Premanifest Subjects Research Articles

Longitudinal Imaging of Regional Brain Volumes, SV2A, and Glucose Metabolism In Huntington's Disease.

Development of disease-modifying treatments for Huntington's disease (HD) could be aided by the use of imaging biomarkers of disease progression. Positron emission tomography (PET) with 11 C-UCB-J, a radioligand for the brain-wide presynaptic marker synaptic vesicle protein 2A (SV2A), detects more widespread brain changes in early HD than volumetric magnetic resonance imaging (MRI) and 18 F-fludeoxyglucose (18 F-FDG) PET, but longitudinal 11 C-UCB-J PET data have not been reported. The aim of this study was to compare the sensitivity of 11 C-UCB-J PET, 18 F-FDG PET, and volumetric MRI for detection of longitudinal changes in early HD. Seventeen HD mutation carriers (six premanifest and 11 early manifest) and 13 healthy controls underwent 11 C-UCB-J PET, 18 F-FDG PET, and volumetric MRI at baseline (BL) and after 21.4 ± 2.7 months (Y2). Within-group and between-group longitudinal clinical and imaging changes were assessed. The HD group showed significant 2-year worsening of Unified Huntington's Disease Rating Scale motor scores. There was significant longitudinal volume loss within the HD group in caudate (-4.5% ± 3.8%), putamen (-3.6% ± 3.5%), pallidum (-3.0% ± 2.7%), and frontal cortex (-2.0% ± 2.1%) (all P < 0.001). Within the HD group there was longitudinal loss of putaminal SV2A binding (6.4% ± 8.8%, P = 0.01) and putaminal glucose metabolism (-2.8% ± 4.4%, P = 0.008), but these changes were not significant after correction for multiple comparisons. Premanifest subjects at BL only had significantly lower SV2A binding than controls in basal ganglia structures, but at Y2 additionally had significant SV2A loss in frontal and parietal cortex, indicating spread of SV2A loss from subcortical to cortical regions. Volumetric MRI may be more sensitive than 11 C-UCB-J PET and 18 F-FDG PET for detection of 2-year brain changes in early HD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Plasma neurofilament light in Huntington's disease: A marker for disease onset, but not symptom progression

ObjectiveTo investigate whether plasma NfL levels correlate with clinical symptom severity in premanifest (PM) and manifest HD (HD) individuals, and whether a NfL cut-point could distinguish PM from HD patients with reasonable accuracy. Method98 participants (33 control, 26 PM, 39 HD), underwent blood sample collection and clinical assessment, using both UHDRS and non-UHDRS measures, at one academic HD Center. Years to onset (YTO), probability of disease onset in 5 years, and predicted years until 60% onset probability were also calculated. NfL levels were measured using a Meso Scale Discovery assay. ResultsCohorts differed by age. NfL levels differed significantly across diagnostic groups and were significantly correlated with age. Age-adjusted NfL levels were not correlated with clinical measures in either HD or PM cohorts, but were correlated when cohorts were combined. In PM subjects, NfL levels correlated with YTO, probability of onset in 5 years, and years until 60% onset probability. Using ROC analysis, a NfL cut-point of <53.15 pg/ml distinguished HD from control; <74.84 pg/ml distinguished HD from PM. ConclusionsThese findings implicate plasma NfL as a peripheral prognostic marker for premanifest-HD. Notably, we show that significant correlations between NfL and clinical symptoms are detected only when PM + HD subjects are combined, but not within HD subjects alone. To date, prior studies have investigated the clinical usefulness of NfL exclusively in merged PM + HD cohorts. Our data suggests a biasing of these previous correlations, and hence potentially limited usefulness of plasma NfL in monitoring HD symptom progression, for example, in clinical trials.

