Microstructural brain abnormalities in Huntington's disease: A two-year follow-up.

OBJECTIVES: To investigate both cross-sectional and time-related changes of striatal and whole-brain microstructural properties in different stages of Huntington's disease (HD) using diffusion tensor imaging. EXPERIMENTAL DESIGN: From the TRACK-HD study, premanifest gene carriers (preHD), early manifest HD and controls were scanned at baseline and 2-year follow-up. Stratification of the preHD group into a far (preHD-A) and near (preHD-B) to predicted disease onset was performed. Age-corrected histograms of whole-brain white matter (WM), gray matter (GM) and striatal diffusion measures were computed and normalised by the number of voxels in each subject's data set. PRINCIPLE OBSERVATIONS: Higher cross-sectional mean, axial and radial diffusivities were found in both WM (P ≤ 0.001) and GM (P ≤ 0.001) of the manifest HD compared to the preHD and control groups. In preHD, only WM axial diffusivity (AD) was higher than in controls (P ≤ 0.01). This finding remained valid only in preHD-B (P ≤ 0.001). AD was also higher in the striatum of preHD-B compared to controls and preHD-A (P ≤ 0.01). Fractional anisotropy (FA) lacked sensitivity in differentiating between the groups. Histogram peak heights were generally lower in manifest HD compared to the preHD and control groups. No longitudinal differences were found in the degree of diffusivity change between the groups in the two year follow-up. There was a significant relationship between diffusivity and neurocognitive measures. CONCLUSIONS: Alterations in cross-sectional diffusion profiles between manifest HD subjects and controls were evident, both in whole-brain and striatum. In the preHD stage, only AD alterations were found, a finding suggesting that this metric is a sensitive marker for early change in HD prior to disease manifestation. The individual diffusivities were superior to FA in revealing pathologic microstructural brain alterations. Diffusion measures were well related to clinical functioning and disease stage.

Longitudinal resting state fMRI analysis in healthy controls and premanifest Huntington's disease gene carriers: a three-year follow-up study.

BACKGROUND: We previously demonstrated that in the premanifest stage of Huntington's disease (preHD), a reduced functional connectivity exists compared to healthy controls. In the current study, we look at possible changes in functional connectivity occurring longitudinally over a period of 3 years, with the aim of assessing the potential usefulness of this technique as a biomarker for disease progression in preHD. METHODS: Twenty-two preHD and 17 healthy control subjects completed resting state functional magnetic resonance imaging (fMRI) scans in two visits with 3 years in between. Differences in resting state connectivity were examined for eight networks of interest using FSL with three different analysis types: a dual regression method, region of interest approach, and an independent component analysis. To evaluate a possible combined effect of gray matter volume change and the change in blood oxygenation level dependent signal, the analysis was performed with and without voxel-wise correction for gray matter volume. To evaluate possible correlations between functional connectivity change and the predicted time to disease onset, the preHD group was classed as preHD-A if ≥10.9 years and preHD-B if <10.9 years from predicted disease onset. Possible correlations between burden of pathology score and functional connectivity change in preHD were also assessed. Finally, longitudinal change in whole brain and striatal volumetric measures was assessed in the studied cohort. RESULTS: Longitudinal analysis of the resting state-fMRI (RS-fMRI) data revealed no differences in the degree of connectivity change between the groups over a period of 3 years, though a significantly higher rate of striatal atrophy was found in the preHD group compared to controls in the same period. DISCUSSION: Based on the results found in this study, the provisional conclusion is that RS-fMRI lacks sensitivity in detecting changes in functional connectivity in HD gene carriers prior to disease manifestation over a 3-year follow-up period.

MRI Susceptibility Changes Suggestive of Iron Deposition in the Thalamus after Ischemic Stroke.

BACKGROUND: Iron accumulation has been linked to neuronal injury following cerebral ischemia. In animals, a hypointense signal on T2*-weighted (T2*-w) MRI correlated with iron deposits in remote brain regions following ischemic stroke. We aim to assess whether such signal changes are present in remote brain structures following ischemic stroke in humans. METHODS: We analyzed T2*-w images of 36 patients with unilateral ischemic stroke and 36 healthy controls. Regions of interest (ROIs) consisted of the thalamus, putamen, globus pallidus, caudate nucleus and white matter. To quantify signal intensity in ROIs ipsilateral to the infarct, signal intensity was measured in the ROIs in both hemispheres and a ratio of signal intensity was calculated. Signal asymmetry was compared between patients and controls and its relation with time after stroke onset was assessed. RESULTS: In 34 (94%) patients, the thalamus ipsilateral to the infarct was hypointense compared to the contralateral thalamus. Ipsilateral thalamic signal hypointensity was significantly different between patients and controls (p < 0.001) and was present as early as 1 day after stroke onset. In other ROIs, no difference was found between patients and controls. No association was found between intensity asymmetry and time. CONCLUSION: We demonstrated that, as early as days after ischemic stroke, T2*-w signal intensity was decreased in the ipsilateral thalamus. This finding might indicate pathophysiologic changes in regions outside the infarcted area, possibly reflecting toxic iron accumulation.

