Huntington's Disease Participants Research Articles

Structural brain correlates of irritability and aggression in early manifest Huntington's disease.

In Huntington's disease (HD), irritability and aggressive behavior represent highly prevalent and disabling neuropsychiatric symptoms. However, their structural brain correlates have not been extensively explored. Here, we rated the severity of irritability and aggression (IAs) using the Problem Behaviors Assessment for HD (PBA-s) in 31 early HD participants. The IAs score was computed as the mean severity score for the irritability plus the mean severity aggression PBA-s items. Seventeen patients were classified as IAs (IAs score > 2) and 14 as non-IAs. All participants had available T1-MRI data. A grey matter volume voxel-based morphometry group comparison was performed, using age, motor status, severity of other PBA-s items and disease burden as covariates. Aside from irritability, aggression and obsessive-compulsive behavior, both groups were comparable in terms of other clinical and sociodemographic variables. In the IAs group, a significant reduction of grey-matter volume (GMV) was found in the bilateral caudate, putamen and globus pallidus, left pulvinar nucleus, right superior temporal pole (BA 38), left mid temporal gyrus (BA 21), right inferior temporal gyrus (BA 20) and left medial OPFC (BA 11). Lower GMV in the left pulvinar nucleus was significantly associated with higher anxiety and lower GMV in the left medial OPFC was significantly associated with higher suicidality. In sum, IAs in HD is associated with structural brain damage in a set of key nodes involved in the expression and down-regulation of negative emotions.

Effects of Pridopidine on Functional Capacity in Early-Stage Participants from the PRIDE-HD Study.

Background:No pharmacological treatment has been demonstrated to provide a functional benefit for persons with Huntington’s disease (HD). Pridopidine is a sigma-1-receptor agonist shown to have beneficial effects in preclinical models of HD.Objective:To further explore the effect of pridopidine on Total Functional Capacity (TFC) in the recent double-blind, placebo-controlled PRIDE-HD study.Methods:We performed post-hoc analyses to evaluate the effect of pridopidine on TFC at 26 and 52 weeks. Participants were stratified according to baseline TFC score and analyzed using repeated measures (MMRM) and multiple imputation assuming missing not-at-random (MNAR) and worst-case scenarios.Results:The pridopidine 45 mg bid dosage demonstrated a beneficial effect on TFC for the entire population at week 52 of 0.87 (nominal p = 0.0032). The effect was more pronounced for early HD participants (HD1/HD2, TFC = 7–13), with a change from placebo of 1.16 (nominal p = 0.0003). This effect remained nominally significant using multiple imputation with missing not at random assumption as a sensitivity analysis. Responder analyses showed pridopidine 45 mg bid reduced the probability of TFC decline in early HD patients at Week 52 (nominal p = 0.02).Conclusion:Pridopidine 45 mg bid results in a nominally significant reduction in TFC decline at 52 weeks compared to placebo, particularly in patients with early-stage HD.

Neocortical morphometry in Huntington's disease: Indication of the coexistence of abnormal neurodevelopmental and neurodegenerative processes.

Huntington's disease (HD) is an inherited, autosomal dominant disorder that is characteristically thought of as a degenerative disorder. Despite cellular and molecular grounds suggesting HD could also impact normal development, there has been scarce systems-level data obtained from in vivo human studies supporting this hypothesis. Sulcus-specific morphometry analysis may help disentangle the contribution of coexisting neurodegenerative and neurodevelopmental processes, but such an approach has never been used in HD. Here, we investigated cortical sulcal depth, related to degenerative process, as well as cortical sulcal length, related to developmental process, in early-stage HD and age-matched healthy controls. This morphometric analysis revealed significant differences in the HD participants compared with the healthy controls bilaterally in the central and intra-parietal sulcus, but also in the left intermediate frontal sulcus and calcarine fissure. As the primary visual cortex is not connected to the striatum, the latter result adds to the increasing in vivo evidence for primary cortical degeneration in HD. Those sulcal measures that differed between HD and healthy populations were mainly atrophy-related, showing shallower sulci in HD. Conversely, the sulcal morphometry also revealed a crucial difference in the imprint of the Sylvian fissure that could not be related to loss of grey matter volume: an absence of asymmetry in the length of this fissure in HD. Strong asymmetry in that cortical region is typically observed in healthy development. As the formation of the Sylvian fissure appears early in utero, and marked asymmetry is specifically found in this area of the neocortex in newborns, this novel finding likely indicates the foetal timing of a disease-specific, genetic interplay with neurodevelopment.

