Huntington's Disease Participants Research Articles

Disease stage, but not sex, predicts depression and psychological distress in Huntington's disease: A European population study

ObjectiveDepression and anxiety significantly affect morbidity in Huntington's disease. Mice.models of Huntington's disease have identified sex differences in mood-like behaviours that vary across disease lifespan, but this interaction has not previously been explored in humans with Huntington's disease. However, among certain medical populations, evidence of sex differences in mood across various disease stages has been found, reflecting trends among the general population that women tend to experience anxiety and depression 1.5 to 2 times more than men. The current study examined whether disease stage and sex, either separately or as an interaction term, predicted anxiety and depression in Huntington's disease. MethodsA cross-sectional study of REGISTRY data involving 453 Huntington's disease participants from 12 European countries was undertaken using the Hospital Anxiety and Depression Scale. A series of multiple regression analyses were undertaken to discover to what extent disease stage and sex predicted anxiety, depression, and general distress after controlling for a number of known predictors of mood difficulties. ResultsDisease stage, but not sex, was found to predict depressive symptoms and general distress. Neither disease stage nor sex predicted anxiety. Furthermore, an interaction term computed for disease stage and sex did not contribute to the models tested. ConclusionIn terms of considering risks to developing depression and anxiety in the Huntington's disease population, practitioners may need to pay special attention to disease stage progression (but not sex differences) to enable early detection and treatment of depression (but not anxiety).

The impact of occipital lobe cortical thickness on cognitive task performance: An investigation in Huntington's Disease

BackgroundThe occipital lobe is an important visual processing region of the brain. Following consistent findings of early neural changes in the occipital lobe in Huntington's Disease (HD), we examined cortical thickness across four occipital regions in premanifest (preHD) and early HD groups compared with controls. Associations between cortical thickness in gene positive individuals and performance on six cognitive tasks, each with a visual component, were examined. In addition, the association between cortical thickness in gene positive participants and one non-visual motor task was also examined for comparison. MethodsCortical thickness was determined using FreeSurfer on T1-weighted 3T MR datasets from controls (N=97), preHD (N=109) and HD (N=69) from the TRACK-HD study. Regression models were fitted to assess between-group differences in cortical thickness, and relationships between performance on the cognitive tasks, the motor task and occipital thickness were examined in a subset of gene-positive participants (N=141). ResultsThickness of the occipital cortex in preHD and early HD participants was reduced compared with controls. Regionally-specific associations between reduced cortical thickness and poorer performance were found for five of the six cognitive tasks, with the strongest associations in lateral occipital and lingual regions. No associations were found with the cuneus. The non-visual motor task was not associated with thickness of any region. ConclusionsThe heterogeneous pattern of associations found in the present study suggests that occipital thickness negatively impacts cognition, but only in regions that are linked to relatively advanced visual processing (e.g., lateral occipital, lingual regions), rather than in basic visual processing regions such as the cuneus. Our results show, for the first time, the functional implications of occipital atrophy highlighted in recent studies in HD.

Cortical inhibitory deficits in premanifest and early Huntington’s disease

Although progress has been made towards understanding the gross cortical and subcortical pathology of Huntington’s disease (HD), there remains little understanding of the progressive pathophysiological changes that occur in the brain circuits underlying the disease. Transcranial magnetic stimulation (TMS) enables investigation of the functional integrity of cortico-subcortical pathways, yet it has not been widely applied in HD research to date. This study sought to characterise profiles of cortical excitability, including inhibition and facilitation, in groups of premanifest and symptomatic HD participants via the use of TMS. We also investigated the clinical, neurocognitive and psychiatric correlates of cortical excitability to better understand the development of phenotypic heterogeneity. The sample comprised 16 premanifest HD, 12 early symptomatic HD and 17 healthy control participants. Single- and paired-pulse TMS protocols were administered to the left primary motor cortex, with surface electromyography recorded from the abductor pollicis brevis muscle. Short-interval cortical inhibition was significantly reduced in symptomatic HD, compared with premanifest HD and controls, and was significantly correlated with pathological burden and neurocognitive performance. There was also reduced long-interval cortical inhibition in both premanifest and symptomatic HD, compared with controls, which was associated with pathological burden and psychiatric disturbances. Motor thresholds, cortical silent periods and intracortical facilitation did not differ across groups. Our results provide important new insights into pathophysiological changes in cortico-subcortical circuits across disease stages in HD. We propose that neurophysiological measures obtained via TMS have potential utility as endophenotypic biomarkers in HD, given their association with both pathological burden and clinical phenotype.