Texture analysis of ultrahigh field T2*-weighted MR images of the brain: application to Huntington's disease.

PURPOSE: To develop a framework for quantitative detection of between-group textural differences in ultrahigh field T2*-weighted MR images of the brain. MATERIALS AND METHODS: MR images were acquired using a three-dimensional (3D) T2*-weighted gradient echo sequence on a 7 Tesla MRI system. The phase images were high-pass filtered to remove phase wraps. Thirteen textural features were computed for both the magnitude and phase images of a region of interest based on 3D Gray-Level Co-occurrence Matrix, and subsequently evaluated to detect between-group differences using a Mann-Whitney U-test. We applied the framework to study textural differences in subcortical structures between premanifest Huntington's disease (HD), manifest HD patients, and controls. RESULTS: In premanifest HD, four phase-based features showed a difference in the caudate nucleus. In manifest HD, 7 magnitude-based features showed a difference in the pallidum, 6 phase-based features in the caudate nucleus, and 10 phase-based features in the putamen. After multiple comparison correction, significant differences were shown in the putamen in manifest HD by two phase-based features (both adjusted P values=0.04). CONCLUSION: This study provides the first evidence of textural heterogeneity of subcortical structures in HD. Texture analysis of ultrahigh field T2*-weighted MR images can be useful for noninvasive monitoring of neurodegenerative diseases.

The structural correlates of functional deficits in early huntington's disease.

Neuropathological studies in Huntington disease (HD) have demonstrated neuronal loss in the striatum, as well as in other brain regions including the cortex. With diffusion tensor MRI we evaluated the hypothesis that the clinical dysfunction in HD is related to regionally specific lesions of circuit-specific cortico-basal ganglia networks rather than to the striatum only. We included 27 HD and 24 controls from the TRACK-HD Paris cohort. The following assessments were used: self-paced tapping tasks, trail B making test (TMT), University of Pennsylvania smell identification test (UPSIT), and apathy scores from the problem behaviors assessment. Group comparisons of fractional anisotropy and mean diffusivity and correlations were performed using voxel-based analysis. In the cortex, HD patients showed significant correlations between: (i) self paced tapping and mean diffusivity in the parietal lobe at 1.8 Hz and prefrontal areas at 3 Hz, (ii) UPSIT and mean diffusivity in the parietal, and median temporal lobes, the cingulum and the insula, and fractional anisotropy in the insula and the external capsule, (iii) TMT B and mean diffusivity in the white matter of the superior frontal, orbital, temporal, superior parietal and post central areas, and (iv) apathy and fractional anisotropy in the white matter of the rectus gyrus. In the basal ganglia, we found correlations between the self paced tapping, UPSIT, TMT tests, and mean diffusivity in the anterior part of the putamen and the caudate nucleus. In conclusion, disruption of motor, associative and limbic cortico-striatal circuits differentially contribute to the clinical signs of the disease.

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.

Early changes in white matter pathways of the sensorimotor cortex in premanifest Huntington's disease.

OBJECTIVES: To investigate the function-structure relationship of white matter within different stages of Huntington's disease (HD) using diffusion tensor imaging (DTI). EXPERIMENTAL DESIGN: From the TRACK-HD study, an early stage HD group and a premanifest gene carrier group (PMGC) were age-matched to two healthy control groups; all underwent 3-T MRI scanning of the brain. Region of interest (ROI) segmentation of the corpus callosum, caudate nucleus, thalamus, prefrontal cortex, and sensorimotor cortex was applied, and the apparent fiber pathways of these regions were analyzed. Functional measures of motor, oculomotor, cognition, and behavior were correlated to DTI measures. PRINCIPLE OBSERVATIONS: In PMGC versus controls, higher apparent diffusion coefficient (ADC) was seen in white matter pathways of the sensorimotor cortex (P < 0.01) and in the ROI of corpus callosum (P < 0.017). In early HD, fiber tract analysis showed higher ADC in pathways of the corpus callosum, thalamus, sensorimotor, and prefrontal region (P < 0.01). ROI analysis showed higher diffusivity in the corpus callosum and caudate nucleus (P < 0.017). Motor, oculomotor, cognition, and probability of onset within 2 and 5 years, correlated well with ADC measures of the corpus callosum (P < 0.01 - P < 0.005), sensorimotor (P < 0.01 - P < 0.005), and prefrontal region (P < 0.01). CONCLUSIONS: Disturbances in the white matter connections of the sensorimotor cortex can be demonstrated not only in manifest HD but also in premanifest gene carriers. Connectivity measures are well related to clinical functioning. DTI measures can be regarded as a potential biomarker for HD, due to their ability to objectify changes in brain structures and their role within brain networks.

