Premanifest Gene Carriers Research Articles

Biological and clinical manifestations of Huntington’s disease in gene carriers very far from predicted onset

IntroductionCrucial to the future success of treatments in Huntington’s disease is identifying a timepoint where there is a measurable biomarker of early neurodegeneration without detectable changes in clinical function. By performing deep phenotyping in premanifest gene carriers (preHD) further from predicted onset than previously studied, we aimed to identify this timepoint and the best measures for efficacy endpoints in future therapeutic trials.MethodsWe recruited 64 young adult preHD, approximately 24 years from predicted clinical onset, and 67 matched controls. All participants underwent detailed cognitive and neuropsychiatric assessments, multi-modal imaging and collection of blood and cerebrospinal fluid (CSF).ResultsWe found no significant evidence of cognitive or psychiatric impairment in preHD (minimum q>0.22). The PreHD cohort had smaller putamen volumes (q=0.03), but this was not related to predicted years to onset. There were no group differences in other brain imaging measures (q>0.16). CSF and plasma neurofilament light (NfL) (q<0.0001 and q=0.01) and YKL-40 (q=0.03) were elevated in preHD.ConclusionWith normal brain function but with sensitive measures of neurodegeneration starting to rise, this stage of preHD may represent an optimal time to initiate future disease-modifying prevention treatments. CSF NfL appears more sensitive at this time than plasma NfL to monitor treatment response.p.d.zeun@gmail.com

Exploring the predictors of financial impairment in Huntington’s disease using the Enroll-HD dataset

ObjectivesHuntington’s disease (HD) is a neurodegenerative disease in which cognitive and behavioural symptoms impair the performance of instrumental activities of daily living, including the handling of finances. We sought to determine the prevalence of financial dysfunction in HD, and the demographic and clinical predictors of such impairments.MethodsWe analysed longitudinal data for pre-manifest gene carriers and HD patients from the Enroll-HD dataset. Financial dysfunction was determined by finance-related items in the Total Functional Capacity (TFC) and Functional Assessment (FA) scales. A binary logistical regression model was used to investigate the predictive value of demographic and clinical factors for the development of financial dysfunction.ResultsFinancial impairment was found to be common in HD gene carriers, and over half required financial assistance within 5 years from diagnosis. Cognitive impairment, apathy, unemployment and disease severity predicted financial dysfunction in manifest patients. For pre-manifest patients, the predictors were proximity to disease onset and depression.ConclusionsLoss of financial autonomy is common in HD, and cognitive and psychiatric factors are important in its development. Clinicians must be vigilant to identify patients that may be vulnerable to financial exploitation.

Identification of Subtle Verbal Memory Deficits in Premanifest Huntington Disease Using the California Verbal Learning Test.

Verbal memory impairment in individuals with Huntington disease (HD) is well-documented; however, the nature and extent of verbal memory impairment in individuals with premanifest HD (pre-HD) are less understood. To evaluate verbal memory function in individuals with pre-HD by comparing their performance on the California Verbal Learning Test to that of individuals with a clinical diagnosis of HD and that of a demographically similar group of adults with no family history of, or genetic risk for, HD, thereby reducing possible complications of psychiatric difficulties commonly experienced by individuals who are at risk for HD but are gene negative. Participant groups included 77 adults with a diagnosis of HD, 23 premanifest gene carriers for HD (pre-HD), and 54 demographically similar, healthy adults. The California Verbal Learning Test-Second Edition (CVLT-II) was used to evaluate the participants' immediate and delayed recall, recognition, learning characteristics, errors, and memory retention. The pre-HD group performed significantly worse than the healthy group, yet significantly better than the HD group, on Short and Long Delay Recall (Free and Cued) and Recognition Discriminability. On Total Immediate Recall, Learning Slope, Semantic Clustering, and Intrusions, the pre-HD group performed similarly to the healthy group and significantly better than the HD group. None of the groups differed in their performance on Repetitions and a measure of retention. Subtle memory deficits can be observed during the premanifest stage of HD with use of a subset of indices from the CVLT-II.