Motor onset and diagnosis in Huntington disease using the diagnostic confidence level.

Huntington disease (HD) is a neurodegenerative disorder characterized by motor dysfunction, cognitive deterioration, and psychiatric symptoms, with progressive motor impairments being a prominent feature. The primary objectives of this study are to delineate the disease course of motor function in HD, to provide estimates of the onset of motor impairments and motor diagnosis, and to examine the effects of genetic and demographic variables on the progression of motor impairments. Data from an international multisite, longitudinal observational study of 905 prodromal HD participants with cytosine-adenine-guanine (CAG) repeats of at least 36 and with at least two visits during the followup period from 2001 to 2012 was examined for changes in the diagnostic confidence level from the Unified Huntington's Disease Rating Scale. HD progression from unimpaired to impaired motor function, as well as the progression from motor impairment to diagnosis, was associated with the linear effect of age and CAG repeat length. Specifically, for every 1-year increase in age, the risk of transition in diagnostic confidence level increased by 11% (95% CI 7-15%) and for one repeat length increase in CAG, the risk of transition in diagnostic confidence level increased by 47% (95% CI 27-69%). Findings show that CAG repeat length and age increased the likelihood of the first onset of motor impairment as well as the age at diagnosis. Results suggest that more accurate estimates of HD onset age can be obtained by incorporating the current status of diagnostic confidence level into predictive models.

Selective vulnerability of Rich Club brain regions is an organizational principle of structural connectivity loss in Huntington's disease.

Huntington's disease can be predicted many years before symptom onset, and thus makes an ideal model for studying the earliest mechanisms of neurodegeneration. Diffuse patterns of structural connectivity loss occur in the basal ganglia and cortex early in the disease. However, the organizational principles that underlie these changes are unclear. By understanding such principles we can gain insight into the link between the cellular pathology caused by mutant huntingtin and its downstream effect at the macroscopic level. The 'rich club' is a pattern of organization established in healthy human brains, where specific hub 'rich club' brain regions are more highly connected to each other than other brain regions. We hypothesized that selective loss of rich club connectivity might represent an organizing principle underlying the distributed pattern of structural connectivity loss seen in Huntington's disease. To test this hypothesis we performed diffusion tractography and graph theoretical analysis in a pseudo-longitudinal study of 50 premanifest and 38 manifest Huntington's disease participants compared with 47 healthy controls. Consistent with our hypothesis we found that structural connectivity loss selectively affected rich club brain regions in premanifest and manifest Huntington's disease participants compared with controls. We found progressive network changes across controls, premanifest Huntington's disease and manifest Huntington's disease characterized by increased network segregation in the premanifest stage and loss of network integration in manifest disease. These regional and whole brain network differences were highly correlated with cognitive and motor deficits suggesting they have pathophysiological relevance. We also observed greater reductions in the connectivity of brain regions that have higher network traffic and lower clustering of neighbouring regions. This provides a potential mechanism that results in a characteristic pattern of structural connectivity loss targeting highly connected brain regions with high network traffic and low clustering of neighbouring regions. Our findings highlight the role of the rich club as a substrate for the structural connectivity loss seen in Huntington's disease and have broader implications for understanding the connection between molecular and systems level pathology in neurodegenerative disease.

Prefrontal cortex white matter tracts in prodromal Huntington disease.