Progressive microstructural changes of the occipital cortex in Huntington's disease.

In this study we longitudinally investigated the rate of microstructural alterations in the occipital cortex in different stages of Huntington's disease (HD) by applying an automated atlas-based approach to diffusion MRI data. Twenty-two premanifest (preHD), 10 early manifest HD (early HD) and 24 healthy control subjects completed baseline and two year follow-up scans. The preHD group was stratified based on the predicted years to disease onset into a far (preHD-A) and near (preHD-B) to disease onset group. Clinical and behavioral measures were collected per assessment time point. An automated atlas-based DTI analysis approach was used to obtain the mean, axial and radial diffusivities of the occipital cortex. We found that the longitudinal rate of diffusivity change in the superior occipital gyrus (SOG), middle occipital gyrus (MOG), and inferior occipital gyrus (IOG) was significantly higher in early HD compared to both preHD and controls (all p's ≤ 0.005), which can be interpreted as an increased rate of microstructural degeneration. Furthermore, the change rate in the diffusivity of the MOG could significantly discriminate between preHD-B compared to preHD-A and the other groups (all p's ≤ 0.04). Finally, we found an inverse correlation between the Stroop Word Reading task and diffusivities in the SOG and MOG (all p's ≤ 0.01). These findings suggest that measures obtained from the occipital cortex can serve as sensitive longitudinal biomarkers for disease progression in preHD-B and early HD. These could in turn be used to assess potential effects of proposed disease modifying therapies.

Apathy and atrophy of subcortical brain structures in Huntington's disease: A two-year follow-up study.

Background: Huntington's disease (HD) is characterized by motor and behavioral symptoms, and cognitive decline. HD gene carriers and their caregivers report the behavioral and cognitive symptoms as the most burdensome. Apathy is the most common behavioral symptom of HD and is related to clinical measures of disease progression, like functional capacity. However, it is unknown whether apathy is directly related to the neurodegenerative processes in HD. Objective: The aim is to investigate whether an association between atrophy of subcortical structures and apathy is present in HD, at baseline and after 2 years follow-up. Method: Volumes of 7 subcortical structures were measured using structural T1 MRI in 171 HD gene carriers of the TRACK-HD study and apathy was assessed with the Problem Behaviors Assessment-Short, at baseline and follow-up visit. At baseline, logistic regression was used to evaluate whether volumes of subcortical brain structures were associated with the presence of apathy. Linear regression was used to assess whether subcortical atrophy was associated with the degree of apathy at baseline and with an increase in severity of apathy over time. Results: At baseline, smaller volume of the thalamus showed a higher probability of the presence of apathy in HD gene carriers, but none of the subcortical structures was associated with the degree of apathy. Over time, no association between atrophy of any subcortical structures and change in degree of apathy was found. Conclusion: The presence of apathy is associated with atrophy of the thalamus in HD, suggesting that apathy has an underlying neural cause and might explain the high incidence of apathy in HD. However, no association was found between atrophy of these subcortical structures and increase in severity of apathy over a 2-year time period.

Dynamics of the connectome in Huntington's disease: A longitudinal diffusion MRI study.

OBJECTIVES: To longitudinally investigate the connectome in different stages of Huntington's disease (HD) by applying graph theoretical analysis to diffusion MRI data. EXPERIMENTAL DESIGN: We constructed weighted structural networks and calculated their topological properties. Twenty-two premanifest (preHD), 10 early manifest HD and 24 healthy controls completed baseline and 2 year follow-up scans. We stratified the preHD group based on their predicted years to disease onset into a far (preHD-A) and near (preHD-B) to disease onset group. We collected clinical and behavioural measures per assessment time point. PRINCIPLE OBSERVATIONS: We found a significant reduction over time in nodal betweenness centrality both in the early manifest HD and preHD-B groups as compared to the preHD-A and control groups, suggesting a decrease of importance of specific nodes to overall network organization in these groups (FDR adjusted ps < 0.05). Additionally, we found a significant longitudinal decrease of the clustering coefficient in preHD when compared to healthy controls (FDR adjusted p < 0.05), which can be interpreted as a reduced capacity for internodal information processing at the local level. Furthermore, we demonstrated dynamic changes to hub-status loss and gain both in preHD and early manifest HD. Finally, we found significant cross-sectional as well as longitudinal relationships between graph metrics and clinical and neurocognitive measures. CONCLUSIONS: This study demonstrates divergent longitudinal changes to the connectome in (pre) HD compared to healthy controls. This provides novel insights into structural correlates associated with clinical and cognitive functions in HD and possible compensatory mechanisms at play in preHD.