Differential Changes in Functional Connectivity of Striatum-Prefrontal and Striatum-Motor Circuits in Premanifest Huntington’s Disease

Background: Huntington’s disease (HD) is a progressive neurodegenerative disorder. The striatum is one of the first brain regions that show detectable atrophy in HD. Previous studies using functional magnetic resonance imaging (fMRI) at 3 tesla (3 T) revealed reduced functional connectivity between striatum and motor cortex in the prodromal period of HD. Neuroanatomical and neurophysiological studies have suggested segregated corticostriatal pathways with distinct loops involving different cortical regions, which may be investigated using fMRI at an ultra-high field (7 T) with enhanced sensitivity compared to lower fields. Objectives: We performed fMRI at 7 T to assess functional connectivity between the striatum and several chosen cortical areas including the motor and prefrontal cortex, in order to better understand brain changes in the striatum-cortical pathways. Method: 13 manifest subjects (age 51 ± 13 years, cytosine-adenine-guanine [CAG] repeat 45 ± 5, Unified Huntington’s Disease Rating Scale [UHDRS] motor score 32 ± 17), 8 subjects in the close-to-onset premanifest period (age 38 ± 10 years, CAG repeat 44 ± 2, UHDRS motor score 8 ± 2), 11 subjects in the far-from-onset premanifest period (age 38 ± 11 years, CAG repeat 42 ± 2, UHDRS motor score 1 ± 2), and 16 healthy controls (age 44 ± 15 years) were studied. The functional connectivity between the striatum and several cortical areas was measured by resting state fMRI at 7 T and analyzed in all participants. Results: Compared to controls, functional connectivity between striatum and premotor area, supplementary motor area, inferior frontal as well as middle frontal regions was altered in HD (all p values <0.001). Specifically, decreased striatum-motor connectivity but increased striatum-prefrontal connectivity were found in premanifest HD subjects. Altered functional connectivity correlated consistently with genetic burden, but not with clinical scores. Conclusions: Differential changes in functional connectivity of striatum-prefrontal and striatum-motor circuits can be found in early and premanifest HD. This may imply a compensatory mechanism, where additional cortical regions are recruited to subserve functions that have been impaired due to HD pathology. Our results suggest the potential value of functional connectivity as a marker for future clinical trials in HD.

Alterations in the tyrosine and phenylalanine pathways revealed by biochemical profiling in cerebrospinal fluid of Huntington\u2019s disease subjects

Huntington’s disease (HD) is a severe neurological disease leading to psychiatric symptoms, motor impairment and cognitive decline. The disease is caused by a CAG expansion in the huntingtin (HTT) gene, but how this translates into the clinical phenotype of HD remains elusive. Using liquid chromatography mass spectrometry, we analyzed the metabolome of cerebrospinal fluid (CSF) from premanifest and manifest HD subjects as well as control subjects. Inter-group differences revealed that the tyrosine metabolism, including tyrosine, thyroxine, L-DOPA and dopamine, was significantly altered in manifest compared with premanifest HD. These metabolites demonstrated moderate to strong associations to measures of disease severity and symptoms. Thyroxine and dopamine also correlated with the five year risk of onset in premanifest HD subjects. The phenylalanine and the purine metabolisms were also significantly altered, but associated less to disease severity. Decreased levels of lumichrome were commonly found in mutated HTT carriers and the levels correlated with the five year risk of disease onset in premanifest carriers. These biochemical findings demonstrates that the CSF metabolome can be used to characterize molecular pathogenesis occurring in HD, which may be essential for future development of novel HD therapies.

DNA damage signatures in peripheral blood cells as biomarkers in prodromal huntington disease.

Easily accessible biomarkers in Huntington disease (HD) are actively searched. We investigated telomere length and DNA double-strand breaks (histone variant pγ-H2AX) as predictive disease biomarkers in peripheral blood mononuclear cells (PBMC) from 25 premanifest subjects, 58 HD patients with similar CAG expansion in the huntingtin gene (HTT), and 44 healthy controls (HC). PBMC from the pre-HD and HD groups showed shorter telomeres (p < 0.0001) and a significant increase of pγ-H2AX compared to the controls (p < 0.0001). The levels of pγ-H2AX correlated robustly with the presence of the mutated gene in pre-HD and HD. The availability of a potentially reversible biomarker (pγ-H2AX) in the premanifest stage of HD, negligible in HC, provides a novel tool to monitor premanifest subjects and find patient-specific drugs. Ann Neurol 2018;00:1-6 ANN NEUROL 2019;85:296-301.