Huntington's disease patients display progressive deficits in hippocampal-dependent cognition during a task of spatial memory

BackgroundCognitive disturbances occur early in Huntington's disease (HD) and place a significant burden on the lives of patients and family members. Whilst these impairments are typically attributed to deterioration of the frontal-striatal pathways, accumulating evidence suggests that hippocampal dysfunction may also contribute to such impairments. Here, we employ a novel spatial memory task that has previously been shown to elicit impairments in individuals with focal hippocampal lesions, as a means to further investigate the role of hippocampal dysfunction in HD. MethodSixty-four individuals participated in the study, including 32 healthy controls, 11 patients with diagnosed HD and 16 premanifest HD gene carriers. We also included an additional control group of 5 individuals with focal unilateral basal ganglia lesions. Participants undertook a task that measured perception and short-term spatial memory using computer-generated visual scenes. ResultsHD patients experienced significant impairments in spatial perception and memory, which strongly correlated with disease burden score (DBS). Premanifest gene carriers performed at a similar level to healthy controls throughout all aspects of the task indicating that the effects seen in the HD patients represent a deterioration in function. Interestingly, basal ganglia lesion patients were not impaired in any aspects of the task. ConclusionThere is evidence of significant deficits in hippocampal-dependent spatial cognition in HD that cannot be explained as a function of degeneration to the basal ganglia. The impairments were greatest in individuals with higher DBSs, suggesting that deficits relate to the disease process in HD.

Parkinsonism in Huntington's disease.

Huntington's disease (HD) is usually characterized by involuntary hyperkinetic movements, called chorea. The intensity of chorea exhibits a peak in middle stages of HD and then decreases as HD progresses. In contrast, Pakinsonian signs of HD are often less appreciated. They typically progress in a fairly linear pattern over time. In fact, bradykinesia is detectable early on in premanifest gene carriers up to two decades prior to the clinical manifestation of HD symptoms using quantitative motor (Q-Motor) assessments such as finger tapping (digitomotography). Other Parkinsonian symptoms besides bradykinesia are rigidity and postural instability. They typically results in falls and injuries in advanced stages of HD. A primarily Parkinsonian motor phenotype, often seen with little to no chorea, is characteristically observed in older, late manifesting patients and in pediatric HD subjects. Establishing a diagnosis of HD is difficult in these groups and patients are often misdiagnosed in early stages.

Premanifest Huntington's disease: Examination of oculomotor abnormalities in clinical practice.

IntroductionDifferent oculomotor abnormalities have been reported to occur in premanifest Huntington’s disease. The aim of this study is to investigate which oculomotor items of the Unified Huntington’s Disease Rating Scale (UHDRS) are affected in premanifest individuals compared to healthy controls, and if CAG repeat length and age are correlated with oculomotor abnormalities in premanifest Huntington’s disease gene carriers.MethodsWe compared baseline data of 70 premanifest individuals and 27 controls who participated in the Enroll-HD study at the Leiden University Medical Center, the Netherlands. Premanifest gene carriers were divided in individuals near to disease onset and individuals far from disease onset.ResultsUsing a logistic regression model, only horizontal ocular pursuit of the six oculomotor items of the UHDRS was significantly more frequently affected in premanifest individuals close to disease onset compared to controls (p = 0.044, OR 13.100). Age was significantly higher in premanifest individuals with affected horizontal ocular pursuit (p = 0.016, OR 1.115) and with affected vertical ocular pursuit (p = 0.030, OR 1.065) compared to premanifest individuals without ocular pursuit deficits.ConclusionsOur results suggest that horizontal ocular pursuit is the only affected oculomotor item of the UHDRS in premanifest individuals and could be used to assess early clinical signs of Huntington’s disease. Saccade initiation and saccade velocity do not seem useful for detecting differences between premanifest individuals and controls.

