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Background: 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.Methods: Using a cohort of early Huntington’s disease (HD) patients (n = 46) and controls (n = 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. We then examined the effect of each of these baseline regions on the ability to detect change over 15 months using the established longitudinal Caudate Boundary Shift Integral (cBSI) method, an automated longitudinal pipeline requiring a baseline caudate region as an input.Results: All tools, except Freesurfer, generated significantly smaller caudate volumes than the manually derived regions. Jaccard indices showed poorer levels of overlap between each automated segmentation and manual delineation in the HD patients compared with controls. Nevertheless, each method was able to demonstrate significant group differences in volume (p < 0.001). STEPS performed best qualitatively as well as quantitively in the baseline analysis. Caudate atrophy measures generated by the cBSI using automated baseline regions were largely consistent with those derived from a manually segmented baseline, with STEPS providing the most robust cBSI values across both control and HD groups.Conclusions: Atrophy measures from the cBSI were relatively robust to differences in baseline segmentation technique, suggesting that fully automated pipelines could be used to generate outcome measures for clinical trials.

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. CSF peak velocity, mean velocity and mean flow at the level of the cerebral aqueduct, and sub‐arachnoid space in the upper and lower spine, were quantified using phase contrast MRI. We calculated Spearman's rank correlations, and tested inter‐group differences with Wilcoxon rank‐sum test. Ten people with early Huntington's disease, and 10 controls were included. None of the quantified measures was associated with potential modifiers of CSF dynamics (demographics, osmolality, and brain volumes), or by known modifiers of Huntington's disease (age and HTT CAG repeat length); and no significant differences were found between the two studied groups. While external validation is required, the attained results are sufficient to conclude tentatively that a clinically relevant alteration of CSF dynamics – that is, one that would justify dose‐adjustments of intrathecal drugs – is unlikely to exist in Huntington's disease.

Background The dynamics of cerebrospinal fluid (CSF) flow have never been studied in Huntington’s disease (HD), and could have a clinically significant impact on the expected distribution of central nervous system delivered drugs such as huntingtin-lowering therapies. Phase contrast MRI (PCMRI) generates a signal contrast between flowing and stationary nuclei, enabling the characterisation of fluid dynamics in vivo. Objectives The objective of this study was to generate pilot data on CSF flow dynamics in HD using PCMRI, to inform the design of future intrathecal drug trials in HD. Methods We performed a prospective cross-sectional analysis of 10 age- and gender-matched healthy controls and 10 manifest HD gene expansion carriers. All participants underwent extensive clinical evaluation and cardiac-gated PCMRI at the level of the cerebral aqueduct, T1 and T8. CSF velocities and flow measurements were derived using a semi-automated method. The influence of age, gender, CAG repeat-length, serum osmolality, whole-brain volume, and ventricle volume on these measurements were tested using Spearman correlations or Fisher’s exact tests. Group comparisons between healthy controls and manifest carriers were achieved via two-sample Wilcoxon rank-sum tests. All tests were two-sided with a significance level of 0.05, and corrected for multiple comparisons. Results Twenty participants were recruited, and no significant age- and gender-imbalances were found. None of the studied covariables was found to have an effect on the CSF velocities and flow measurements after corrected for multiple comparisons. No apparent differences were found between study groups in regards to CSF velocities and flow measurements. Conclusions Although exploratory, our pilot results add to the view that CSF dynamics are not altered in HD. These results need external validation but offer reassurance that clinically-relevant disease-related alterations in CSF flow, that might justify dose-adjustments of intrathecal drugs, are very unlikely to exist.

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. Manual delineation and voxel-based morphometry were used to assess between-group differences in cerebellar volume, and diffusion metrics were compared between groups within the cerebellar gray and white matter. Associations between these imaging measures and clinical scores were examined within the HD group. Reduced paravermal volume was detected in HD compared with controls using voxel-based morphometry (P

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. Macrostructural volumetrics were obtained for the whole brain, caudate, putamen, corpus callosum (CC) and ventricles. Microstructural diffusion metrics of fractional anisotropy (FA), mean-, radial- and axial-diffusivity (MD, RD, AD) were computed for white matter (WM), CC, caudate and putamen. Group differences were examined adjusting for age, gender and site. A formal comparison of effect sizes determined which modality and metrics provided a statistically significant advantage over others. Results Macrostructural measures showed decreased regional and global volume in HD (p, Highlights ► Macro and microstructural metrics are sensitive to HD pathology cross-sectionally. ► Largest effect sizes for putamen volume, caudate volume and putamen diffusivity ► No significant advantage of highest performing macro over microstructural metrics ► Grey matter regions outperformed CC and global measures within each modality. ► FA appears to be relatively insensitive to disease effects.

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. This review summarizes findings from the wealth of longitudinal imaging studies in the literature, focusing on the most widely available imaging modalities: structural MRI (volumetric and diffusion imaging), functional MRI and PET. We discuss the longitudinal sensitivity, reproducibility and feasibility of each imaging modality for use in clinical trials.

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. In addition, a whole-brain based statistical between-group comparison was performed using FA maps. Results The ex post facto statistical evaluation of CV and FA-values in a priori defined ROIs showed no differences between sites above chance indicating that data were not systematically biased by center specific factors. Conclusion Averaging FA-maps from DTI data acquired at different study sites and different MR scanner types does not appear to be systematically biased. A suitable recipe for testing on the possibility to pool multicenter DTI data is provided to permit averaging of DTI-derived metrics to differentiate patients from healthy controls at a larger scale., Highlights ► Alternative procedure to evaluate prerequisites for multicenter DTI data pooling. ► Procedure may serve as reference for future multicenter MRI-DTI trials in HD. ► FA differences between HD and controls consistent with single center reports.