Huntington disease (HD) is most widely known for its selective degeneration of striatal neurons but there is also growing evidence for white matter (WM) deterioration. The primary objective of this research was to conduct a large-scale analysis using multisite diffusion-weighted imaging (DWI) tractography data to quantify diffusivity properties along major prefrontal cortex WM tracts in prodromal HD. Fifteen international sites participating in the PREDICT-HD study collected imaging and neuropsychological data on gene-positive HD participants without a clinical diagnosis (i.e., prodromal) and gene-negative control participants. The anatomical prefrontal WM tracts of the corpus callosum (PFCC), anterior thalamic radiations (ATRs), inferior fronto-occipital fasciculi (IFO), and uncinate fasciculi (UNC) were identified using streamline tractography of DWI. Within each of these tracts, tensor scalars for fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity coefficients were calculated. We divided prodromal HD subjects into three CAG-age product (CAP) groups having Low, Medium, or High probabilities of onset indexed by genetic exposure. We observed significant differences in WM properties for each of the four anatomical tracts for the High CAP group in comparison to controls. Additionally, the Medium CAP group presented differences in the ATR and IFO in comparison to controls. Furthermore, WM alterations in the PFCC, ATR, and IFO showed robust associations with neuropsychological measures of executive functioning. These results suggest long-range tracts essential for cross-region information transfer show early vulnerability in HD and may explain cognitive problems often present in the prodromal stage. Hum Brain Mapp 36:3717-3732, 2015. © 2015 Wiley Periodicals, Inc.

Dual Task Performance May be a Better Measure of Cognitive Processing in Huntington's Disease than Traditional Attention Tests.

Past research has found cancellation tasks to be reliable markers of cognitive decline in Huntington's disease (HD). The aim of this study was to extend previous findings by adopting the use of a dual task paradigm that paired cancellation and auditory tasks. We compared performance in 14 early stage HD participants and 14 healthy controls. HD participants were further divided into groups with and without cognitive impairment. Results suggested that HD participants were not slower or less accurate compared with controls; however, HD participants showed greater dual task interference in terms of speed. In addition, HD participants with cognitive impairment were slower and less accurate than HD participants with no cognitive impairment, and showed greater dual task interference in terms of speed and accuracy. Our findings suggest that dual task measures may be a better measure of cognitive processing in HD compared with more traditional measures.

Fat-free mass and its predictors in Huntington's disease.

The causes of weight loss in Huntington's disease (HD) are not entirely clear. The aim was to identify risk factors that are associated with a loss of metabolically active tissues, i.e. fat-free mass. A consecutive cohort of non-diabetic HD participants (manifest HD, n = 43; CAG: mean 43.6.0 ± 3.6; preHD, n = 10; CAG: mean 41.4 ± 1.4) and 36 healthy controls was recruited. Twenty-five HD participants were early-stage HD (UHDRS Total Functional Capacity [TFC] stages I and II), 12 mid-stage HD (TFC stage III), and 6 participants were in late-stage HD (TFC stages IV and V). Food intake, basic metabolic rate and glucose homeostasis were assessed. In addition, fat-free mass was determined using bioelectric impedance analysis, and leptin, insulin and ghrelin as key metabolic regulators. Sex ratio and age were similar in HD participants (71 % women; age 50.6 ± 10.9) and controls (66 % women; age 46.4 ± 14.5). Body mass index (BMI) was lower in HD participants than controls (median 24.1 vs. 25.9, p = 0.04). However, fat-free mass and basic metabolic rate were not statistically different between groups and showed no association with disease burden. In controls and HD participants, leptin was the most important predictor of fat-free mass. While BMI was lower in HD participants, fat-free mass was similar to controls with leptin as its most important predictor. Leptin levels and fat-free mass measurements using bioelectric impedance analysis may be good screening tools to identify HD patients at risk for weight loss.

Validity of the 12-item World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) in individuals with Huntington disease (HD).