Loss of extra-striatal phosphodiesterase 10A expression in early premanifest Huntington's disease gene carriers

Huntington's disease (HD) is a monogenic neurodegenerative disorder with an underlying pathology involving the toxic effect of mutant huntingtin protein primarily in striatal and cortical neurons. Phosphodiesterase 10A (PDE10A) regulates intracellular signalling cascades, thus having a key role in promoting neuronal survival. Using positron emission tomography (PET) with [11C]IMA107, we investigated the in vivo extra-striatal expression of PDE10A in 12 early premanifest HD gene carriers. Image processing and kinetic modelling was performed using MIAKAT™. Parametric images of [11C]IMA107 non-displaceable binding potential (BPND) were generated from the dynamic [11C]IMA107 scans using the simplified reference tissue model with the cerebellum as the reference tissue for nonspecific binding. We set a threshold criterion for meaningful quantification of [11C]IMA107 BPND at 0.30 in healthy control data; regions meeting this criterion were designated as regions of interest (ROIs). MRI-based volumetric analysis showed no atrophy in ROIs. We found significant differences in mean ROIs [11C]IMA107 BPND between HD gene carriers and healthy controls. HD gene carriers had significant loss of PDE10A within the insular cortex and occipital fusiform gyrus compared to healthy controls. Insula and occipital fusiform gyrus are important brain areas for the regulation of cognitive and limbic function that is impaired in HD. Our findings suggest that dysregulation of PDE10A-mediated intracellular signalling could be an early phenomenon in the course of HD with relevance also for extra-striatal brain areas.

Sleep deficits but no metabolic deficits in premanifest Huntington's disease.

ObjectiveHuntington disease (HD) is a fatal autosomal dominant, neurodegenerative condition characterized by progressively worsening motor and nonmotor problems including cognitive and neuropsychiatric disturbances, along with sleep abnormalities and weight loss. However, it is not known whether sleep disturbances and metabolic abnormalities underlying the weight loss are present at a premanifest stage.MethodsWe performed a comprehensive sleep and metabolic study in 38 premanifest gene carrier individuals and 36 age‐ and sex‐matched controls. The study consisted of 2 weeks of actigraphy at home, 2 nights of polysomnography and multiple sleep latency tests in the laboratory, and body composition assessment using dual energy x‐ray absorptiometry scanning with energy expenditure measured over 10 days at home by doubly labeled water and for 36 hours in the laboratory by indirect calorimetry along with detailed cognitive and clinical assessments. We performed a principal component analyses across all measures within each studied domain.ResultsCompared to controls, premanifest gene carriers had more disrupted sleep, which was best characterized by a fragmented sleep profile. These abnormalities, as well as a theta power (4–7Hz) decrease in rapid eye movement sleep, were associated with disease burden score. Objectively measured sleep problems coincided with the development of cognitive, affective, and subtle motor deficits and were not associated with any metabolic alterations.InterpretationThe results show that among the earliest abnormalities in premanifest HD is sleep disturbances. This raises questions as to where the pathology in HD begins and also whether it could drive some of the early features and even possibly the pathology. Ann Neurol 2015;78:630–648

Altered PDE10A expression detectable early before symptomatic onset in Huntington's disease.

There is an urgent need for early biomarkers and novel disease-modifying therapies in Huntington's disease. Huntington's disease pathology involves the toxic effect of mutant huntingtin primarily in striatal medium spiny neurons, which highly express phosphodiesterase 10A (PDE10A). PDE10A hydrolyses cAMP/cGMP signalling cascades, thus having a key role in the regulation of striatal output, and in promoting neuronal survival. PDE10A could be a key therapeutic target in Huntington's disease. Here, we used combined positron emission tomography (PET) and multimodal magnetic resonance imaging to assess PDE10A expression in vivo in a unique cohort of 12 early premanifest Huntington's disease gene carriers with a mean estimated 90% probability of 25 years before the predicted onset of clinical symptoms. We show bidirectional changes in PDE10A expression in premanifest Huntington's disease gene carriers, which are associated with the probability of symptomatic onset. PDE10A expression in early premanifest Huntington's disease was decreased in striatum and pallidum and increased in motor thalamic nuclei, compared to a group of matched healthy controls. Connectivity-based analysis revealed prominent PDE10A decreases confined in the sensorimotor-striatum and in striatonigral and striatopallidal projecting segments. The ratio between higher PDE10A expression in motor thalamic nuclei and lower PDE10A expression in striatopallidal projecting striatum was the strongest correlate with higher probability of symptomatic conversion in early premanifest Huntington's disease gene carriers. Our findings demonstrate in vivo, a novel and earliest pathophysiological mechanism underlying Huntington's disease with direct implications for the development of new pharmacological treatments, which can promote neuronal survival and improve outcome in Huntington's disease gene carriers.