This work has been supported by the European Union — PADDINGTON project and all authors, with the exception of RS, SG and HZ receive funding from this project. RS, SG and HZ are supported by the CHDI/High Q Foundation, a not-for-profit organization dedicated to finding treatments for Huntington's disease. This work was undertaken at UCLH/UCL supported by the National Institute for Health Research [NIHR] University College London Hospitals [UCLH] Biomedical Research Centre [BRC]. 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. METHODS: In 48 early-stage HD patients and 36 controls from the multi-site PADDINGTON project, diffusion tensor imaging (DTI) was employed to measure changes in fractional anisotropy (FA) and axial (AD) and radial diffusivity (RD) in 24 white matter regions-of-interest (ROIs). RESULTS: Cross-sectional analysis indicated widespread baseline group differences, with significantly decreased FA and increased AD and RD found in HD patients across multiple ROIs. Longitudinal rates of change differed between HD patients and controls in the genu and body of corpus callosum, corona radiata and anterior limb of internal capsule. Change in RD in the body of the corpus callosum was associated with baseline disease burden, but other clinical associations were not significant. CONCLUSIONS: We detected subtle longitudinal white matter changes in early HD patients. Progressive white matter abnormalities in HD may not be uniform throughout the brain, with some areas remaining static in the early symptomatic phase. Longer assessment periods across disease stages will help map this progressive trajectory. Postprint

This work has been supported by the European Union—PADDINGTON project, contract no HEALTH-F2-2010-261358. RIS is supported by the CHDI/High Q Foundation, a not for profit organisation dedicated to finding treatments for Huntington's disease. This work was undertaken at UCLH/UCL, which received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme. SJT acknowledges support of the National Institute for Health Research through the Dementias and Neurodegenerative Research Network, DeNDRoN 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. Neuroimaging analysis included global and regional change in macrostructure (atrophy and cortical thinning), and microstructure (diffusion metrics). The main outcome was longitudinal effect size (ES) for each outcome. Such ESs can be used to calculate sample-size requirements for clinical trials for hypothesised treatment efficacies. Results Longitudinal changes in macrostructural neuroimaging measures such as caudate atrophy and ventricular expansion were significantly larger in HD than controls, giving rise to consistently large ES over the 6-month, 9-month and 15-month intervals. Analogous ESs for cortical metrics were smaller with wide CIs. Microstructural (diffusion) neuroimaging metrics ESs were also typically smaller over the shorter intervals, although caudate diffusivity metrics performed strongly over 9 and 15 months. Clinical and cognitive outcomes exhibited small longitudinal ESs, particularly over 6-month and 9-month intervals, with wide CIs, indicating a lack of precision. Conclusions To exploit the potential power of specific neuroimaging measures such as caudate atrophy in disease-modifying trials, we propose their use as (1) initial short-term readouts in early phase/proof-of-concept studies over 6 or 9 months, and (2) secondary end points in efficacy studies over longer periods such as 15 months. Postprint

Background: Possession of one or more apolipoprotein E (APOE) ε4 alleles may influence the distribution of atrophy and clinical phenotype. We aimed to assess the influence of APOE genotype on cortical thickness and regional brain volumes in AD (Alzheimer’s disease). Methods: We included 38 patients (9 ε4 non-carriers, 23 ε4 heterozygotes, 6 ε4 homozygotes) and 23 controls. Each subject had 2 magnetic resonance imaging (MRI) scans and a neuropsychological battery. Cortical thickness and isthmus cingulate volume were measured using FreeSurfer; the volumes of the hippocampus, whole brain, and lateral ventricles were calculated using manual and semi-automated volumetry. Results: Compared with controls, cortical thickness was significantly lower: in the bilateral temporal, posterior parietal and occipital regions in non-carriers, in the medial temporal and left parietal regions in heterozygotes, and in the medial temporal lobe in homozygotes. Comparisons between AD subgroups did not show significant differences. A trend for larger brain and isthmus cingulate volumes and smaller hippocampal and ventricular volumes with increasing ε4 dose were seen. These differences were supported by neuropsychological profiles. Conclusion: These results suggest that APOE genotype may influence the topography of regional atrophy and cortical thinning in AD.

Objective: Caudate atrophy rate measured from serial MRI is proposed as a biomarker of HD progression that may be of use in assessing putative disease-modifying agents. Manual measurement techniques are the most widely applied but are time-consuming. We describe and evaluate an automated technique based on a local registration and boundary shift integral (BSI) approach at the caudate–CSF and caudate–white matter boundaries; caudate boundary shift integral (CBSI). Methods: Two-year caudate volume change was measured in controls, premanifest HD and early HD using the CBSI and compared with a detailed manual measure in terms of 1) raw caudate volume change, 2) group differentiation, 3) associations with clinical variables and 4) rater requirements. CBSI additivity was assessed by comparing measurements over a single scan pair (baseline → 2 years), with the sum of measurements from two scan pairs (baseline → 1 year → 2 years). Results: Techniques produced comparable caudate volume change measurements, although CBSI under-reported by 0.04 ml relative to manual. Both techniques distinguished controls, premanifest and early HD with a stepwise increase in rates across groups. Higher rates (CBSI and manual) were associated with increased proximity to estimated disease onset but not clinical change scores. CBSI reduced rater requirements by 2/3 (2 h per subject) relative to manual for this three time-point investigation. CBSI measurements over one scan pair showed good agreement with the sum of measurements from two scan pairs. Conclusions: CBSI results were comparable to a manual measure but with reduced rater requirements. CBSI may be of use in large-scale studies of HD.