Mild cognitive impairment and dementia in motor manifest Huntington's disease: Classification and prevalence

ObjectivesTo identify the characteristics and prevalence of mild cognitive impairment in patients with motor-manifest Huntington's disease (HD) and to propose a new mild cognitive impairment (HD-MCI) classification for HD. MethodsWe included 307 motor-manifest HD participants from the ENROLL-HD study who completed the evaluation in four neurocognitive domains including executive functions, processing speed, language, and memory. Cognitive impairment in each domain was determined by age- and education-adjusted cutoffs (> 1.5 standard deviations below the mean). HD-MCI was defined as an impairment in at least one cognitive domain without a loss of functional independence (Function Independence Scale, FIS ≥85). Dementia (HD-Dem) was defined as at least two domains of cognitive impairment with functional impairment (FIS ≤80). ResultsAt the onset of motor symptoms, MCI was present in 84% and dementia in 5% of patients. After 5 years of motor symptoms, 24% of participants met the criteria for MCI and 69% for dementia. Executive dysfunction was the most common impairment, being present in 70% of participants, followed by slowed processing speed in 67%. Language impairment was reported in 55% and memory deficits in 53%. MCI subtypes were classified as “Executive-predominant” (executive impairment and slowed processing speed), “Representational-predominant” (impaired language and memory) and “Mixed Executive-Representational”. Executive-predominant MCI comprised 30%, Representational-predominant 15% and Mixed 55% of this cohort. ConclusionMCI is highly prevalent in the early stage of motor-manifest HD. Three MCI subgroups are defined suggesting at the earlier stage of this disease the frontal-striatal-executive and/or the temporoparietal-representational functional network can be impaired.

Discrete changes in the frequency and functions of autobiographical reminiscence in Huntington's disease

ABSTRACTAutobiographical memory is widely posited to serve self, social and directive functions. Recent evidence suggests marked autobiographical memory impairments in Huntington's disease (HD), however, no study to date has determined how the perceived functions of autobiographical reminiscence may be altered in HD. The current study aimed to assess the self-reported frequency and function of autobiographical reminiscence in HD. We assessed autobiographical reminiscence in late premanifest (n = 16) and early stage HD (n = 14), relative to healthy controls (n = 30). Participants completed the Thinking About Life Experiences Scale Revised (TALE-R), which measures three putative functions of autobiographical memory (self, social, directive). People with manifest HD reported talking less frequently about the past compared to controls. In contrast, no group differences were found in terms of thinking about the past. Manifest HD participants further reported using their autobiographical memories for social functions less frequently compared to controls. No other group differences were evident in terms of self or directive functions of autobiographical memory. These self-report findings complement recent reports of autobiographical memory disruption on performance-based tasks in HD. Future studies exploring how changes in autobiographical reminiscence impact a sense of self continuity in HD will be important in this regard.

Insensitivity to loss predicts apathy in huntington's disease.