Cortical atrophic-hypometabolic dissociation in the transition from premanifest to early-stage Huntington's disease.

Huntington's disease (HD) is a fatal neurodegenerative disorder with no effective treatment currently available. Although the pathological hallmark of HD is massive striatal atrophy, it has been suggested that cortical deterioration may concomitantly occur and play a major role in the patient's functional independence. Our objective was to characterize cortical structural and metabolic neurodegeneration in the transition from premanifest to early-stage Huntington's disease (HD). Using a surface-based neuroimaging approach, we compared cortical thickness and intracortical FDG-PET uptake in 19 early-symptomatic HD patients with respect to 21 premanifest HD individuals. Early-HD patients showed significant cortical atrophy and intracortical hypometabolism when compared to premanifest subjects (p < 0.05, corrected for multiple comparisons). However, whereas the atrophy pattern was restricted to precentral and parieto-occipital regions, a pronounced frontotemporal hypometabolism was observed. Importantly, structural changes correlated with motor and cognitive performance, and metabolic changes were associated with the presence and severity of apathy in this population, a core neuropsychiatric feature of this disorder. Our findings reveal an asynchronous neuronal loss and metabolic compromise across the cerebral cortex in early HD. Hence, the use of structural and metabolic imaging indicators to characterize disease progression in this population should take into consideration the dissociation which occurs between cortical atrophy and hypometabolism.

Effects of stimulus-related variables on mental states recognition in Huntington’s disease

Background: Cognitive abnormalities in Huntington’s Disease (HD) can involve the specific impairment of the social perspective taking as well as difficulties in recognizing others’ mental state many years before the onset of motor symptoms.Aims: At the scope of assessing how the difficulties in mental state recognition might be an HD early sign before motor symptoms appear, our study was aimed to investigate how the recognition of others’ mental states in HD subjects is moderated by different stimulus related features (gender, difficulty (low, medium, high), and valence (positive, negative, neutral) of the mental states that are to be recognized).Methods: Subjects with premanifest (n = 20) and manifest (n = 40) HD performed the revised ‘Reading the Mind in the Eyes Test’ and were compared with age-matched healthy controls (HC, 40 subjects per cohort).Results: Our results highlight an early impairment in mental state recognition preceding manifest HD symptoms and a deterioration of these abilities with HD progression. Moreover, we found in HD premanifest subjects an impairment concerning the recognition of negative and neutral mental states, as well as of mental states with moderate recognition difficulty. Finally, we found that participant gender did not influence the performance in recognizing others’ mental states, while all participants recognized mental states displayed by females more accurately than those displayed by males.Conclusions: We conclude that difficulties in the recognition of complex mental states can be considered as an early sign of HD, before evident behavioral manifestations, and peculiar features of the stimulus influence it.

Task-switching abilities in pre-manifest Huntington's disease subjects

IntroductionHuntington's Disease (HD) cognitive dysfunction occurs before unequivocal motor signs become apparent. The predominant early cognitive abnormal domains may include deficits in psychomotor speed, negative emotion recognition and executive functioning. Our study is aimed to investigate the executive control of cognition in pre-manifest (pre) HD subjects, by means of a task-switching protocol. MethodsWe recruited 30 pre-HD subjects and 18 age-, sex- and education-matched Healthy Controls (HC). Subjects were assigned to two experimental groups: 15 pre-HD1 with a Total Motor Score (TMS) ≤4 (far from onset) and 15 pre-HD2 with a 5 ≤ TMS≤9 (near to onset and Diagnostic Confidence Level (DCL) still<4). Two different tasks were performed in rapid and random succession, so that the task was either changed from one trial to the next one (switch trials) or repeated (repetition trials). Switch trials are usually slower than repetitions, causing a so-called Switch Cost (SC). ResultsPre-HD subjects had worse performance than HC in the switch and repetition trials, as indicated by increased SC and reaction times. In particular, pre-HD2 showed impaired switching abilities with reaction times slower than pre-HD1 and HC. ConclusionsOur study highlighted a task-switching impairment since HD was still at a pre-manifest stage. Such abnormalities worsen when pre-HD subjects start to show subtle motor manifestations, still nonspecific and insufficient to define the clinical diagnosis of HD (DCL<4). Considering that such abilities have obvious implications for activities of daily living, early cognitive rehabilitation programs addressing such deficits might be useful in the premanifest stage of the disease.

