HD association, Brain Research Trust, Dementia and Neurodegenerative Diseases Network (Dendron) and the UCL/UCLH BRC for her research. Huntington9s disease (HD) is a neurodegenerative condition characterised by deterioration of motor and cognitive function as well as neuropsychiatric disturbance. The mean age of onset is 40 years, and progression is slow and inexorable, with death occurring typically 15–20 years later. It is inherited in an autosomal dominant manner, causing devastation to affected families. Currently there are no treatments available which modify disease progression. However, novel therapeutic agents specifically targeting HD pathology are now on the horizon.¹ TRACK-HD is an ongoing, large multi-national observational study which aims to investigate a range of potential biomarkers in premanifest HD gene carriers and early HD subjects which may have utility in clinical trials. Standardised data collection of state-of-the-art 3 T MR imaging and novel cognitive, quantitative motor, oculomotor, and neuropsychiatric assessments across four international sites has been achieved, with minimal dropout of subjects over a 3-year period. Baseline analysis of 123 controls, 120 premanifest gene carriers and 123 early HD subjects identified measures which were able to detect disease effects several years prior to symptom onset.² Follow-up analysis found that imaging measures were the most sensitive to change at all stages of the disease from premanifest to early HD³; these techniques were able to identify subtle changes over just 1 year in this slowly progressive, heterogeneous condition and consequently show promise as potential biomarkers for future therapeutic trials. TRACK-HD is also undertaking genetic, biochemical and epigenetic profiling of all subjects to help identify key modifiers of the pathogenic disease process. Data from TRACK-HD has been presented at meetings of the European Medicines Agency and FDA (8th November 2010 Expert meeting in familial neurodegenerative disorders London) as an example of how international collaborative studies can set the benchmark towards identifying outcomes measures to test novel therapies in subjects many years before symptom onset, or with very early disease. TRACK-HD has advanced our understanding of both the clinical manifestation and underlying pathobiology of HD in the earliest phase of the neurodegenerative disease process, such that we are now better-equipped to enter disease-modifying clinical trials and offer hope to the families affected by this devastating disease. <h3>References</h3> 1. <b>Ross CA</b>, Tabrizi SJ. Huntington9s disease: from molecular pathogenesis to clinical treatment. <i>Lancet Neurol</i> 2011;<b>10:</b>83–98. 2. <b>Tabrizi SJ</b>, Langbehn DR, Leavitt BR, <i>et al.</i> Biological and clinical manifestations of Huntington9s disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. <i>Lancet Neurol</i> 2009;<b>8</b>:791–801. 3. <b>Tabrizi SJ</b>, Scahill RI, Durr A, <i>et al.</i> Biological and clinical changes in premanifest and early stage Huntington9s disease in the TRACK-HD study: the 12-month longitudinal analysis. <i>Lancet Neurol</i> 2011;<b>10</b>:31–42.

G03 Corpus callosal atrophy in Huntington's disease

<h3>Background</h3> Research into Huntington9s disease (HD) has revealed white-matter loss in individuals more than 10 years prior to predicted disease onset, focused around the striatum, corpus callosum (CC) and posterior white-matter tracts. Degeneration of the CC is of interest since it provides interhemispheric connections to cortical areas known to be affected in HD. <h3>Aims</h3> This study aims to investigate the utility of volumetric measurements of the CC in HD using a novel segmentation technique, multiple time-points and a large well-characterised cohort. Structure-function relationship in the CC will also be explored. <h3>Methods</h3> Volumetric 3T MRI from controls, premanifest gene carriers and early HD subjects enrolled in the TRACK-HD study will be analysed at baseline and 24 months. The CC will be delineated using a semi-automated segmentation protocol. Differences in baseline volumes and atrophy rates between groups will be examined, as well as correlations between volume loss and clinical impairment. <h3>Results</h3> Preliminary analysis of a subset of subjects indicates that early HD subjects have reduced CC volume compared with controls and premanifest subjects (p&lt;0.001). Increased longitudinal CC volume change was found in early HD subjects, compared with controls (p&lt;0.001). Interestingly there was significant difference in longitudinal change between controls and premanifest subjects close to disease onset (p&lt;0.05). This work will be extended to include multi-site data and correlations between atrophy and clinical and cognitive decline. <h3>Conclusions</h3> Measurement of CC atrophy may have potential as an imaging biomarker for HD and may prove useful for exploring interhemispheric structure-function relationships. <h3>Funding</h3> Helen Crawford is supported by the CHDI Foundation, a not for profit organisation dedicated to finding treatments for HD.