Huntington's disease (HD) is an inherited neurodegenerative disorder that classically presents with motor, cognitive and psychiatric symptoms. However, other abnormalities also occur in this condition, notably deficient recognition of facial emotional expressions. Deficits in emotion recognition impact significantly on the lives of HD patients and their families and thus it is important to clarify the onset and pattern of impairment. This study investigated facial emotion recognition in a large cohort of early HD patients, and premanifest gene-carriers. We used voxel-based morphometry (VBM) to examine the neuroanatomical correlates of emotion recognition performance. Forty patients with early HD, 21 premanifest gene carriers and 20 controls were assessed using 24 faces from the Ekman Pictures of Facial Affect, and volumetric brain MRI. The HD group was significantly worse than controls at recognising, surprise, disgust, anger and fear, and worse than the premanifest group at recognising disgust and anger. When patient data were expressed as z-scores, recognition of anger was significantly worse than disgust in the early HD group. In the VBM analysis, these deficits were associated with common regional atrophy: impaired recognition of surprise, disgust, anger and fear were all associated with striatal volume loss. Fear was associated with additional atrophy of the right insula and left and right lateral orbitofrontal cortex. Even in early HD there is a wide-ranging impairment in recognition of negative emotions denoting 'threat'. Our findings implicate a generic fronto-subcortical network in the pathogenesis of these emotion recognition deficits.

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. METHODS Baseline and 24-month 3T MRI were analysed from 106 premanifest (PreHD), (59 preHD-A ≥10.8 and 47 preHD-B

This study has been supported by the European Union - PADDINGTON project, Contract no. HEALTH-F2-2010-261358. SJT acknowledges support of the National Institute for Health Research through the Dementias and Neurodegenerative Research Network, DeNDRoN. 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. Methods: Fifteen early HD and 17 control participants were tested on emotion recognition from static facial photographs, non-verbal vocal expressions and one second dynamic film clips, all depicting different emotions. Results: Statistically significant evidence of impairment of anger, disgust and fear recognition was seen in HD participants compared with healthy controls across multiple stimulus modalities. The extent of the impairment, as measured by the difference in the number of errors made between HD participants and controls, differed according to the combination of emotion and modality (p=0.013, interaction test). The largest between-group difference was seen in the recognition of anger from film clips. Conclusions: Consistent with previous reports, anger, disgust and fear were the most poorly recognised emotions by the HD group. This impairment did not appear to be due to task demands or expression complexity as the pattern of between-group differences did not correspond to the pattern of errors made by either group; implicating emotion-specific cognitive processing pathology. There was however evidence that the extent of emotion recognition deficits significantly differed between stimulus modalities. The implications in terms of designing future tests of emotion recognition and care giving are discussed. Postprint

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). T1 data was used to generate further ROIs for analysis in a reduced sample of 18 participants. The results suggest that fractional anisotropy (FA) and other diffusivity metrics are generally highly reliable, with ICCs indicating considerably lower within-subject compared to between-subject variability in both HD patients and controls. Where ICC was low, particularly for the diffusivity measures in the caudate and putamen, this was partly influenced by outliers. The analysis suggests that the specific DTI methods used here are appropriate for cross-sectional research in HD, and give confidence that they can also be applied longitudinally, although this requires further investigation. An important caveat for DTI studies is that test-retest reliability may not be evenly distributed throughout the brain whereby highly anisotropic white matter regions tended to show lower relative within-subject variability than other white or grey matter regions.

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. Manual delineation and voxel-based morphometry were used to assess between-group differences in cerebellar volume, and diffusion metrics were compared between groups within the cerebellar gray and white matter. Associations between these imaging measures and clinical scores were examined within the HD group. Reduced paravermal volume was detected in HD compared with controls using voxel-based morphometry (P 0.05), but no significant volumetric differences were found using manual delineation. Diffusion abnormalities were detected in both cerebellar gray matter and white matter. Smaller cerebellar volumes, although not significantly reduced, were significantly associated with impaired gait and psychiatric morbidity and of borderline significance with pronate/supinate-hand task performance. Abnormal cerebellar diffusion was associated with increased total motor score, impaired saccade initiation, tandem walking, and timed finger tapping. In conclusion, atrophy of the paravermis, possibly encompassing the cerebellar nuclei, and microstructural abnormalities within the cerebellum may contribute to HD neuropathology. Aberrant cerebellar diffusion and reduced cerebellar volume together associate with impaired motor function and increased psychiatric symptoms in stage I HD, potentially implicating the cerebellum more centrally in HD presentation than previously recognized.

This work was supported by the European Union under the Seventh Framework programme– PADDINGTON Project, Grant Agreement No. 261358, and the European Huntington’s Disease Network (EHDN), project 070 – PADDINGTON. 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.Methods: Sixty-one HD patients in early stages and forty matched healthy controls were studied in a longitudinal design (baseline and two follow-ups at three time points over 15 months), in a multicenter setting with similar acquisition protocols on four different MR scanners at four European study sites. A QC algorithm was used to identify corrupted GD in DTI data sets. Differences in fractional anisotropy (FA) maps at the group level with and without elimination of corrupted GD were analyzed.Results: The elimination of corrupted GD had an impact on individual FA maps as well as on cross-sectional group comparisons between HD subjects and controls. Following application of the QC algorithm, less small clusters of FA changes were observed, compared to the analysis without QC. However, the main pattern of regional reductions and increases in FA values with and without QC-based elimination of corrupted GD was unchanged.Conclusion: An impact on the result patterns of the comparison of FA maps between HD subjects and controls was observed depending on whether QC-based elimination of corrupted GD was performed. QC-based elimination of corrupted GD in DTI scans reduces the risk of type I and type II errors in cross-sectional group comparison of FA maps contributing to an increase in reliability and stability of group comparisons. Publisher PDF

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. Caudate and total white matter volumes were quantified using FIRST and SIENAX respectively. Multiple regression analysis was used to assess which of the imaging metrics predicted disease severity in the HD subjects. Results Diffusion metrics were significantly altered in premanifest and early HD gene carriers in comparison with controls throughout the white matter skeleton. Correlations between diffusion and volumetric metrics and disease progression were also present. Together, caudate volume and mean white matter fractional anisotropy and mean diffusivity predicted disease burden score in the HD subjects. Conclusions The diffusion properties of white matter are extensively altered in HD, and are associated with markers of HD severity, and with caudate and white matter volumes. The correlation between diffusion metrics and white matter volume is stronger in HD subjects than in controls, but there is no such significant interaction for the correlation between diffusion and caudate volume: we propose that many of the changes in white matter diffusion in HD occur as a ‘normal’ physiological response to pathological caudate volume loss. We have defined the extent to which mean white matter fractional anisotropy, white matter volume and caudate volume are associated with disease burden score.