Constructing disease onset signatures using multi-dimensional network-structured biomarkers

Potential disease-modifying therapies for neurodegenerative disorders need to be introduced prior to the symptomatic stage in order to be effective. However, current diagnosis of neurological disorders mostly rely on measurements of clinical symptoms and thus only identify symptomatic subjects in their late disease course. Thus, it is of interest to select and integrate biomarkers that may reflect early disease-related pathological changes for earlier diagnosis and recruiting pre-sypmtomatic subjects in a prevention clinical trial. Two sources of biological information are relevant to the construction of biomarker signatures for time to disease onset that is subject to right censoring. First, biomarkers' effects on disease onset may vary with a subject's baseline disease stage indicated by a particular marker. Second, biomarkers may be connected through networks, and their effects on disease may be informed by this network structure. To leverage these information, we propose a varying-coefficient hazards model to induce double smoothness over the dimension of the disease stage and over the space of network-structured biomarkers. The distinctive feature of the model is a non-parametric effect that captures non-linear change according to the disease stage and similarity among the effects of linked biomarkers. For estimation and feature selection, we use kernel smoothing of a regularized local partial likelihood and derive an efficient algorithm. Numeric simulations demonstrate significant improvements over existing methods in performance and computational efficiency. Finally, the methods are applied to our motivating study, a recently completed study of Huntington's disease (HD), where structural brain imaging measures are used to inform age-at-onset of HD and assist clinical trial design. The analysis offers new insights on the structural network signatures for premanifest HD subjects.

P35. Cortico-striatal functional connectivity in Huntington’s disease measured with high-field functional MRI: A biomarker for disease progression?

Background Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by CAG expansion in the Huntingtin gene. HD manifests by involuntary movements, cognitive and behavioral changes. The approximate time-to-onset can be predicted from the length of CAG repeat in HD subjects, which allows for the identification of subjects in the pre-manifest stage of HD, who do not have symptoms or structural brain changes (atrophy). Disease modifying treatment may have special value if it is initiated in the premanifest stage of HD, before structural brain changes occur. Aim Cortico-striatal functional connectivity may be altered in HD many years before symptoms onset. Thus cortico-striatal functional connectivity as assess by functional Magnetic Resonance Imaging (fMRI) may be a promising biomarker to be used for trials of disease modifying treatment. In particular, fMRI may of special interest to assess disease progression in HD subjects in the pre-manifest stage who do not have symptoms clinically. Question Is cortico-striatal functional connectivity in HD as assessed by fMRI at 7 T a biomarker for disease progression? Method We assessed 24 pre-manifest HD subjects, 12 manifest HD subjects as well as 16 healthy controls at baseline. 13 HD subjects (9 in the pre-manifest stage of HD) and 8 healthy controls participated in a one year follow-up study. The functional connectivity between the striatum and several cortical areas were analysis. Two tailed t-test was applied. ANOVA was used for the analysis of the one year follow-up data with group as between-subjects factor and time as within-subjects factor. Results Functional connectivity between striatum and supplementary motor area was impaired comparing manifest HD subjects with controls (p = 0.01) and premanifest HD subjects with controls (p = 0.03) at baseline. At the one year follow-up, functional connectivity between striatum and premotor area was impaired comparing manifest HD subjects with controls (group p = 0.002, time p = 0.04, group by time p = 0.02). Likewise, premanifest HD subjects showed decline compared to control subjects over time (group p Conclusion These data indicate progressive impairment of functional connectivity between striatum and premotor area in HD subjects. Assessment of cortico-striatal functional connectivity by fMRI is a promising biomarker to assess disease progression including the premanifest stage of HD, when subjects do not have symptoms.