J13 Distributed neural networks associated with emotion processing are altered in premanifest Huntington's disease and correlated with genetic load

<h3>Background</h3> HD is associated with an early decline in ability to recognise emotional states in others. The pathophysiology underlying this is not fully understood; our objective was to clarify this. Disgust, anger and happiness were chosen as emotions of interest; recognition deficits have commonly been found for disgust and anger, and happiness was chosen as a contrasting positive emotion. <h3>Aims</h3> To investigate changes in brain mechanisms of emotion recognition in premanifest HD gene carriers by using functional MRI (fMRI) to characterise neural networks involved in processing pictures of facial expressions of emotion, and to relate these findings to brain structure and markers of genetic load (CAG repeat length and probability of manifest disease onset in 5 years). <h3>Methods</h3> 16 premanifest HD and 14 control subjects viewed pictures of facial expressions from the Ekman and Friesen series while undergoing 1.5T fMRI scanning. The Ekman 60 faces test was used to quantify emotion recognition accuracy outside the scanner and structural MRI with voxel-based morphometry was used to assess the relationship between this and regional grey matter volume. <h3>Results</h3> Emotion processing in premanifest HD was associated with reduced neural activity for all three emotions in partially separable functional networks. The HD-associated modulation of disgust and happiness processing was negatively correlated with genetic load in distributed, largely extrastriatal networks. These effects were not driven merely by striatal dysfunction. There were no equivalent associations between brain structure and emotion recognition. The premanifest HD cohort did not have a behavioural deficit in emotion recognition relative to controls. Increased neural activity was seen in the premanifest HD subjects in response to all emotions in frontal regions of the brain. <h3>Conclusions</h3> Both positive and negative emotion processing in premanifest HD is associated with reduced neural activity in distributed networks. Concurrent increased frontal neural activity suggests compensatory mechanisms might maintain functional ability in early stages of the disease. Overall, the pathophysiological effects of HD appear to precede the development of overt clinical symptoms and detectable cerebral atrophy.

I03 Evaluation of life time physical activity levels in Huntington's disease

Background Environmental factors may influence the onset and progression of neurodegenerative disorders, either directly or by interacting with genetic risk factors. Trembath and colleagues interviewed individuals with a formal clinical diagnosis of Huntington's disease (HD) and found that those who led a more passive lifestyle had an earlier age of onset than those who were less passive.1 Aims To establish the feasibility of using self-completion questionnaires to gather life time physical activity levels in a group of early stage and premanifest HD individuals from the TRACK-HD cohort so that this data could be compared to clinical outcomes in TRACK-HD study. Methods A self-report questionnaire was developed based on the Leisure Time Exercise Questionnaire by Godin et al.2 Activity levels were calculated across activities undertaken at home, at work and during recreation and for life stages from the teenage years, across each decade to the current age or age of disease onset. Life-time activity was categorised as strenuous, moderate or light, and activity scores were calculated from the frequency and duration of each activity. Results Retrospective data were collected from 277 participants (89 controls, 109 premanifest gene carriers, 79 HD Stage I/II) and the data used to distinguish the most and least physically active individuals. Modes of activity were also investigated. Conclusions Although retrospective data may be limited by recall bias, our data suggests that it is possible to use a general measure of life time physical activity levels. Such a life course perspective on physical activity may be a useful adjunct to the assessment of physical activity with more direct quantitative measures.