Apathy is a deficit in goal-directed behavior that significantly affects quality of life and function. It is common in Huntington's disease and other disorders affecting corticostriatal pathways. Deficits in processing of reward, altered effort, and executive dysfunction are associated with apathy in other disorders, but the cognitive processes leading to apathy in Huntington's disease remain largely unknown. A previously reported deficit in learning from losses in Huntington's disease raises the possibility of a hitherto unrecognized mechanism leading to apathy. This study's objective was to delineate the cognitive processes associated with apathy in HD. We tested 51 Huntington's disease participants and 26 controls on a battery of novel and established measures to assess the contribution to apathy in Huntington's disease of executive function, reward value, reward-effort calculations, instrumental learning, and response to reward and loss. Huntington's disase participants had deficits in instrumental learning with impaired response to loss, but no evidence to suggest altered reward-related behavior or effort. We also saw an executive dysfunction contribution to apathy in Huntington's disease. We report the novel finding that apathy in Huntington's disease is associated with blunted responses to losses and impaired instrumental learning. This association is consistent with the known early degeneration of the indirect pathway and amygdala involvement in apathy in Huntington's disease, but is previously unreported in any disorder. In keeping with the comparative preservation of the ventral striatum and orbitofrontal cortex in Huntington's disease, reward valuation and reward-effort calculations did not contribute to apathy. © 2019 International Parkinson and Movement Disorder Society.

‘Real-life’ hippocampal-dependent spatial memory impairments in Huntington's disease

Hippocampal-dependent spatial memory impairments are seen in Huntington's disease animal models. Similar impairments were recently reported in Huntington's disease participants on analogous spatial memory tasks (e.g., virtual Morris Water Maze), however, these tasks do not translate well to the range of functions involved in day-to-day spatial cognition. In this study we examined ‘real-life’ hippocampal-dependent spatial memory in Huntington's disease participants. We studied premanifest Huntington's disease (N = 24), early manifest Huntington's disease (N = 14), and matched healthy controls (N = 33) with a virtual environment, which demanded spatial memory function on three levels: navigation, object location, and plan drawing. To examine the case for hippocampal-dependent spatial memory more closely, we compared the performance of our Huntington's disease participants to that of a group of temporal lobe epilepsy patients (N = 30) who were previously tested on the virtual environment. Spatial memory performance was also compared to two common neuropsychological tests of spatial cognition, the Paired Associates Learning from the Cambridge Neuropsychological Automated Test Battery, and the Rey–Osterrieth Complex Figure Test. People with early manifest Huntington's disease were impaired across all spatial memory tasks. Premanifest Huntington's disease participants were most notably impaired on the object location measure of the virtual environment, which is heavily dependent on hippocampal function, but showed no such impairments on the Paired Associates Learning or the Rey–Osterrieth Complex Figure Test. Object location memory and navigation performance did not differ between people with Huntington's disease and temporal lobe epilepsy. Aligned with studies in Huntington's disease animal models, ‘real-life’ spatial memory is impaired in people with Huntington's disease prior to clinical diagnosis. This alignment has important implications for testing treatments for Huntington's disease. From the standpoint of neurodegeneration, the dependence of our spatial memory measures on hippocampal function extends the focus of cognitive assessment research in Huntington's disease beyond its primary pathology within the striato-frontal circuit.

Pervasive autobiographical memory impairments in Huntington’s disease

Autobiographical memory dysfunction is a pervasive feature of neurodegenerative disorders, but less is known about the integrity of autobiographical memory in Huntington’s disease (HD). Deficits in anterograde verbal episodic memory on traditional neuropsychological tests have been detected in HD, however, whether personally-relevant autobiographical retrieval is also affected is unknown. We examined autobiographical memory performance in 26 participants genetically confirmed to have HD who were in the peri-manifest stage of the disease (including 12 in the late premanifest stage and 14 who were early diagnosed), and 24 matched controls using the Autobiographical Interview (AI), a semi-structured interview assessing retrieval of autobiographical details from discrete epochs across the lifetime. Relative to controls, people with HD exhibited global episodic autobiographical memory impairments, regardless of recency or remoteness of the memory being retrieved. While specific cues bolstered the retrieval of episodic (internal) details in HD participants, their performance remained significantly below that of controls. Moreover, following probing, people with HD retrieved more extraneous (external) details not directly related to the autobiographical event they originally retrieved, including semantic details, repetitions, and metacognitive statements. Our results reveal marked autobiographical memory dysfunction in HD, not directly attributable to strategic retrieval deficits, and suggest that autobiographical memory impairment may represent an overlooked feature of the cognitive phenotype of HD.