The reliability and construct validity of the 12-item World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) were examined in individuals with Huntington disease (HD). We examined factor structure (confirmatory factor analysis), internal consistency reliability (Cronbach's alpha), floor and ceiling effects, convergent validity (Pearson correlations), and known-groups validity (multivariate analysis). Results of a confirmatory factor analysis replicated the six-factor latent model that reflects the six separate scales within the WHODAS 2.0 (understanding and communicating; getting around; self-care; getting along with others; life activities; participation). Cronbach's alpha for the scale was 0.94, suggesting good internal consistency reliability. The WHODAS demonstrated a ceiling effect for 19.5% of participants; there were no floor effects. There was evidence for convergent validity; the WHODAS demonstrated moderate significant correlations with other general measures of health-related quality of life (HRQOL; i.e., RAND-12, EQ5D). Multivariate analyses indicated that late-stage HD participants indicated poorer HRQOL than both early-stage HD and prodromal HD participants for all HRQOL measures. Findings provide support for both the reliability and validity of the WHODAS 2.0 in individuals with HD.

Everyday cognition in prodromal Huntington disease.

Assessment of daily functions affected by cognitive loss in prodromal Huntington's disease (HD) is necessary in practice and clinical trials. We evaluated baseline and longitudinal sensitivity of the Everyday Cognition (ECog) scales in prodromal HD and compared self- and companion-ratings. Everyday cognition was self-assessed by 850 participants with prodromal HD and 768 companions. We examined internal structure using confirmatory factor analysis (CFA) on baseline data. For longitudinal analysis, we stratified participants into Low, Medium, and High disease progression groups. We examined ECog scores for group differences and participant-and-companion differences using linear mixed effects regression (LMER). Comparison with the Total Functional Capacity (TFC) scale was made. CFA revealed good fit of a 5-factor model having a global factor (total score), and subfactors (subscales) of memory, language, visuospatial perception, and executive function. At study entry, participants and companions in the Medium and High groups reported significantly worsened everyday cognition as well as significant functional decline over time. Losses became more pronounced and participant and companion ratings diverged as individuals progressed. TFC showed significant functional loss over time in the High group but not in the Medium group. Disease progression is associated with reduced self- and companion-reported everyday cognition in prodromal HD participants who are less than 13 years to estimated motor onset. Our findings suggest companion ratings are more sensitive than participants' for detecting longitudinal change in daily cognitive function. ECog appears more sensitive to specific functional changes in the prodrome of HD than the TFC.

Intra-individual Variability in Prodromal Huntington Disease and Its Relationship to Genetic Burden.

The current study sought to examine the utility of intra-individual variability (IIV) in distinguishing participants with prodromal Huntington disease (HD) from nongene-expanded controls. IIV across 15 neuropsychological tasks and within-task IIV using a self-paced timing task were compared as a single measure of processing speed (Symbol Digit Modalities Test [SDMT]) in 693 gene-expanded and 191 nongene-expanded participants from the PREDICT-HD study. After adjusting for depressive symptoms and motor functioning, individuals estimated to be closest to HD diagnosis displayed higher levels of across- and within-task variability when compared to controls and those prodromal HD participants far from disease onset (F ICV(3,877)=11.25; p<.0001; F PacedTiming(3,877)=22.89; p<.0001). When prodromal HD participants closest to HD diagnosis were compared to controls, Cohen's d effect sizes were larger in magnitude for the within-task variability measure, paced timing (-1.01), and the SDMT (-0.79) and paced tapping coefficient of variation (CV) (-0.79) compared to the measures of across-task variability [CV (0.55); intra-individual standard deviation (0.26)]. Across-task variability may be a sensitive marker of cognitive decline in individuals with prodromal HD approaching disease onset. However, individual neuropsychological tasks, including a measure of within-task variability, produced larger effect sizes than an index of across-task IIV in this sample.

Effects of task difficulty during dual-task circle tracing in Huntington's disease.