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. Results provide new detail in the progression pattern of these diseases, while confirming known features, and give unique insight into the variability of progression over the cohort. The key advantage of the new model and algorithms over previous progression models is that they do not require a priori division of the patients into clinical stages. The model and its formulation extend naturally to a wide range of other diseases and developmental processes and accommodate cross-sectional and longitudinal input data.

Background Macrostructural and microstructural neuroimaging measures are potential biomarkers in Huntington’s disease (HD). Macrostructural measures are generally derived from structural T1-weighted magnetic resonance imaging (MRI), while microstructure can be measured using diffusion tensor imaging (DTI), which indexes the properties of water molecules within white matter (WM) tissue. HD is associated with WM volume and integrity loss but how these two measures interact is not fully understood. Aims To investigate the relationship between diffusion metrics and brain volume in healthy controls. Methods 3T MRI and DTI data from 51 control subjects taken from the TRACK-HD and PADDINGTON studies were analysed. Regression analysis and Tract Based Spatial Statistics (TBSS) were used to assess the associations between whole brain diffusion metrics: fractional anisotropy; mean diffusivity; axial diffusivity and radial diffusivity, and volumetric measures: whole brain volume; WM and grey matter (GM) volumes (all adjusted for total intracranial volume). Results Regression analysis revealed a significant relationship between all diffusion metrics and both whole brain and WM volumes. No significant relationship was found between GM and FA. Preliminary TBSS results suggest a significant positive association between whole brain volume and FA in several regions, including the cingulate gyrus, pre- and post central gyri and the putamen. Conclusions We demonstrated an association between whole brain and WM volume and diffusion-based measures of tissue integrity; this relationship is present in the absence of any disease-related changes. These results may aid our understanding of the underlying pathology and heterogeneity in HD and have implications for biomarker development in the condition.

Background Previous Huntington’s disease studies have revealed occipital lobe atrophy and cortical thinning, although it is unclear when this develops and whether it is uniform across the lobe. Visual deficits are not typical of HD symptomatology, however it is possible that more subtle visual functions are impaired and, in turn, influence performance on cognitive tasks with a visual component. Aims To identify the regional distribution of disease-related occipital cortical thinning and investigate associations with cognitive and motor impairment. Methods T1-weighted 3T MR scans from controls (n = 107), pre-HD (n = 116) and early HD subjects (n = 90) from the TRACK-HD study were processed using the FreeSurfer software; cuneus, pericalcarine, lingual and lateral occipital regions were outputted. Generalised least squares regression models were fitted to assess between-group differences. Relationships between visual cognitive and motor task performance and cortical occipital thinning in gene-positive participants were assessed using general linear regression models. Results The occipital cortex was significantly thinner in pre-HD and early HD participants. These between-group differences were heterogeneous across regions, with the lateral occipital region showing the most pronounced effects. Significant associations were found between reduced occipital cortical thickness and poorer performance on a number of cognitive tasks involving a visual component. No association was found with finger tapping. Conclusions Regionally-specific thinning of the occipital cortex was evident more than a decade before estimated HD symptom onset. Associations were found with cognitive tasks, but not finger tapping, suggesting that occipital thickness plays an important role in cognitive tasks with a visual component. This has implications for the interpretation of impaired cognitive performances in HD, which is typically attributed to frontal and executive circuits, rather than to visual regions.

Huntington’s disease (HD) produces progressive and ultimately widespread impairment of brain function. Neostriatal atrophy alone cannot account for whole-brain losses seen postmortem, and the mutant huntingtin protein and its neuropathologic sequelae are evident throughout the brain. Whole-brain atrophy quantification encompasses the totality of mutant huntingtin’s effects on brain volume and may be useful in tracking progression in trials. We studied whole-brain atrophy in HD using a 2-year follow-up design, with three annual MRI scans. We recruited 20 control subjects, 21 premanifest mutation carriers, and 40 patients with early HD and used the brain boundary shift integral to study rate and acceleration of atrophy. Among subjects with an acceptable quality 2-year scan pair, age- and gender-standardized mean brain atrophy rate was greater (P < 0.001) in the patients with HD (n = 21; 0.88%/yr; 95% confidence interval: 0.62–1.13%/yr) than that in controls (n = 13; 0.16%/yr; 0.00–0.32%/yr). In the 12 patients with early HD in whom acceleration could be directly assessed there was evidence (P = 0.048) of acceleration year-on-year (mean acceleration = 0.69% yr(−2); 95% confidence interval: 0.01% yr(−2) to 1.37% yr(−2)), although this was not formally significantly different from that in controls (n = 7, P = 0.055). Statistically significantly increased atrophy rates and acceleration were not seen overall in the premanifest group, who were on average 18 years from predicted disease onset. We conclude that the study of whole-brain atrophy has the potential to inform our understanding of the neurobiology of HD and warrants further study as one means of assessing the outcomes of future clinical trials.