Identification of symbol digit modality test score extremes in Huntington's disease.

Studying individuals with extreme phenotypes could facilitate the understanding of disease modification by genetic or environmental factors. Our aim was to identify Huntington's disease (HD) patients with extreme symbol digit modality test (SDMT) scores. We first examined in HD the contribution of cognitive measures of the Unified Huntington's Disease Rating Scale (UHDRS) in predicting clinical endpoints. The language-independent SDMT was used to identify patients performing very well or very poorly relative to their CAG and age cohort. We used data from REGISTRY and COHORT observational study participants (5,603 HD participants with CAG repeats above 39 with 13,868 visits) and of 1,006 healthy volunteers (with 2,241 visits), included to identify natural aging and education effects on cognitive measures. Separate Cox proportional hazards models with CAG, age at study entry, education, sex, UHDRS total motor score and cognitive (SDMT, verbal fluency, Stroop tests) scores as covariates were used to predict clinical endpoints. Quantile regression for longitudinal language-independent SDMT data was used for boundary (2.5% and 97.5% quantiles) estimation and extreme score analyses stratified by age, education, and CAG repeat length. Ten percent of HD participants had an extreme SDMT phenotype for at least one visit. In contrast, only about 3% of participants were consistent SDMT extremes at two or more visits. The thresholds for the one-visit and two-visit extremes can be used to classify existing and new individuals. The identification of these phenotype extremes can be useful in the search for disease modifiers.

The Effects of Dual-Task Cognitive Interference and Environmental Challenges on Balance in Huntington's Disease.

Huntington's disease (HD) is characterized by chorea, balance and gait impairments, and cognitive deficits, which increase fall risk. Dual task (DT) and environmentally challenging paradigms reflect balance related to everyday life. Furthermore, the impact of cognitive deficits on balance dysfunction and falls in HD is unknown. To determine the impact of DT interference, sensory feedback, and cognitive performance on balance and falls in HD. Seventeen participants with HD (55 ± 9.7 years) and 17 age-matched controls (56.5 ± 9.3 years) underwent quantitative balance testing with APDM inertial sensors. Postural sway was assessed during conditions of manipulated stance, vision, proprioception, and cognitive demand. The DT was a concurrent verbal fluency task. Neuropsychological assessments testing multiple cognitive domains were also administered. HD participants exhibited significantly greater total sway area, jerk, and variability under single-task (ST) and DT conditions compared to controls (P = 0.0002 - < 0.0001). They also demonstrated greater DT interference with vision removed for total sway area (P = 0.01) and variability (P = 0.02). Significantly worse postural control was observed in HD with vision removed and reduced proprioception (P = 0.001 - 0.01). Decreased visuospatial performance correlated with greater total sway and jerk (P = 0.01; 0.009). No balance parameters correlated with retrospective falls in HD. HD participants have worse postural control under DT, limited proprioception/vision, and greater DT interference with a narrowed base and no visual input. These findings may have implications for designing motor and cognitive strategies to improve balance in HD.

Statin use and delayed onset of Huntington's disease.

There is evidence to suggest that 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins) may be beneficial in Huntington's disease (HD). This study aimed to determine if statin use was associated with delayed motor diagnosis in participants with premotor HD. Among premotor HD participants from the Enroll-HD database, statin users were propensity score matched with statin nonusers based on cytosine-adenine-guanine-age product score, cytosine-adenine-guanine repeat length, baseline age, sex, and region. A Cox regression survival analysis compared the annualized hazard ratio (HR) of receiving a motor diagnosis between the 2 groups. The annualized HR of progressing to an HD motor diagnosis was lower in the statin users (n = 89) when compared with the statin nonusers (n = 89; HR = 0.27 [95% CI 0.18-0.50], P < .0001). In patients with premotor HD, statin use was associated with a delayed motor diagnosis of HD. Further studies are warranted to investigate if statins would be an effective disease-modifying therapy for HD. © 2018 International Parkinson and Movement Disorder Society.