Huntington's disease (HD) is associated with impairments in dual-task performance. Despite that, only a few studies have investigated dual-tasking in HD. We examined dual-task performance in 15 participants in the early stages of HD and 15 healthy controls. Participants performed direct circle tracing (able to view arm) and indirect circle tracing (arm obscured) either on their own (single tasks) or paired with serial subtraction by twos or threes (dual tasks). Overall, our results suggested that HD participants were significantly slower and less accurate than controls. Both groups were slower and less accurate when performing indirect circle tracing compared with direct circle tracing. HD participants experienced greater dual-task interference in terms of accuracy when performing direct circle tracing compared with indirect circle tracing. Despite that, controls were more inclined to speed-accuracy trade-offs compared with HD participants. Importantly, unlike controls, HD participants were not disproportionately faster when performing direct circle tracing as a single task compared with the dual-task conditions. Our results suggest that simple tasks place greater attentional demands on HD participants compared with controls. These findings support that impaired automaticity may be responsible for some of the attentional deficits manifested in HD.

Destination and source memory in Huntington's disease.

Destination memory refers to the recall of the destination of previously relayed information, and source memory refers to the recollection of the origin of received information. We compared both memory systems in Huntington's disease (HD) participants. For this, HD participants and healthy adults had to put 12 items in a black or a white box (destination task), and to extract another 12 items from a blue or a red box (source task). Afterwards, they had to decide in which box each item had previously been deposited (destination memory), and from which box each item had previously been extracted (source memory). HD participants showed poorer source as well as destination recall performance than healthy adults in the proposed tasks. Correlation analysis showed that destination recall was significantly correlated with episodic recall in HD participants. Destination memory impairment in HD participants seems to be considerably influenced by their episodic memory performance.

G03 The Type Of Concurrent Task Affects Dual-task Performance In Huntington's Disease

Background Huntington’s disease (HD) is associated with difficulty in dual-tasking, which is performing two tasks at the same time. Aims We investigated whether different dual-tasks and levels of difficulty are affected in people with early HD. Methods/techniques Twelve HD participants and 12 controls performed four pairs of dual-tasks. Each task within each dual-task had easy and hard levels. Pair 1 was circle tracing with counting backward: participants traced a circle while viewing (easy) or not viewing their arm (hard), and counted backward in twos (easy) or threes (hard). Pair 2 was simple choice reaction time (CRT) with digit forward: participants viewed single letters and responded to two (easy) or four target letters (hard) while repeating 4 (easy) or 5 (hard) digits forward. Pair 3 was complex CRT with digit backward: participants viewed 3X3 matrices of Xs and Os. They responded whether 3 Xs (easy) or 3 Xs or 3 Os (hard) appeared in a row, while repeating 3 (easy) or 4 (hard) digits backward. Pair 4 was cancellation with auditory tasks. Participants circled the target letter O on a sheet with distractor letters: other letters (easy) or the letter Q (hard). Concurrently, they reported the number of high-pitched sounds from a series of high-pitched sounds (easy) or a combination of high- and low-pitched sounds (hard). We measured speed and accuracy. Results/outcome Participants with HD were slower and less accurate across all task conditions, compared to controls. Dual-tasks were performed slower and less accurately than single tasks; and harder levels slower and less accurately than easier levels. Differences reached statistical significance either in terms of speed or in terms of accuracy within each task pair. Conclusion Our findings suggest differential effects of dual-task performance on HD versus controls, and highlight the importance of considering different performance measures, as the relationship between HD and these measures may be different.

E12 Abnormal Cortico-striatal Structural Connectivity In Premanifest Huntington's Disease