BACKGROUND AND PURPOSE: Longitudinal MR imaging measures provide an opportunity to track progression in HD before the emergence of clinical symptoms. This may prove useful in assessing disease-modifying treatments. We investigated how caudate and global volumes change as HD progresses from premanifest to early disease. MATERIALS AND METHODS: Forty HD gene-positive individuals and 19 controls underwent serial volumetric MR imaging (baseline, 12 and 27 months; 2 or 3 scans per person). At baseline, 3 patients with HD were premanifest but developed overt motor features during the study, and 37 had early HD. All had dates of motor onset recorded. Caudates, lateral ventricles, and TIVs were measured using semiautomated procedures. Linear mixed models were used to investigate differences between HD and controls in relation to motor onset, controlling for TIV, sex, and age. RESULTS: Extrapolating backwards in time, we found that differences in caudate and ventricular volumes between patients with HD and controls were evident 14 and 5 years, respectively, before motor onset (P < .05). At onset, caudate volume was 2.58 mL smaller than that in controls (P < .0001); ventricular volume was 9.27 mL larger (P < .0001). HD caudate atrophy rates were linear, showed low variability between subjects, and were approximately 10-fold higher than those in controls (P < .001). HD ventricular enlargement rates were variable between subjects, were approximately 4-fold higher than those in controls at onset (P < .001), and accelerated with disease duration (P = .02). CONCLUSIONS: We provide evidence of acceleration of global atrophy in HD with disproportionate caudate involvement. Both caudate and global measures may be of use as early markers of HD pathology.

Imaging studies of cerebral volumes often adjust for factors such as age that may confound between-subject comparisons. However the use of nuisance covariates in imaging studies is inconsistent, which can make interpreting results across studies difficult. Using magnetic resonance images of 78 healthy controls we assessed the effects of age, gender, head size and scanner upgrade on region of interest (ROI) volumetry, cortical thickness and voxel-based morphometric (VBM) measures. We found numerous significant associations between these variables and volumetric measures: cerebral volumes and cortical thicknesses decreased with increasing age, men had larger volumes and smaller thicknesses than women, and increasing head size was associated with larger volumes. The relationships between most ROIs and head size volumes were non-linear. With age, gender, head size and upgrade in one model we found that volumes and thicknesses decreased with increasing age, women had larger volumes than men (VBM, whole-brain and white matter volumes), increasing head size was associated with larger volumes but not cortical thickness, and scanner upgrade had an effect on thickness and some volume measures. The effects of gender on cortical thickness when adjusting for head size, age and upgrade showed some non-significant effect (women>-men), whereas the independent effect of head size showed little pattern. We conclude that age and head size should be considered in ROI volume studies, age, gender and upgrade should be considered for cortical thickness studies and all variables require consideration for VBM analyses. Division of all volumes by head size is unlikely to be adequate owing to their non-proportional relationship. (C) 2010 Elsevier Inc. All rights reserved.

Background Unbiased longitudinal studies are needed to understand the distributed neurodegenerative changes of Huntington9s disease (HD). They may also provide tools for assessing disease-modifying interventions. The authors investigated the progression of regional atrophy in premanifest and early HD compared with controls. Methods Nine controls, 17 premanifest and 21 early HD subjects underwent volumetric MRI at baseline and 2 years. Premanifest subjects were on average 18.1 years before predicted motor onset. Non-linear registration was used to model within-subject change over the scanning interval, and statistical parametric mapping was used to examine group differences and associations with clinical variables. Results In early HD, increased grey-matter (GM) atrophy rates were evident throughout the subcortical GM and over selective cortical regions compared with controls. This group also demonstrated strikingly widespread increases in white-matter (WM) atrophy rates. The authors observed no significant differences between premanifest HD and controls. Longer CAG was associated with higher atrophy rates over large WM areas including brainstem and internal capsule and over small GM regions including thalamus and occipital cortex. Worse baseline motor score was associated with regionally increased rates in the thalamus, internal capsule and occipital lobe. Sample-size calculations indicate that 19 and 24 early HD subjects per treatment arm would need to complete a 2-year trial in order to detect a 50% reduction in WM and GM atrophy rates respectively. Conclusions Degeneration of structural connectivity may play an important role in early HD symptoms. Assessment of WM and GM changes will be important in understanding the complexity of HD and its treatment.

Therapeutic trials in Huntington's disease (HD) are challenging as clinical progression is slow and variable and reliable biomarkers are lacking. We used magnetic resonance imaging and the brain boundary shift integral to quantify whole-brain atrophy rates over 1 year in early and premanifest HD subjects, and controls. Early HD subjects had statistically significantly (P = 0.007) increased (threefold higher) rates of whole-brain atrophy compared with controls. Higher atrophy rates were associated with longer CAG repeat length. MRI-based measures of whole-brain atrophy may have potential as a measure of progression in HD.

The known genetic mutation causing Huntington's disease (HD) makes this disease an important model to study links between gene and brain function. An autosomal dominant family history and the availability of a sensitive and specific genetic test allow pre-clinical diagnosis many years before the onset of any typical clinical signs. This review summarizes recent magnetic resonance imaging (MRI)–based findings in HD with a focus on the requirements if imaging is to be used in treatment trials. Despite its monogenetic cause, HD presents with a range of clinical manifestations, not explained by variation in the number of CAG repeats in the affected population. Neuroimaging studies have revealed a complex pattern of structural and functional changes affecting widespread cortical and subcortical regions far beyond the confines of the striatal degeneration that characterizes this disorder. Besides striatal dysfunction, functional imaging studies have reported a variable pattern of increased and decreased activation in cortical regions in both pre-clinical and clinically manifest HD-gene mutation carriers. Beyond regional brain activation changes, evidence from functional and diffusion-weighted MRI further suggests disrupted connectivity between corticocortical and corticostriatal areas. However, substantial inconsistencies with respect to structural and functional changes have been reported in a number of studies. Possible explanations include methodological factors and differences in study samples. There may also be biological explanations but these are poorly characterized and understood at present. Additional insights into this phenotypic variability derived from study of mouse models are presented to explore this phenomenon.