Progress in Huntington's disease: the search for markers of disease onset and progression.

Unlike most neurodegenerative disorders, individuals at risk from Huntington's disease can be identified prior to the onset of clinical signs of the disease by virtue of it being an autosomal dominant condition. This provides the hypothetical opportunity to delay disease onset and/or slow down the progression of the disease in the very early stages ahead of overt features of disease. To help prepare for therapeutic trials of disease-modifying compounds, extensive work has gone into (1) finding ways of better predicting the onset of disease in pre-manifest HD gene carriers (PMGC), (2) defining the extent of non-motor features of HD and (3) identifying robust and reliable tests by which to measure disease progression. In this short review, we summarise some of the major findings in this area of clinical research.

The role of the amygdala during emotional processing in Huntington's disease: From pre-manifest to late stage disease

BackgroundDeficits in emotional processing can be detected in the pre-manifest stage of Huntington's disease and negative emotion recognition has been identified as a predictor of clinical diagnosis. The underlying neuropathological correlates of such deficits are typically established using correlative structural MRI studies. This approach does not take into consideration the impact of disruption to the complex interactions between multiple brain circuits on emotional processing. Therefore, exploration of the neural substrates of emotional processing in pre-manifest HD using fMRI connectivity analysis may be a useful way of evaluating the way brain regions interrelate in the period prior to diagnosis. MethodsWe investigated the impact of predicted time to disease onset on brain activation when participants were exposed to pictures of faces with angry and neutral expressions, in 20 pre-manifest HD gene carriers and 23 healthy controls. On the basis of the results of this initial study went on to look at amygdala dependent cognitive performance in 79 Huntington's disease patients from a cross-section of disease stages (pre-manifest to late disease) and 26 healthy controls, using a validated theory of mind task: “the Reading the Mind in the Eyes Test” which has been previously been shown to be amygdala dependent. ResultsPsychophysiological interaction analysis identified reduced connectivity between the left amygdala and right fusiform facial area in pre-manifest HD gene carriers compared to controls when viewing angry compared to neutral faces. Change in PPI connectivity scores correlated with predicted time to disease onset (r=0.45, p<0.05). Furthermore, performance on the “Reading the Mind in the Eyes Test” correlated negatively with proximity to disease onset and became progressively worse with each stage of disease. ConclusionAbnormalities in the neural networks underlying social cognition and emotional processing can be detected prior to clinical diagnosis in Huntington's disease. Connectivity between the amygdala and other brain regions is impacted by the disease process in pre-manifest HD and may therefore be a useful way of identifying participants who are approaching a clinical diagnosis. Furthermore, the “Reading the Mind in the Eyes Test” is a surrogate measure of amygdala function that is clinically useful across the entire cross-section of disease stages in HD.

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

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

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.

E24 Frontostriatal Abnormalities In Huntington's Disease: An Fmri Study

Background Executive dysfunction is present from early in the disease process in HD although there is little consensus as to the nature and extent of these deficits. Aims To evaluate planning and working memory ability across disease stages in HD from pre-manifest to advances disease. Methods The computerised one touch Tower of London task was used in a large cross-sectional population of HD patients ranging from pre-manifest to late stage disease (n = 108); a small subgroup of whom were followed longitudinally (n = 40). In a separate study 20 pre-manifest HD gene carriers and 23 healthy controls completed the Tower of London whilst undergoing functional imaging. Results Analysis of the cross-sectional data showed that task accuracy reduced with advancing disease especially for the harder 4 and 5 move problems. However, the absence of changes in the longitudinal study suggests that the Tower of London is not sensitive to cognitive decline in manifest disease over a short period of follow-up (mean 1.3 years, 0.75 SD). Performance of pre-manifest HD gene carriers on the Tower of London did not differ from controls but their planning related BOLD response and functional connectivity were reduced. Conclusions Changes in planning related neural responses precede the onset of disease and changes in performance on the Tower of London task. However, once behavioural abnormalities are observed, performance deteriorates but not at a rate that makes it useful for tracking cognitive decline over short periods of time.