Background Huntington’s disease (HD) is a genetic condition that affects both the white and grey matter of the brain. One of the structures most affected by HD is the basal ganglia, which shows significant atrophy prior to disease manifestation. Using voxel connectivity maps we investigate differences in the patterns of cortical connectivity of the striatum in premanifest HD compared to controls. Aims Our aim was to detect differences in patterns of cortico-striatal structural connectivity between premanifest HD and controls using voxel connectivity maps obtained by diffusion tractography. Methods The cohort consists of 16 pre-manifest HD participants (8 female; mean age 42.20 ± 8.15 years; mean CAG repeat length 43.06 ± 2.01) and 18 controls (6 female; mean age 49.13 ± 8.09 years). Participants underwent MRI scanning and diffusion weighted and T1 images were obtained. Following this constrained spherical deconvolution reconstruction and probabilistic tractography were performed and voxel connectivity maps generated. Each voxel in the striatum was allowed to connect to multiple cortical targets. Classical canonical variate analysis, a multivariate technique, was then used to compare the patterns of connectivity between groups. Results Significant between group differences are seen in the structural connectivity to cortical regions of the right caudate (p = 0.034), right globus pallidum (p = 0.022) and left putamen (p = 0.036). Lateral orbitofrontal, pars triangularis and paracentral regions predominantly account for these differences in the caudate and putamen. In the globus pallidum group differences are observed in frontal, temporal, parietal and occipital connexions. Conclusions In this work we show a method that is sensitive enough to detect differences in patterns of connectivity between controls and pre-manifest HD patients. In future work, we aim to apply this methodology to a larger cohort and correlate connectivity patterns with several clinical scores.

E17 Diffusion Weighted Imaging Study Of Prefrontal Cortex White Matter In Prodromal Huntington Disease

<h3>Background</h3> There is considerable interest in finding reliable indicators of Huntington’s disease (HD) progression to judge the efficacy of novel treatments that slow or stop disease onset before debilitating signs appear. Diffusion-weighted imaging (DWI) may provide a reliable marker of disease progression by characterising diffusivity changes in white matter (WM) in individuals with prodromal HD. The prefrontal cortex (PFC) may play a role in HD progression due to its prominent striatal connexions and documented role in executive function. <h3>Aims</h3> The primary goal is to assess alterations in the white matter tracts of HD gene-positive individuals using DWI and examine its association with motor, cognitive, psychiatric, demographic and genetic variables. <h3>Methods</h3> Imaging and clinical data were collected from 15 PREDICT-HD sites. This study uses DWI to characterise diffusivity in specific regions of PFC WM defined by FreeSurfer in 53 prodromal HD participants and 34 controls. A streamline-specific alteration was assessed in four major PFC WM tracts: forceps minor (FM), anterior thalamic radiations (ATR), inferior fronto-occipital fasciculi (IFO), uncinate fasciculi (UNC). <h3>Results</h3> Statistically significant increases in mean diffusivity (MD) and radial diffusivity (RD) among CAP groups relative to controls were seen in inferior and lateral PFC regions. White matter alterations in FM, ATR, and IFO showed robust associations with neuropsychological measures of executive functioning. <h3>Conclusions</h3> The gradient of effects that tracked with CAP group suggests DWI may provide markers of disease progression with increasing diffusivity abnormalities in the lateral PFC of prodromal HD individuals. Our tract study also suggests that long-range tracts that are essential for cross-region information that shows early vulnerability in HD and may help to explain cognitive problems in the prodromal stage. <h3>Funding</h3> National Institutes for Health, National Institute of Neurological Disorders and Stroke 040068, and CHDI Foundation, Inc. <h3>Reference</h3> Matsui JT, Vaidya JG, Johnson HJ, <i>et al</i>. Diffusion weighted imaging of prefrontal cortex in prodromal huntington’s disease. <i>Human Brain Mapping</i>2013;1–12:doi:10.1002/hbm.22273

D07 Levels Of The Light Subunit Of Neurofilatment Protein In Cerebrospinal Fluid In Huntington's Disease