Huntington’s disease (HD) is caused by an expanded CAG repeat on the gene encoding for the protein huntingtin. There are conflicting findings about the extent to which repeat length predicts signs of the disease or severity of disease progression in adults. This study examined the relationship between CAG repeat length and brain volume in a large cohort of pre- and post-motor onset HD gene carriers, using voxel-based morphometry (VBM), an approach which allowed us to investigate the whole brain without defining a priori regions of interest. We also used VBM to examine group differences between 20 controls, 21 premanifest, and 40 early HD subjects. In the 61 mutation-positive subjects higher CAG repeat length was significantly associated with reduced volume of the body of the caudate nucleus bilaterally, left putamen, right insula, right parahippocampal gyrus, right anterior cingulate, and right occipital lobe, after correcting for age. The group contrasts showed significant reduction in grey matter volume in the early HD group relative to controls in widespread cortical as well as subcortical areas but there was no evidence of difference between controls and premanifest subjects. Overall we have demonstrated that increased CAG repeat length is associated with atrophy in extra-striatal as well as striatal regions, which has implications for the monitoring of disease-modifying therapies in the condition.

Huntington's disease (HD) is a hereditary neurodegenerative disorder for which biological indicators of disease progression, or disease stage, would be especially important for therapeutic trials. 24S-hydroxycholesterol (24OHC) is a brain-generated cholesterol metabolite which has been associated with neurodegeneration, and alterations of cholesterol metabolism in murine HD models and patients' tissues have been recently identified. On these grounds, and with the aim of identifying putative biomarkers in HD, we studied cholesterol metabolism through the analysis in vivo of plasma 24OHC and cholesterol in two independent cohorts of controls and patients of Italian and British origin. We analysed a total of 62 controls, 96 HD symptomatic patients at different disease stages (stage 1-3), and 33 HD gene-positive pre-manifest subjects [pre-manifest HD (pre-HD)]. Cholesterol and 24OHC plasma levels were comparable in both the British and Italian subjects, and were not influenced by fasting or post-meal status. Cholesterol levels did not show differences between controls, pre-HD subjects and HD patients. In contrast, the plasma levels of 24OHC were significantly higher in controls than in HD patients at all disease stages (P < 0.001). Interestingly, in pre-HD subjects plasma 24OHC concentrations were similar to those of controls, and thus significantly greater than those of HD patients at any disease stage (P < 0.001). As expected, significant differences in caudate volumes between stage 1-2 HD patients and pre-HD subjects, and pre-HD subjects and controls were found. The pre-HD cohort of subjects was heterogeneous as to 24OHC levels, since subjects closer to predicted development of motor signs of disease had lower 24OHC levels than those far from onset. Our data indicate that the brain-generated cholesterol metabolite 24OHC measured in plasma was significantly depleted in HD patients at any disease stage, and it could discriminate pre-manifest subjects from patients with overt motor disease. However, 24OHC levels failed to mark further disease progression in patients with manifest HD. Overall, we demonstrate that 24OHC levels parallel the large decrease in caudate volumes observed in gene-positive subjects from pre-manifest to HD stage 1, thus reflecting a critical phase characterized by neuronal loss. We conclude that that 24OHC levels complement MRI morphometry as a valuable tool to follow neurodegenerative changes in the early stages of Huntington disease. Huntington's disease (HD) is a hereditary neurodegenerative disorder for which biological indicators of disease progression, or disease stage, would be especially important for therapeutic trials. 24S-hydroxycholesterol (24OHC) is a brain-generated cholesterol metabolite which has been associated with neurodegeneration, and alterations of cholesterol metabolism in murine HD models and patients' tissues have been recently identified. On these grounds, and with the aim of identifying putative biomarkers in HD, we studied cholesterol metabolism through the analysis in vivo of plasma 24OHC and cholesterol in two independent cohorts of controls and patients of Italian and British origin. We analysed a total of 62 controls, 96 HD symptomatic patients at different disease stages (stage 1-3), and 33 HD gene-positive pre-manifest subjects [pre-manifest HD (pre-HD)]. Cholesterol and 24OHC plasma levels were comparable in both the British and Italian subjects, and were not influenced by fasting or post-meal status. Cholesterol levels did not show differences between controls, pre-HD subjects and HD patients. In contrast, the plasma levels of 24OHC were significantly higher in controls than in HD patients at all disease stages (P < 0.001). Interestingly, in pre-HD subjects plasma 24OHC concentrations were similar to those of controls, and thus significantly greater than those of HD patients at any disease stage (P < 0.001). As expected, significant differences in caudate volumes between stage 1-2 HD patients and pre-HD subjects, and pre-HD subjects and controls were found. The pre-HD cohort of subjects was heterogeneous as to 24OHC levels, since subjects closer to predicted development of motor signs of disease had lower 24OHC levels than those far from onset. Our data indicate that the brain-generated cholesterol metabolite 24OHC measured in plasma was significantly depleted in HD patients at any disease stage, and it could discriminate pre-manifest subjects from patients with overt motor disease. However, 24OHC levels failed to mark further disease progression in patients with manifest HD. Overall, we demonstrate that 24OHC levels parallel the large decrease in caudate volumes observed in gene-positive subjects from pre-manifest to HD stage 1, thus reflecting a critical phase characterized by neuronal loss. We conclude that that 24OHC levels complement MRI morphometry as a valuable tool to follow neurodegenerative changes in the early stages of Huntington disease. © The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