Comparable rates of simulator sickness in Huntington’s disease and healthy individuals

ObjectiveInvestigating driving competence with a simulator provides a controlled setting and has a high reproducibility. In addition, there is less risk of physical harm compared to on-road tests. A disadvantage of using simulators is the occurrence of simulator sickness, which is comparable to symptoms of motion sickness.The aim of this study was to examine whether patients with Huntington’s disease (HD) are more susceptible to develop simulator sickness compared to healthy individuals. Further, we investigated if the clinical symptoms of HD, such as motor disabilities and cognitive deterioration, might increase the occurrence of simulator sickness. MethodsEighty-three participants (54 HD, 29 controls) drove in a driving simulator that included urban and motorway scenarios. All participants were still active drivers. Motor, cognitive, and oculomotor assessments were administered. Participants completed a questionnaire after the driving session to report possible symptoms of simulator sickness. ResultsFifty-eight (70%) participants completed the driving session, while 25 (30%) participants dropped out due to simulator sickness. The most reported symptoms of simulator sickness by dropouts were difficulties concentrating, dizziness, nausea, sweating, and vomiting. Dropouts were significantly older and more often female compared to completers. Decreased smooth ocular pursuit was predictive of dropout due to simulator sickness. The number of HD participants and controls in the dropout group was comparable. There was no significant difference in cognitive performance and motor functioning between completers and dropouts. ConclusionsHD participants did not have a higher chance of developing simulator sickness while driving in a simulator compared to controls. Female gender, older age, and smooth ocular pursuit were associated with increased simulator sickness, whereas cognitive and motor functioning were unrelated to dropout due to simulator sickness.

Executive impairment is associated with unawareness of neuropsychiatric symptoms in premanifest and early Huntington's disease.

Unawareness of neuropsychiatric symptoms appears to be common in Huntington's disease (HD), but the clinical correlates of unawareness are unclear. Identifying predictors of unawareness is important for improving diagnosis of neuropsychiatric symptoms, and cognitive impairment, specifically executive impairment, may be a potential important predictor of unawareness. The authors examined whether unawareness of neuropsychiatric symptoms is more common in early HD compared to premanifest HD, and whether executive task performance was associated with awareness, independent of demographic, motor or mood variables. One hundred thirty-two gene-positive participants (60 premanifest and 72 early diagnosed) from the multicenter TRACK-HD study were included. Participants and their informants completed self and informant versions of the Frontal Systems Behavior Scale, which measures executive dysfunction, apathy, and disinhibition symptoms. Awareness was measured as the discrepancy between self- and informant-reports across premanifest and early HD groups. Participants' executive task performance was then assessed as a predictor of unawareness across the whole group. Premanifest participants reported higher levels of executive dysfunction, apathy and disinhibition than their informants, whereas early HD participants reported less executive dysfunction and apathy than their informants, indicating that unawareness is more common after diagnosis. Impaired executive task performance was related to unawareness of executive dysfunction and apathy, independent of demographic, motor and mood variables. Executive impairment is a useful early predictor of unawareness of neuropsychiatric symptoms in HD. Clinicians should closely monitor HD patients with executive impairment for unawareness, and consider this when assessing neuropsychiatric symptoms in HD and providing education to patients and families. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Regional subcortical shape analysis in premanifest Huntington's disease.