Cortical thickness, stance control, and arithmetic skill: An exploratory study in premanifest Huntington disease

BackgroundHuntington disease (HD) is an inherited neurodegenerative disorder most commonly manifesting in adulthood. Identification of biomarkers tracking neurodegeneration before the onset of motor symptoms is important for future interventional studies. Our study aimed to contribute in the phenotypic characterization of the premanifest HD phase. Methods28 premanifest subjects (preHD), 25 age-matched controls, and 12 manifest HD patients were enrolled for the study. The participants underwent a multimodal protocol including cognitive evaluations, arithmetic ability test, posturography, composite cerebellar functional test (CCFS), and brain 3T-MRI. PreHD were divided at the group median for predicted years to expected onset into “far-from-onset” (>15 years, PreHD-far), and “close-to-onset” (≤15 years, preHD-close). Basal ganglia volumes and cortical thickness were computed using FreeSurfer. ResultsPreHD-close showed significantly lower scores than controls in Symbol Digit Modalities Test (p = 0.017), Arithmetic subtraction task (p = 0.04), and MMSE (p < 0.006). At posturography, preHD-close showed increased sway velocity (<0.04) and distance (p < 0.02) compared to controls. PreHD-close had reduced striatum and globus pallidus volumes and left occipital cortical thinning compared to controls. Compared to PreHD far-from-onset, PreHD-close showed bilateral cortical thinning in occipital and parahippocampal regions, inversely correlating with burden score and prognostic index for HD. CCFS only differed between controls and manifest HD. PreHD far-from-onset did not show significant differences in comparison with controls. ConclusionsWe confirmed that quantitative brain MRI represents a valid biomarker of neurodegeneration in preHD. Posturography and Arithmentic tests seem promising tools for detecting early changes in premanifest HD, but need to be further confirmed in large cohorts.

Striatal hypometabolism in premanifest and manifest Huntington's disease patients.

To assess metabolic changes in cerebral 18F-FDG PET/CT in premanifest and manifest Huntington's disease (HD) subjects compared to a control group and to correlate 18F-FDG uptake patterns with different disease stages. Thirty-three gene-expanded carriers (Eight males; mean age: 43y/o; CAG > 39) were prospectively included. Based on the Unified Huntington's Disease Rating Scale Total Motor Score and the Total Functional Capacity, subjects were classified as premanifest (preHD = 15) and manifest (mHD = 18). Estimated time disease-onset was calculated using the Langbehn formula, which allowed classifying preHD as far-to (preHD-A) and close-to (PreHD-B) disease-onset. Eighteen properly matched participants were included as a control group (CG). All subjects underwent brain 18F-FDG PET/CT and MRI. 18F-FDG PET/CT were initially assessed by two nuclear medicine physicians identifying qualitative metabolic changes in the striatum. Quantitative analysis was performed using SPM8 with gray matter atrophy correction using the BPM toolbox. Visual analysis showed a marked striatal hypometabolism in mHD. A normal striatal distribution of 18F-FDG uptake was observed for most of the preHD subjects. Quantitative analysis showed a significant striatal hypometabolism in mHD subjects compared to CG (p < 0.001 uncorrected, k = 50voxels). In both preHD groups we observed a significant striatal hypometabolism with respect to CG (p < 0.001 uncorrected, k = 50voxels). In mHD subjects we observed a significant striatal hypometabolism with respect to both preHD groups (p < 0.001 uncorrected, k = 50voxels). 18F-FDG PET/CT might be a helpful tool to identify patterns of glucose metabolism in the striatum across the stages of HD and might be relevant in assessing the clinical status of gene-expanded HD carriers due to the fact that dysfunctional glucose metabolism begins at early preHD stages of the disease. 18F-FDG PET/CT appears as a promising method to monitor the response to disease-modifying therapies even if applied in premanifest subjects.