Magnetization Transfer Imaging in Premanifest and Manifest Huntington Disease: A 2-Year Follow-Up

MTI is a quantitative MR imaging technique that has recently demonstrated structural integrity differences between controls and patients with HD. Potentially, MTI can be used as a biomarker for monitoring disease progression. To establish the value of MTI as a biomarker, we aimed to examine the change in these measures during the course of HD. From the Leiden TRACK-HD study, 25 controls, 21 premanifest gene carriers, and 21 patients with manifest HD participated at baseline and during a 2-year follow-up visit. Brain segmentation of the cortical gray matter, white matter, caudate nucleus, putamen, pallidum, thalamus, amygdala, and hippocampus was performed by using the automated tools FAST and FIRST in FSL. Individual MTR values were calculated from these regions, and MTR histograms were constructed. In the premanifest HD group stage "far from disease onset," a significant increase in MTR peak height of the putamen was observed with time. During the manifest HD stage, neither the mean MTR nor the MTR peak height showed a significant change during a 2-year follow-up. MTI-derived measures are not suitable for monitoring in Huntington disease during a 2-year period because there was no decrease in structural integrity detected in any of the manifest HD groups longitudinally. The finding of increased putaminal MTR peak height in the premanifest far from disease onset group could relate to a predegenerative process, compensatory mechanisms, or aberrant development but should be interpreted with caution until future studies confirm this finding.

Elevated brain iron is independent from atrophy in Huntington's Disease

Increased iron in subcortical structures in patients with Huntington's Disease (HD) has been suggested as a causal factor of neuronal degeneration. The present study examines iron accumulation, measured using magnetic resonance imaging (MRI), in premanifest gene carriers and in early HD patients as compared to healthy controls. In total 27 early HD patients, 22 premanifest gene carriers and 25 healthy controls, from the Leiden site of the TRACK-HD study, underwent 3T MRI including high resolution 3D T(1)- and T(2)-weighted and asymmetric spin echo (ASE) sequences. Magnetic Field Correlation (MFC) maps of iron levels were constructed to assess magnetic field inhomogeneities and compared between groups in the caudate nucleus, putamen, globus pallidus, hippocampus, amygdala, accumbens nucleus, and thalamus. Subsequently the relationship of MFC value to volumetric data and disease state was examined. Higher MFC values were found in the caudate nucleus (p<0.05) and putamen (p<0.005) of early HD compared to controls and premanifest gene carriers. No differences in MFC were found between premanifest gene carriers and controls. MFC in the caudate nucleus and putamen is a predictor of disease state in HD. No correlation was found between the MFC value and volume of these subcortical structures. We conclude that Huntington's disease patients in the early stages of the disease, but not premanifest gene carriers, have higher iron concentrations in the caudate nucleus and putamen. We have demonstrated that the iron content of these structures relates to disease state in gene carriers, independently of the measured volume of these structures.

Magnetization Transfer Imaging in Premanifest and Manifest Huntington Disease

MTI has the potential to detect abnormalities in normal-appearing white and gray matter on conventional MR imaging. Early detection methods and disease progression markers are needed in HD research. Therefore, we investigated MTI parameters and their clinical correlates in premanifest and manifest HD. From the Leiden TRACK-HD study, 78 participants (28 controls, 25 PMGC, 25 MHD) were included. Brain segmentation of cortical gray matter, white matter, caudate nucleus, putamen, pallidum, thalamus, amygdala, and hippocampus was performed using FSL's automated tools FAST and FIRST. Individual MTR values were calculated from these regions and MTR histograms constructed. Regression analysis of MTR measures from all gene carriers with clinical measures was performed. MTR peak height was reduced in both cortical gray (P = .01) and white matter (P = .006) in manifest HD compared with controls. Mean MTR was also reduced in cortical gray matter (P = .01) and showed a trend in white matter (P = .052). Deep gray matter structures showed a uniform pattern of reduced MTR values (P < .05). No differences between premanifest gene carriers and controls were found. MTR values correlated with disease burden and motor and cognitive impairment. Throughout the brain, disturbances in MTI parameters are apparent in early HD and are homogeneous across white and gray matter. The correlation of MTI with clinical measures indicates the potential to act as a disease monitor in clinical trials. However, our study does not provide evidence for MTI as a marker in premanifest HD.

Visual Working Memory Impairment in Premanifest Gene-Carriers and Early Huntington's Disease.