Eye-of-the-tiger-sign in a 48 year healthy adult.

We report a healthy adult male, who underwent, as a control subject, part of a Huntington's disease study, extensive testing during three visits in a two year follow-up, including clinical examination and 3.0 T MRI scans. The T2-weighted MRI sequences revealed the "eye-of-the-tiger-sign". No clinical abnormalities in either motor, cognitive or behavioural domains were observed. PKAN2 and FTL gene mutation analysis were negative. This finding implies that an eye-of-the-tiger sign, which is considered a pathognomonic feature of neurodegeneration with brain iron accumulation (NBIA), can occur without any clinical symptoms.

Longitudinal metabolite changes in Huntington's disease during disease onset.

BACKGROUND: Previous cross-sectional magnetic resonance spectroscopy (MRS) studies in Huntington's disease (HD) have demonstrated differences in metabolite concentrations in several regions of interest, especially the putamen and caudate nucleus. OBJECTIVE: To assess metabolite changes in both premanifest and early HD over a two year follow up period using MRS at 7 Tesla in several regions of interest. METHODS: In 13 HD gene carriers (10 premanifest and 3 manifest HD) proton MRS was performed at baseline and after 24 months. At follow up, four of the premanifest HD gene carriers had progressed into manifest HD, as assessed by clinical measures. 7T MR proton spectroscopy was performed in three regions of interest; the caudate nucleus, putamen and prefrontal cortex. Six metabolites were quantified for each region at each time point. Statistical analysis was performed using Wilcoxon signed rank tests. RESULTS: Across all subjects, a longitudinal decrease in the caudate nucleus in creatine (p = 0.038) and myo-inositol (p = 0.015) concentrations was found. A significant decrease in the putamen was seen in the total N-acetylaspartate (tNAA) (p = 0.028) and choline concentrations (p = 0.028). For premanifest HD converters, a non-significant high rate of tNAA decrease in the putamen was found compared to non-converting premanifest HD. CONCLUSION: Over a two year period we have demonstrated metabolite changes in the caudate nucleus and putamen of HD gene carriers around disease onset. This demonstrates the potential of MRS for providing a biomarker of disease progression and for evaluating future therapeutic interventions.

The role of iron imaging in Huntington's disease.

Huntington's disease (HD) is a devastating neurological disorder that affects the brain. The cause of HD is an expanded CAG trinucleotide repeat in the Htt gene. The Htt gene is responsible for the protein huntingtin, the exact functions of which have yet to be elucidated. The role of iron in the pathological cascade is usually mentioned in the context of an inability to regulate iron homeostasis, which generates a surplus of reactive iron and free radical toxicity, resulting in increased oxidative stress. In this review, we discuss the role of iron within the existing hypotheses of HD pathology, ex vivo findings in support of increased iron in HD, and finally in vivo MRI findings in manifest and premanifest HD. Both in vivo and ex vivo findings support the notion that excess iron is present in the brain of HD patients. There does not seem to be much evidence that iron accumulation is the initiator of the pathological cascade as little or no evidence can be found for very early increased iron in the HD brain, when neuronal cell loss is already extensive.

A review of cognition in Huntington's disease.

With the prospect of potential treatments for Huntington's disease (HD), non-invasive markers of disease progression are needed. Cognitive impairment has long been recognised as one of the core symptoms of HD. The first aim of this review is to provide insight into the onset and nature of cognitive loss in the progressing stages of HD. The second aim is to provide an overview of the cognitive functions that have been examined in an attempt to identify those areas that have the most potential to yield a cognitive biomarker. Literature, consisting of 110 studies, since the implementation of genetic testing until the beginning of 2011 has been included in this review. The clinical features of premanifest HD include deficits in psychomotor speed, negative emotion recognition and to some extent in executive functioning. The clinical profile of manifest HD includes impairment in memory, psychomotor speed, negative emotion recognition and executive functioning. Furthermore, potential candidate biomarkers should be most expected from such domains as working memory, psychomotor speed, recognition of negative emotions, attentional and visuospatial executive functions.

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

BACKGROUND: Huntington'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. METHODS: At 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. RESULTS: Brain 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). DISCUSSION: Brain 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.

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.

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.

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.