Drug repositioning in Alzheimer rsquo s disease

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

I13 Variability In Interval Production Is Due To Timing Dependent Deficits In Early Huntington's Disease

Background In Huntington’s disease (HD) increased variability is seen in performance of motor tasks that require implicit control of timing. We examined if timing variability was also evident in an explicit interval-timing task. Methods Sixty subjects (21 controls, 19 manifest HD and 20 pre-manifest HD) performed a single interval production task with three target intervals (1.1s, 2.2s, 3.3s). We analysed accuracy (proportional error) and precision (standard deviation) across groups and intervals. Results No differences were seen in accuracy across groups or intervals. Precision was significantly lower in manifest (p = 0.0001) and pre-manifest HD (p = 0.04) compared with controls. This was particularly true for pre-manifest subjects close to diagnosis (based on probability of diagnosis in five years). Precision was correlated with proximity to diagnosis (r2=0.3, p Conclusions Timing precision is impaired before clinical diagnosis in Huntington’s disease. Slope analysis suggests that timing variability (decreased precision) was due to deficits in timing dependent processes. Our results provide additional support for the proposal that the basal ganglia are implicated in central timekeeping functions. Since the single interval production task was sensitive to deficits in pre-manifest HD, temporal precision may be a useful outcome measure in future clinical trials.

Diagnostic criteria for Huntington's disease based on natural history.

Huntington's disease (HD) is currently diagnosed based on the presence of motor signs indicating 99% "diagnostic confidence" for HD. Recent advances in the understanding of HD natural history and neurobiology indicate that disease-related brain changes begin at least 12 to 15 years before the formal diagnosis based on motor onset. Furthermore, subtle motor dysfunction, cognitive changes, and behavioral alterations are often seen before diagnosis made according to the current criteria. As disease-modifying treatments are developed, likely beginning therapy early will be desirable. We therefore suggest that expanded diagnostic criteria for HD should be adapted to better reflect the natural history of the disease, to enable the conduct of clinical trials in premanifest subjects targeting prevention of neurodegeneration, and to facilitate earlier symptomatic treatment. We propose a new set of criteria for HD diagnostic categories in the International Classification of Diseases that reflect our current understanding of HD natural history and pathogenesis. Based on defined criteria, for example, the Diagnostic Confidence Level and the Total Functional Capacity scales of the Unified Huntington's Disease Rating Scale, HD should be divided in the categories "genetically confirmed" with the subcategories "presymptomatic," "prodromal," and "manifest" and "not genetically confirmed" subdivided into "clinically at risk," "clinically prodromal," and "clinically manifest."

Variability in interval production is due to timing-dependent deficits in Huntington's disease.

In Huntington's disease (HD), increased variability is seen in performance of motor tasks that require implicit control of timing. We examined whether timing variability was also evident in an explicit interval-timing task. Sixty subjects (21 controls, 19 manifest HD, and 20 pre-manifest HD) performed a single-interval production task with three target intervals (1.1 s, 2.2 s, 3.3 s). We analyzed accuracy (proportional error) and precision (standard deviation) across groups and intervals. No differences were seen in accuracy across groups or intervals. Precision was significantly lower in manifest (P = 0.0001) and pre-manifest HD (P = 0.04) compared with controls. This was particularly true for pre-manifest subjects close to diagnosis (based on probability of diagnosis in 5 years). Precision was correlated with proximity to diagnosis (r2 = 0.3, P < 0.01). To examine the source of reduced precision, we conducted linear regression of standard deviation with interval duration. Slope of the regression was significantly higher in manifest HD (P = 0.02) and in pre-manifest HD close to diagnosis (P = 0.04) compared with controls and pre-manifest participants far from diagnosis. Timing precision is impaired before clinical diagnosis in Huntington's disease. Slope analysis suggests that timing variability (decreased precision) was attributable to deficits in timing-dependent processes. Our results provide additional support for the proposal that the basal ganglia are implicated in central timekeeping functions. Because the single interval production task was sensitive to deficits in pre-manifest HD, temporal precision may be a useful outcome measure in future clinical trials.

Cognition in Huntington's disease in manifest, premanifest and converting gene carriers over ten years.