Working memory deficits have been found in Huntington's disease (HD) and in a small group of premanifest (PreHD) gene-carriers. However, the nature and extent of these deficits are unknown. In a large cross-sectional study, we aimed to determine the degree of visuospatial working memory dysfunction across multiple stages of HD. Specifically, visuospatial working memory capacity and response times across various degrees of difficulty were examined, as well as the relationship between visuospatial working memory and motor dysfunction. We examined 62 PreHD-A gene-carriers (>10.8 years from estimated disease onset), 58 PreHD-B gene-carriers (<10.8 years from estimated disease onset), 77 stage-1 HD patients (HD1), 44 stage-2 HD patients (HD2), and 122 healthy controls. Participants viewed coloured squares (in sets of 3, 5 and 7) on a screen and were to decide whether on a subsequent screen the encircled square has changed colour. Accuracy and response times were recorded. Compared to controls, significant group differences in visuospatial working memory capacity (accuracy) were seen in PreHD-B, HD1 and HD2 groups across the difficulty levels. Significant group differences on response times were found for all groups (PreHD-A to HD2) compared to controls; the most difficult level producing the only group difference in speed between PreHD-A and controls. Accuracy and speed were positively correlated only in the HD groups. These findings suggest that visuospatial working memory impairments are detectable in both premanifest and manifest HD; the manifest HD showed evidence for a "worse-worse phenomenon" whereby reductions were present in both motor speed and accuracy.

Increased levels of hemoglobin and alpha1-microglobulin in Huntington s disease

Hemoglobin released from damaged erythrocytes is a major pro-oxidant, generator of free radicals and inflammatory mediator. Huntington's disease is an inherited neurodegenerative disorder characterized by both neurological and systemic abnormalities, in which oxidative stress has been suggested as a possible pathogenic mechanism. In the present work we have investigated levels of hemoglobin and markers of oxidative damage, including the heme- and radical-scavenger alpha1-microglobulin, in plasma and urine samples from two separate sample cohorts, including controls, premanifest gene carriers and subjects at different stages of Huntington's disease. The results show statistically significant increased levels of hemoglobin and alpha1-microglobulin in Huntington's disease urine samples. Interestingly, urine hemoglobin levels correlate with clinical severity. The results suggest that hemolysis may be linked to the pathogenesis of Huntington's disease and that assay of hemoglobin and alpha1-microglobulin may provide biomarkers that are linked to biologically relevant processes.

Potential endpoints for clinical trials in premanifest and early Huntington's disease in the TRACK-HD study: analysis of 24 month observational data

TRACK-HD is a prospective observational biomarker study in premanifest and early Huntington's disease (HD). In this report we define a battery of potential outcome measures for therapeutic trials. We assessed longitudinal data collected at baseline, 12 months, and 24 months at sites in Leiden (Netherlands), London (UK), Paris (France), and Vancouver (Canada). Participants were individuals without HD but carrying the mutant HTT gene (ie, premanifest HD), patients with early HD, and healthy control individuals matched by age and sex to the combined HD groups. Data were collected with 3T MRI, clinical, cognitive, quantitative motor, oculomotor, and neuropsychiatric assessments. We estimated adjusted, between-group differences in rates of change in these measures and concomitant longitudinal effect sizes. Longitudinal data were available for 116 control individuals, 117 premanifest gene carriers, and 116 participants with early HD. Significantly greater progressive grey-matter, white-matter, whole-brain, and regional atrophy was recorded in the premanifest and early HD groups than in the control group. Effect sizes for atrophy rates between participants with early HD and controls were largest in the caudate (2·04, 95% CI 1·68 to 2·48) and white matter (1·70, 1·40 to 2·08). Functional, quantitative motor, and cognitive measures deteriorated to a greater extent in the early HD group than in controls, with the largest effect size in the symbol digit modality test (1·00, 0·67 to 1·27). In the early HD group, changes in structural imaging and various cognitive and quantitative motor scores were associated with worsening total motor score (TMS) and total functional capacity (TFC). In the premanifest group, despite significant declines in regional and overall brain volumes, few functional variables showed significant 24 month change compared with controls; TMS, emotion recognition, and speeded tapping were exceptions. Premanifest individuals with progression, predefined as an increase in TMS score of 5 points or more, any TFC decline, or a new diagnostic confidence score of 4, exhibited higher rates of brain atrophy and deterioration on some quantitative motor tasks compared with other premanifest participants. On the basis of longitudinal effect size, we recommend several objective outcome measures for clinical trials in participants with early HD. Hypothetical treatment effects defined by slower longitudinal changes in these measures would be detectable over a realistic timescale with practical sample sizes. The restricted 24 month cognitive or motor decline in the premanifest sample illustrates the greater challenge in trial design for this group. CHDI/HighQ Foundation Inc.