F02 Cognitive And Oculomotor Performance In Premanifest Huntington Disease: One-year Follow-up

Background Cognitive and oculomotor performance have been extensively studied in Huntington Disease (HD), but evidence for significant deficits in premanifest gene carriers is still controversial. Moreover, their role as markers of disease status and progression is not yet convincingly established. Aims This study aims to understand the evolution of neuropsychological and saccadic performance in premanifest HD (preHD) over a course of 3 years. The results of the baseline assessment and preliminary longitudinal data regarding the one-year follow-up visit of the preHD group are shown here. Methods 15 preHD participants and 22 controls completed the baseline assessment. 10 preHD participants have completed the second visit so far. A comprehensive neuropsychological test battery was used to evaluate the overall cognitive functioning of the participants. An experimental paradigm was designed to assess oculomotor function. Participants completed four different horizontal saccadic tasks with an increasing executive/memory load: prosaccade, antisaccade, 1-or-2 back memory prosaccade and antisaccade. Success rate (percentage of error free trials), latency, directional and timing errors were calculated. Results No significant differences were found between preHD and controls in any of the neuropsychological tests, suggesting a similar overt cognitive baseline at visit #1. The cognitive results of the preHD group at visits #1 and #2 showed that their performance improved in some of the tests used. Concerning saccadic parameters, the preHD group exhibited at baseline a significantly faster response time compared to controls, specifically in memory antisaccades. At visit #2, preHD participants showed a lower success rate and an increased latency, particularly in tasks involving inhibitory processes. Conclusions These data suggest that oculomotor performance of the preHD group may rely on more automatic responses when an executive/memory load is added to the task, deteriorates in time, and also that temporal saccade properties can mark the presence of early neurodegeneration in HD. Furthermore, despite an already evident decline in the saccadic performance of preHD individuals after one year, this is not paralleled by overt cognitive deficits as measured by conventional neuropsychological tests.

E06 Neuroimaging In Huntington's Disease: On Brain Function, And On Brain Structure From Classical Approaches To Application Of Multivoxel Pattern Analysis

<h3>Background</h3> In Huntington’s disease, structural and functional changes of the central nervous system affect primarily the basal ganglia and fronto-striatal circuitry, as demonstrated by large cohort studies. <h3>Aims</h3> This project aims at detecting earliest functional/structural alterations in premanifest gene carriers (preHD). Here, we present year1 assessments with neuroimaging, including brain function, structure, and application of support vector machines. <h3>Methods</h3> 18 controls, 14 preHD (far YEO), and 11 early-HD patients underwent MRI in a 3T Siemens Scanner. Acquisitions comprised two structural MRI scans, diffusion weighted imaging (60 directions, b = 1000), and fMRI study of oculomotor function. The latter included pro-saccades, anti-saccades, and 1-and-2 back memory-antisaccade. Additionally, oculomotor psychophysics were performed out-bore. <h3>Results</h3> Early-HD participants have significant decreased volumes of basal ganglia structures, which correlated significantly with saccade express errors, and cortical thinning throughout an extended area. To preHD, thinning is identified once using less conservative thresholds. PreHD participant had decreased volume of the left caudate, and express and direction errors correlated with striatal volumes. On the other hand, when applying support vector machines to grey matter or fractional anisotropy (whole-brain, basal-ganglia ROIs), classification of HD versus pre-HD/controls attained accuracies above 80%, whereas preHD vs. Controls results were not significant. Finally, fMRI results showed robust difference between preHD and control group (RFX, cluster thresholded) for oculomotor tasks involving inhibitory components, in areas comprising caudate, ACC and pre-frontal cortex. <h3>Conclusions</h3> HD patients had overall alterations whereas first HD-related detectable alterations might derive from neural dysfunction preceding and/or simultaneous to initial neural loss.