Huntington's disease (HD) involves preferential and progressive degeneration of striatum and other subcortical regions as well as regional cortical atrophy. It is caused by a CAG repeat expansion in the Huntingtin gene, and the longer the expansion the earlier the age of onset. Atrophy begins prior to manifest clinical signs and symptoms, and brain atrophy in premanifest expansion carriers can be studied. We employed a diffeomorphometric pipeline to contrast subcortical structures' morphological properties in a control group with three disease groups representing different phases of premanifest HD (far, intermediate, and near to onset) as defined by the length of the CAG expansion and the participant's age (CAG-Age-Product). A total of 1,428 magnetic resonance image scans from 694 participants from the PREDICT-HD cohort were used. We found significant region-specific atrophies in all subcortical structures studied, with the estimated abnormality onset time varying from structure to structure. Heterogeneous shape abnormalities of caudate nuclei were present in premanifest HD participants estimated furthest from onset and putaminal shape abnormalities were present in participants intermediate to onset. Thalamic, hippocampal, and amygdalar shape abnormalities were present in participants nearest to onset. We assessed whether the estimated progression of subcortical pathology in premanifest HD tracked specific pathways. This is plausible for changes in basal ganglia circuits but probably not for changes in hippocampus and amygdala. The regional shape analyses conducted in this study provide useful insights into the effects of HD pathology in subcortical structures.

Automated Assessment of Movement Impairment in Huntington's Disease.

Quantitative assessment of movement impairment in Huntington’s disease (HD) is essential to monitoring of disease progression. This paper aimed to develop and validate a novel low cost, objective automated system for the evaluation of upper limb movement impairment in HD in order to eliminate the inconsistency of the assessor and offer a more sensitive, continuous assessment scale. Patients with genetically confirmed HD and healthy controls were recruited to this observational study. Demographic data, including age (years), gender, and unified HD rating scale total motor score (UHDRS-TMS), were recorded. For the purposes of this paper, a modified upper limb motor impairment score (mULMS) was generated from the UHDRS-TMS. All participants completed a brief, standardized clinical assessment of upper limb dexterity while wearing a tri-axial accelerometer on each wrist and on the sternum. The captured acceleration data were used to develop an automatic classification system for discriminating between healthy and HD participants and to automatically generate a continuous movement impairment score (MIS) that reflected the degree of the movement impairment. Data from 48 healthy and 44 HD participants was used to validate the developed system, which achieved 98.78% accuracy in discriminating between healthy and HD participants. The Pearson correlation coefficient between the automatic MIS and the clinician rated mULMS was 0.77 with a p-value < 0.01. The approach presented in this paper demonstrates the possibility of an automated objective, consistent, and sensitive assessment of the HD movement impairment.

Diminished facial EMG responses to disgusting scenes and happy and fearful faces in Huntington's disease

Huntington's disease (HD) is a neurodegenerative disorder associated with impaired facial emotion recognition and altered subjective experience of emotion. These impairments likely result from the effects of the disease on underlying neurobiological mechanisms. Studies using self-report to examine emotional experiences have been ambiguous regarding whether experiences are diminished or exaggerated, possibly due to cognitive impairment and lack of insight in HD. To infer affective states more objectively and overcome the limitations of self-report, we used facial EMG to measure muscle responses to emotionally-evocative scenes. Further, we examined muscle responses to emotionally-expressive faces, because facial mimicry is thought to facilitate emotion recognition and social affiliation. Twenty-three HD participants (late pre-manifest and early symptomatic) were compared to twenty-five healthy controls in a scene condition and a face condition. EMG activity was measured from facial muscles associated with expressing particular emotions: 1) corrugator supercilii for anger, 2) frontalis for fear, 3) levator labii for disgust, and 4) both zygomaticus major and orbicularis oculi for happiness. Compared to controls, HD participants showed diminished responses to disgusting scenes, and to happy and fearful faces. Our findings provide evidence for a loss of disgust experience in HD. Further, consistent with the alleged affiliative function of facial mimicry, diminished mimicry responses may be relevant to social-emotional changes in HD. Our findings help understand the neural mechanisms underlying emotion processing impairments in HD.

Rethinking Functional Outcome Measures: The Development of a Novel Upper Limb Token Transfer Test to Assess Basal Ganglia Dysfunction.