Introduction Light subunit of neurofilament protein (NFL) is a structural element of neurons. Its levels are increased in cerebrospinal fluid (CSF) in the setting of neurological diseases, including Huntington’s disease (HD), and are considered a marker of neuronal damage. HD is a paradigm of neurodegeneration in the need of appropriate biomarkers. Objectives To compare the levels of CSF-NFL of HD patients and healthy controls. To correlate CSF-NFL levels with demographic and clinical variables. Methods The ELISA for NFL was performed according to previously published methods. Twenty-four HD participants (11 women; mean age 47.3 (SD 12.3)) and 37 controls (26 women; mean age 34.1 (SD 9.4)) were included. We compared levels of NFL-CSF levels with a regression model adjusted for age and gender. We examined the relationships (Pearson correlations) between NFL-CSF levels and demographic (age, gender) and clinical (CAG repeat number, disease burden, UHDRS motor, behavioural, functional total scores and NPI scale) variables. Results CSF levels were significantly higher in all HD subjects [5014.4 (1557.3) ng/l] as compared to controls [335.4 (193.3) ng/l] (p Conclusions These results indicate that NFL-CSF levels is a marker of neuronal damage in HD and warrant future efforts towards establishing its sensitivity to track disease progression and reactivity to therapeutical interventions.

H10 An Investigation into Gender Influence on Anxiety and Depression in Huntington's Disease (HD) Across Disease-stage

Background Depression and anxiety are common in HD. A consistent finding among the general population is that women are more likely to experience anxiety and depression than men. There is some evidence of increased depression among women with HD, though results are mixed, and relatively little is known about anxiety in HD. Aims To examine gender influence on depression and anxiety using the Hospital Anxiety and Depression scale (HADS) by disease stage and to explore whether there are gender differences among those who are pre-motor symptomatic for HD. Methods/techniques A cross-sectional study using Registry 3 data was undertaken, using the Hospital Anxiety and Depression scale (HADS). Data was analysed according to disease stage, determined by TFC score. Those who were pre-motor symptomatic for HD were also examined for gender differences. Results/outcome A significant gender difference (p = 0.016) was found for total HADS score among a pre-motor symptomatic HD sample (n = 86), with females demonstrating greater psychological distress than males. No significant gender difference in total HADS score was revealed among the motor symptomatic HD participants (n = 410) or across the entire sample of HD expansion carriers (n = 496). Across all HD expansion carriers (n = 504), females reported significantly higher levels of anxiety (p = 0.031). Among the pre-motor symptomatic HD sample, females reported significantly higher levels of anxiety than males (p = 0.02), but no significant gender difference in anxiety levels was found among the motor symptomatic HD group. No significant gender difference in depression levels were found across all groups of HD expansion carriers. Analysis of the data by disease stage revealed no significant gender differences in anxiety and depression. Conclusions Gender differences in anxiety and overall psychological distress were apparent in pre-motor symptomatic HD, but these diminished in the motor symptomatic group.

E02 Longitudinal Shape Analysis Study of Striatal Nuclei in Manifest Huntington's Disease

<h3>Background</h3> Huntington’s disease (HD) is marked by brain degeneration in striatum. Localised atrophy identified through shape analysis of these structures was recently suggested to be a more sensitive biomarker of disease evolution than global volume variations (van der Bogaard <i>et al</i>., 2011). <h3>Aims</h3> To identify longitudinal changes in shape of striatal structures in a group of patients with manifest HD. <h3>Methods</h3> In the Multicenter Intracerebral Grafting trial for Huntington’s disease (MIG-HD), a group of 15 patients with manifest HD was followed-up during 20 months before intrastriatal grafting. The mean UHDRS Total Motor Score was 29.7 at first evaluation. T1-weighted brain MRIs of these patients were achieved at both the beginning and the end of this period. Segmentations of striatal nuclei (Freesurfer processing) were submitted to shape analysis using the SPHARM method (Brechbuhler <i>et al</i>., 1995) which creates parametric surface models using spherical harmonics. Longitudinal changes in atrophy using shape analysis method was compared to global volumetric changes and voxel based morphometry (SPM8/VBM8). <h3>Results</h3> Using global volumetric evaluation (Freesurfer) or voxel based morphometry (VBM), progressive atrophy was only found in left putamen during this period. However, using the SPHARM method, longitudinal shape analysis showed local atrophy in all striatal nuclei during the same period. <h3>Conclusions</h3> Longitudinal shape analysis of striatum constitutes a promising tool to track Huntington’s disease evolution and to better evaluate the benefits of innovative therapies in cohorts with small number of HD participants.

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

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