E16 Diffusion Tensor Imaging And Neuropsychiatric Disturbance In Huntington 's Disease

Background Huntington’s disease (HD) is commonly associated with psychiatric disturbance. Often evident in premanifest gene-carriers, little is understood about the neural bases underlying these HD symptoms. While structural imaging has so far failed to provide any major insight, Diffusion Tensor Imaging (DTI) can be used to investigate connectivity between brain regions and any putative microstructural changes that may occur in HD. Aims To examine structural connectivity associated with depression, apathy and irritability in HD gene-carriers. Methods DTI data was collected from 39 premanifest and 45 early-HD participants, as part of the TrackHD study and was analysed using whole-brain Tract-Based Spatial Statistics to extract fractional anisotropy (FA) values – a surrogate marker for tract integrity and efficacy of communication between brain regions. Regression analyses were performed on all gene-carriers using HADS depression and PBA apathy and irritability scores. Results High disease load (measured by CPO) was associated with highly significant, whole-brain corrected correlations between depression scores and reduced FA in the bilateral splenium of the corpus callosum. There were significant widespread negative associations between irritability scores and FA. Interestingly, low disease load participants demonstrated significant correlations between irritability scores and FA reduction. There were no significant associations between apathy and FA. Conclusions Both depression and irritability are associated with reductions in white matter integrity in HD. The opposite relationships between FA and measures of depression and irritability as a function of disease progression suggest that diverse mechanisms associated with both the onset and progression of psychiatric disturbance in HD.

Abnormal synchrony of resting state networks in premanifest and symptomatic Huntington disease: the IMAGE-HD study

Functional neural impairments have been documented in people with symptomatic Huntington disease (symp-HD) and in premanifest gene carriers (pre-HD). This study aimed to characterize synchrony in resting state cerebral networks in both pre-HD and symp-HD populations and to determine its association with disease burden and neurocognitive functions. We acquired functional magnetic resonance imaging (fMRI) data from pre-HD, symp-HD and healthy control participants. The fMRI data were analyzed using multisubject independent component analysis and dual regression. We compared networks of interest among the groups using a nonparametric permutation method and correcting for multiple comparisons. Our study included 25 people in the pre-HD, 23 in the symp-HD and 18 in the healthy control groups. Compared with the control group, the pre-HD group showed decreased synchrony in the sensorimotor and dorsal attention networks; decreased level of synchrony in the sensorimotor network was associated with poorer motor performance. Compared with the control group, the symp-HD group showed widespread reduction in synchrony in the dorsal attention network, which was associated with poorer cognitive performance. The posterior putamen and superior parietal cortex were functionally disconnected from the frontal executive network in the symp-HD compared with control and pre-HD groups. Furthermore, the left frontoparietal network showed areas of increased synchrony in the symp-HD compared with the pre-HD group. We could not directly correct for influence of autonomic changes (e.g., heart rate) and respiration on resting state synchronization. Our findings suggest that aberrant synchrony in the sensorimotor and dorsal attention networks may serve as an early signature of neural change in pre-HD individuals. The altered synchrony in dorsal attention, frontoparietal and corticostriatal networks may contribute to the development of clinical symptoms in people with Huntington disease.

The Visual Spatial Learning Test: Differential impairment during the premanifest and manifest stages of Huntington's disease

Visual spatial memory was assessed using the Visual Spatial Learning Test (VSLT) in individuals with mild to moderate Huntington's disease (HD), pre-manifest gene carriers for HD, and demographically similar controls. The VSLT has been demonstrated to be a valid, normed measure of non-verbal memory involving minimal motoric responses. The VSLT assesses immediate and delayed memory for designs, positions of the designs, and design/position associations. The HD group was significantly impaired (p < .05) relative to both the control and Pre-HD groups on immediate and delayed memory for the designs, positions, and design/position associations. Although there were no differences between the Pre-HD and control groups on immediate or delayed memory for designs or positions, the Pre-HD group was significantly impaired (p < .05) relative to the control group on immediate and delayed memory for design/position associations. The results offer novel insight into a relatively unexamined memory deficit that may occur in gene carriers for HD prior to phenoconversion. The data indicate that the VSLT may be a useful measure of visuospatial memory during the premanifest and manifest stages of HD.

White matter integrity in premanifest and early Huntington's disease is related to caudate loss and disease progression

IntroductionHuntington'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. MethodsTract-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. ResultsDiffusion 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. ConclusionsThe 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.