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 a quality control (QC) algorithm 1 was employed to eliminate corrupted GD from DTI data. Effects of this procedure on comparisons between Huntington disease (HD) subjects and controls were assessed at the group level. Methods Sixty-one HD patients in early stages and forty matched healthy controls were studied in a longitudinal design (baseline and two follow-ups at three time points over 15 months), in a multicenter setting with standardised acquisition protocols on four different MR scanners at four European study sites 2 . QC was used to identify corrupted GD in DTI data sets. Differences in fractional anisotropy (FA) maps at the group level with and without elimination of corrupted GD were analysed. Results The elimination of corrupted GD had an impact on individual FA maps as well as on cross-sectional group comparisons between HD subjects and controls. Following application of the QC algorithm, a lower number of small clusters of FA changes were observed, compared with the analysis without QC-based elimination. However, the grosso modo pattern of regional reductions and increases in FA values was unchanged. Conclusion An impact on the result patterns of the comparison of FA maps between HD subjects and controls was observed depending on whether QC-based elimination of corrupted GD was performed. QC-based elimination of corrupted GD in DTI scans reduces the risk of type I and type II errors in cross-sectional group comparison of FA maps contributing to an increase in reliability and stability of group comparisons. Acknowledgment This work was supported by the European Union under the Seventh Framework programme – PADDINGTON Project, Grant Agreement No. 261358, and the European Huntington’s Disease Network (EHDN), project 070 – PADDINGTON. References Muller HP, et al . PLoS Curr 2011, RRN1232 Muller HP, et al . Neuroimage Clinical 2013,2:161–167

Background TRACK-HD and PADDINGTON are both longitudinal studies whose aims included assessing the potential of various biomarkers as outcomes for clinical trials of new Huntington’s disease (HD) therapies. One such biomarker is caudate atrophy. This potential is dependent upon the distribution of change in patients, with the distribution of change in healthy controls being indicative of what a successful treatment might achieve. Aims Appropriate statistical models may be fitted to repeated measures to predict the distribution of changes that would be seen over time intervals not utilised in the index study. TRACK-HD involved yearly follow up over 36 months whilst PADDINGTON assessed changes over shorter intervals. Our aim was to compare the distributions of observed 6, 9 and 15 month caudate atrophy seen in PADDINGTON with that predicted from TRACK-HD. Methods/techniques Linear mixed models were fitted separately to data from the early-HD and control subjects in TRACK-HD to predict the mean and standard deviation of caudate atrophy rates over 6, 9 and 15 months. These predictions (and their 95% confidence intervals) were compared with the observed means and standard deviations from PADDINGTON and their confidence intervals. Predicted and observed effect sizes were also compared. Results/outcome As assessed using confidence intervals, predictions from TRACK-HD and observed results in PADDINGTON were consistent with one another. Confidence intervals for predictions made from TRACK-HD were narrower than those for the analogous observed estimates from PADDINGTON. The predictions did not exhibit implausible patterns of behaviour over time that sometimes occurred with the observed PADDINGTON data, which were likely the result of chance variability. Conclusions Appropriate statistical models,when used with repeated measures of caudate atrophy, have great utility in predicting the distribution of atrophy rates time over intervals shorter than those used in the index study.

Background Huntington9s disease (HD) has been associated with white matter (WM) abnormalities, evident using diffusion tensor imaging (DTI) analysis. However, the limited longitudinal work in this area has been inconclusive and further research into the progressive WM degeneration in HD is required. A key factor in the validity of results from longitudinal DTI research is the reliability of these measurements, which is not well-established. Aim To assess the test-retest reliability of DTI-based measures of brain structure. Methods Using repeat DTI data from 12 participants scanned at the London and Paris sites of the PADDINGTON study (scan interval range 0–24 days), the reliability of measures derived from different analysis methods was assessed by calculating intra-class correlations coefficients (ICC) for each measure. Results Fractional anisotropy (FA) across the whole brain showed a mean reliability of ICC=0.79. The regional distribution of reliability was also mapped, using voxelwise ICC, with WM regions showing higher ICC compared to grey matter or cerebro-spinal fluid. Tensor-based atlas registration showed substantial variation in reliability between different WM regions, however, assessed across all regions, reliability was high for FA (ICC=0.98) and the trace of diffusivity (ICC=0.98). Using manually delineated regions-of-interest, reliability was high for WM (ICC=0.96) and both the caudate (ICC=0.96) and putamen (ICC=0.97), while corpus callosum reliability was lower (ICC=0.83). Comparable measures of reliability were found for the trace of diffusivity. Conclusions DTI scanning generally produces highly reliable measures of brain structure. There is considerable heterogeneity in reliability between different brain regions and imaging methods. These results will be informative when designing longitudinal research to map progressive brain changes in HD and other degenerative disorders.

Aim Assessment of the feasibility of averaging diffusion tensor imaging (DTI) metrics of MRI data acquired in the course of a multicentre study. Materials and methods 61 patients with early stage Huntington9s disease and 40 healthy controls were studied at four study sites distributed across Europe using different MR scanner types with acquisition protocols that were as close as possible to a given standard protocol. Whole-brain based statistical comparison was performed on the basis of fractional anisotropy (FA) maps. The potential and feasibility of grouping and averaging data acquired at different sites was evaluated by comparison to previously published results. This approach seems to be suitable especially for DTI because of the measurement of physical quantities. Results The affectation pattern of whole-brain based comparison of FA-maps showed reproducible results for all data sets of each study site as compared with previous results of other research groups. Averaging of all data sets of all study sites was performed and an improvement of the signal-to-noise ratio was found. Conclusion Averaging of FA-maps of DTI data acquired from different subjects at multiple study sites with diverse MR scanner types has proven to be feasible. A suitable proposal is provided for testing the possibility of grouping multicentric DTI data to allow averaging of DTI-derived metrics to differentiate patients from healthy controls. Funding This work has been supported by the European Union – PADDINGTON project, contract n. HEALTH-F2-2010-261358.

Background 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. Aims 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. Methods 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. Results Preliminary analysis of a subset of subjects indicates that early HD subjects have reduced CC volume compared with controls and premanifest subjects (p Conclusions Measurement of CC atrophy may have potential as an imaging biomarker for HD and may prove useful for exploring interhemispheric structure-function relationships. Funding Helen Crawford is supported by the CHDI Foundation, a not for profit organisation dedicated to finding treatments for HD.