Cognitive decline in Huntington's disease (HD) remains an area of inconsistencies, especially far from disease onset. To clarify the course of cognition in premanifest HD. Twenty-six premanifest HD, 19 manifest HD, and 87 control subjects were followed for ten years, using an extensive cognitive battery. Differences in baseline levels and change over time, on four factors (motor speed, global cognition, executive functioning (EF), and memory) were examined, using multilevel regression analyses. Converters were additionally analysed as a separate group. Also, the influence of motor speed and predicted years to disease onset on the cognitive factors was studied. Manifest HD subjects showed lower baseline scores compared to controls on the motor speed (p=0.002), memory (p<0.001) and EF (p<0.001). They additionally deteriorated over the ten-year follow-up on memory (p=0.01). Converters deteriorated on EF (p=0.04). Further analyses of premanifest subjects 'far from and close to predicted onset' revealed lower baseline scores for the 'close' group on EF, as compared to controls (p=0.001). They also deteriorated on memory (p=0.01). Motor speed substantially mediated the results of the three cognitive factors; when added as covariate to the model several baseline and slope differences for the cognitive factors ceased to be significant. Memory and EF are highly sensitive for ascertaining deterioration in premanifest HD gene carriers, especially in subjects close to onset. Lack of deterioration for the subjects further away from onset suggests that both domains are largely unaffected in those far from onset. Also, motor influence on cognition is substantial and should be taken into account in cognitive HD research.

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

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

A3 Studying and managing the behavioural phenotypes of Huntington's disease

Honorary Consultant in Neuropsychiatric Genetics. David graduated in Medicine from London University (St. Bartholomew9s) in 1976 and moved to Manchester to study Psychiatry in 1979. After completing his training in general psychiatry, he arranged a temporary secondment to Clinical Genetics in 1986 to pursue an interest in the genetic aspects of psychiatric disorders, and ended up “going native”. He is now a senior lecturer and honorary consultant in neuropsychiatric genetics. His research interests are concerned mainly with the neuropsychiatric aspects of Huntington9s disease (HD), and with the psychological and social impact of predictive DNA testing for late-onset genetic disorders. He set up the UK9s first multidisciplinary management clinic for HD, currently the largest contributing site to the European HD Network (EHDN) case registry, and is actively involved in a number of European and worldwide research projects and clinical trials. He is a member of the Scientific Review Committee of the EHDN, leads the EHDN Behavioural Phenotype Working Group and is a former Secretary-General of the World Federation of Neurology Research Group on HD. He is co-Director of the MSc programme and teaches on the Clinical Genetics and Advanced Genetic Counselling modules. Behavioural symptoms have been recognised as a key component of the clinical phenotype of HD ever since the first description by Huntington in 1872, but remain a relatively under-researched aspect of the condition. Depression has received more attention than other psychiatric symptoms, but factor analysis of several large datasets has revealed that apathy and irritability are more common, and arguably cause more distress and disability. Longitudinal analysis of behavioural symptoms has confirmed that these three symptom clusters follow different trajectories over time, suggesting that each has a different neurobiological basis, and recent imaging studies lend some support to this hypothesis. It has long been recognised that many affected individuals display characteristic behavioural changes for some years before the onset of motor symptoms, and there has been considerable recent interest in the possibility of using these early manifestations as end points for clinical trials of disease-modifying interventions in known gene carriers prior to diagnosis. However, it has proved difficult to detect substantial changes in well-conducted longitudinal studies of pre-manifest subjects such as PREDICT and TRACK-HD. One reason may be the emergence of impaired insight (or denial) as the behavioural symptoms begin to occur, a phenomenon which has been noted by clinicians for many years; another is likely to be the use of concomitant medication for symptomatic treatment. Mood disturbances, anxiety, irritability and perseveration all respond to treatment with serotonin reuptake inhibitors, but apathy may be exacerbated by the use of neuroleptic medication for symptomatic treatment of involuntary movements or aggressive behaviours.

G03 Corpus callosal atrophy in Huntington's disease

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