Behavioral Measures of Saccade Latency and Inhibition in Manifest and Premanifest Huntington's Disease

ABSTRACT Initiation and inhibition of saccadic eye movements has been shown to be impaired in patients with Huntington's disease (HD) and premanifest gene carriers (PMGC), and may provide biomarkers useful in tracking phenotypic change. Computerized behavioral tests of prosaccade latency and disinhibition presented to 31 non–gene carriers (NGC), 25 PMGC, and 12 HD patients. These tests provided quantitative performance measures without use of eye-tracking equipment. Significant differences on saccade tests were found, with PMGC intermediate between NGC and HD patients. Saccade latency discriminated PMGC from NGC, whereas saccade disinhibition discriminated PMGC from HD patients. Results suggest utility of behavioral saccade measures as premanifest indicators of phenoconversion in HD.

Assessment of involuntary choreatic movements in Huntington's disease—Toward objective and quantitative measures

Objective measures of motor impairment may improve the sensitivity and reliability of motor end points in clinical trials. In Huntington's disease, involuntary choreatic movements are one of the hallmarks of motor dysfunction. Chorea is commonly assessed by subitems of the Unified-Huntington's Disease Rating Scale. However, clinical rating scales are limited by inter- and intrarater variability, subjective error, and categorical design. We hypothesized that assessment of position and orientation changes interfering with a static upper extremity holding task may provide objective and quantitative measures of involuntary movements in patients with Huntington's disease. Subjects with symptomatic Huntington's disease (n = 19), premanifest gene carriers (n = 15; Unified-Huntington's Disease Rating Scale total motor score ≤ 3), and matched controls (n = 19) were asked to grasp and lift a device (250 and 500 g) equipped with an electromagnetic sensor. While subjects were instructed to hold the device as stable as possible, changes in position (x, y, z) and orientation (roll, pitch, yaw) were recorded. These were used to calculate a position index and an orientation index, both depicting the amount of choreatic movement interfering with task performance. Both indices were increased in patients with symptomatic Huntington's disease compared with controls and premanifest gene carriers for both weights, whereas only the position index with 500 g was increased in premanifest gene carriers compared with controls. Correlations were observed with the Disease Burden Score based on CAG-repeat length and age and with the Unified-Huntington's Disease Rating Scale. We conclude that quantitative assessment of chorea is feasible in Huntington's disease. The method is safe, noninvasive, and easily applicable and can be used repeatedly in outpatient settings. A use in clinical trials should be further explored in larger cohorts and follow-up studies.

Exploratory 7-Tesla magnetic resonance spectroscopy in Huntington’s disease provides in vivo evidence for impaired energy metabolism

Huntington’s disease (HD) is a neurodegenerative genetic disorder that affects the brain. Atrophy of deep grey matter structures has been reported and it is likely that underlying pathologic processes occur before, or in concurrence with, volumetric changes. Measurement of metabolite concentrations in these brain structures has the potential to provide insight into pathological processes. We aim to gain understanding of metabolite changes with respect to the disease stage and pathophysiological changes. We studied five brain regions using magnetic resonance spectroscopy (MRS) using a 7-Tesla MRI scanner. Localized proton spectra were acquired to obtain six metabolite concentrations. MRS was performed in the caudate nucleus, putamen, thalamus, hypothalamus, and frontal lobe in 44 control subjects, premanifest gene carriers and manifest HD. In the caudate nucleus, HD patients display lower NAA (p = 0.009) and lower creatine concentration (p = 0.001) as compared to controls. In the putamen, manifest HD patients show lower NAA (p = 0.024), lower creatine concentration (p = 0.027), and lower glutamate (p = 0.013). Although absolute values of NAA, creatine, and glutamate were lower, no significant differences to controls were found in the premanifest gene carriers. The lower concentrations of NAA and creatine in the caudate nucleus and putamen of early manifest HD suggest deficits in neuronal integrity and energy metabolism. The changes in glutamate could support the excitotoxicity theory. These findings not only give insight into neuropathological changes in HD but also indicate that MRS can possibly be applied in future clinical trails to evaluate medication targeted at specific metabolic processes.