Background Major Depressive Disorder can be seen as a neuropsychological syndrome, associated with morphometric and functional changes in various brain regions, amongst these the anterior cingulate (ACC) and frontal cortex. In addition we found in a previous study a significant correlation between symptom severity and morphometric changes of the insular cortex in participants with Major Depression.1 Aims Using baseline data from the Paddington project WP 2, we wanted to confirm our previous findings and support our hypothesis, that the insula forms an important part of the neural network which underlies depression. Methods and Results To identify neural structures associated with depression, we used MRI DTI sequences and compared fractional anisotropy (FA)-maps of people with Huntington's disease with low and higher depression scores on the Hamilton scale. Groups were separated by a median split. This resulted in a group of 30 non-depressed participants with a mean depression score of 0.8 (SD 0.7), and a group of 31 mildly depressed participants with a mean depression score of 7.2 (SD 3.5). Imaging data of the non-depressed and the mildly depressed HD group was compared voxel by voxel using t-tests. Statistical results were corrected for multiple comparisons using the false-discovery-rate (FDR) algorithm with a significance level set at p

Background Putamen atrophy is widely assumed to be associated with several motor symptoms of HD but less so cognitive impairment. This study specifically examines two cognitive functions associated with the putamen and potentially affected in HD, namely emotion recognition and associative learning. Aims A novel cognitive test of putamen function was designed alongside imaging measures (putamen, caudate and whole-brain volumes). Cross-sectional and longitudinal change will be investigated in both domains along with the interactions between them. Method 15 early HD and 15 controls will be tested, 13 with follow-up at 9 months. A novel forced-choice multi-modal emotion recognition task is followed by an associative learning task in which participants learn to pair shapes with numbers. Manual segmentation of T1 scans is conducted in MIDAS. Results Preliminary results suggest that emotion recognition deficits correlate with striatal and whole-brain volumes. Patients find auditory emotion recognition more difficult than the visual modalities, with fear and anger recognition scoring the most errors in the HD group. A general deficit in facial recognition (as assessed by the Benton Facial Recognition Test) is also seen. Associative learning is impaired in early HD but error rates do not clearly correlate with imaging measures. Conclusions Further cross-sectional and additional longitudinal data will help clarify questions such as: do cognitive measures correlate with cross-sectional and longitudinal putamen change? Are some emotions/emotion modalities more impaired than others? Funding This work has been supported by the European Union–PADDINGTON project, contract n. HEALTH-F2-2010-261358. FP7 logos and/or EU emblem has been used according to European Commission guideline and recommendations. http://www.paddingtonproject.eu/.

Background Macro- and micro-structural brain changes are of interest as markers of Huntington9s Disease (HD) progression, which may prove useful in future clinical trials. The relative sensitivity of these markers is unknown. Aims To evaluate macro-structural volume measurements and micro-structural diffusion measurements in HD. Methods 40 controls and 61 early stage HD subjects, recruited across four EU sites, underwent 3T MRI plus a clinical and cognitive battery. Volumetric measurements of the whole brain, caudate, putamen, corpus callosum and ventricles were performed using MIDAS. Diffusion metrics of fractional anisotropy (FA), mean- radial- and axial-diffusivity (MD, RD and AD) were computed over the white matter, corpus callosum, caudate and putamen. Group differences were examined adjusting for age, gender and site. Results Compared with controls, HD subjects showed strong evidence of reduced volume in all brain regions examined (p Conclusion Both volumetric and diffusion metrics are sensitive to disease effects in HD. Robust statistical comparison of effect sizes for these measures will help inform the design of future clinical trials. Funding This work has been supported by the European Union – PADDINGTON project, contract n. HEALTH-F2-2010-261358.

Background TRACK-HD is an international multi-site study of premanifest and early Huntington9s disease (HD) which aims to investigate a range of biomarkers for use in future therapeutic trials. Detecting subtle brain changes in slowly progressive heterogeneous diseases such as HD is a challenge. Manual techniques, the current ‘gold standard’, are time consuming, reliant on the rater skill and impractical for large scale use. Linear registration of serial MRI has successfully been used to detect whole brain and caudate atrophy in HD using the boundary shift integral (BSI). However, it is less robust when applied to structures without brain–CSF boundaries. Non-linear (fluid) registration allows assessment of within subject change across the entire brain so may be applicable to a wider array of structures, thus providing more regionally specific information. Aims To develop and apply a fully automated technique sensitive to 1 year global and regional volumetric changes in premanifest and early HD subjects using fluid registration of serial MRI. Methods/techniques T1 weighted 3T MR images were acquired at baseline and 1 year from 303 subjects (97 controls; 110 premanifest; 96 early HD) in the TRACK-HD study. Regions of interest (ROI) were generated on the baseline scans using the automated FSL software. Fluid registration was used to model within subject voxel level change over the scanning interval and the 1 year volume change was quantified by summing voxel change within each ROI. Results/outcome Preliminary fluid derived results (whole brain and caudate) show good group discrimination, consistent with BSI findings. We will present fluid derived regional and global atrophy rates, group differences and a comparison of our data with BSI results where appropriate. Conclusions We describe a technique which has the potential to provide fully automated global and regional measures of atrophy using multi site data. This may have utility as an outcome measure for future therapeutic trials in HD.

When blood flows through an artificial environment for prolonged periods of time, the red blood cells are gradually destroyed due to the high shear stresses to which they are exposed. The ability to measure the degree of haemolysis accurately and in real time is becoming increasingly important, especially in the context of organ preservation and of the implantation of heart‐assist devices as a long‐term method for treating heart failure. A recent study indicated that the backscattering coefficient (BSC) of red cell suspensions containing damaged red blood cells is significantly higher than the BSC of suspensions containing exclusively healthy cells. Using a specially designed acoustic chamber, suspensions containing different proportions of healthy and damaged cells were exposed to 15‐MHz ultrasound. A thin tungsten wire immersed in each suspension was used to quantify the speed of sound and attenuation through increasingly haemolysed suspensions. It is intended to utilize a combination of measurements of...