The basal ganglia are implicated in a wide range of motor, cognitive and behavioral activities required for normal function. This region is predominantly affected in Huntington's disease (HD), meaning that functional ability progressively worsens. However, functional outcome measures for HD, particularly those for the upper limb, are limited meaning there is an imperative for well-defined, quantitative measures. Here we describe the development and evaluation of the Moneybox test (MBT). This novel, functional upper limb assessment was developed in accordance with translational neuroscience and physiological principles for people with a broad disease manifestation, such as HD. Participants with HD (n = 64) and healthy controls (n = 21) performed the MBT, which required subjects to transfer tokens into a container in order of size (Baseline Transfer), value (Complex Transfer) with and without reciting the alphabet (Dual Transfer). Disease specific measures of motor, cognition, behavior, and function were collected. HD patients were grouped into disease stage, from which, discriminative and convergent validity was assessed using Analysis of Variance and Pearson's correlation respectively. Manifest HD participants were slower than pre-manifest and control participants, and achieved significantly lower MBT total scores. Performance in the Complex Transfer and Dual Transfer tasks were significantly different between pre-manifest and stage 1 HD. All MBT performance variables significantly correlated with routinely used measures of motor, cognition, behavior, and function. The MBT provides a valid, sensitive, and affordable functional outcome measure. Unlike current assessments, MBT performance significantly distinguished the subtle differences between the earliest disease stages of HD, which are the populations typically targeted in clinical trials.

Understanding How Chorea Affects Health-Related Quality of Life in Huntington Disease: An Online Survey of Patients and Caregivers in the United States.

BackgroundChorea is the hallmark motor feature of Huntington disease (HD) and can negatively impact daily functioning and health-related quality of life (HRQoL).ObjectiveThe objective of this study was to evaluate how chorea impacts HRQoL and overall functioning among HD patients participating on the PatientsLikeMe website (www.PatientsLikeMe.com).MethodsA survey was provided to HD participants and/or their caregivers via PatientsLikeMe (9 February 2017–22 March 2017), comprising multiple-choice and open-ended questions designed to assess how chorea impacts HRQoL and overall functioning, and the importance of treating chorea. The HDQLIFE measurement system was used to evaluate patient-reported outcomes of chorea and compare Anxiety and Stigma scores in participants with high chorea versus those with low chorea [HDQLIFE Chorea scores ≥ 60 (n = 45) vs. < 60 (n = 38)].ResultsA total of 115 participants (n = 35 caregivers; n = 80 individuals with HD) were included in this study. Among those experiencing chorea (n = 83, 74% of respondents), 66% indicated it was ‘Very Important’ to manage chorea; however, only 47% agreed that their current medication regimen helped manage their movements. In general, respondents reported that chorea negatively affected HRQoL [HDQLIFE Chorea mean score (standard deviation): 59.3 (6.1)]. Consistent with this, significantly higher Anxiety (P = 0.0423) and stigma (P < 0.0001) scores were observed among respondents with high chorea than in those with low chorea.ConclusionsThese results highlight the negative impact of chorea on HRQoL and overall functioning in individuals with HD. Better chorea treatment options are needed to successfully manage symptoms and to help improve HRQoL in these individuals, and patient experiences of anxiety and stigma should be considered in treatment plans.Electronic supplementary materialThe online version of this article (10.1007/s40271-018-0312-x) contains supplementary material, which is available to authorized users.

Structural and metabolic brain correlates of apathy in Huntington's disease.

Apathy is the most prevalent and characteristic neuropsychiatric feature of Huntington's disease. Congruent with the main early pathological changes, apathy is primarily associated with subcortical damage in frontal-striatal circuits. However, little is known about its precise subserving mechanisms and the contribution of regions other than the basal ganglia. We aimed to define the neural correlates of apathy in Huntington's disease based on gray matter volume and PET/CT of 18 F-fluorodeoxyglucose metabolism. We rated the severity of apathy in 40 mild Huntington's disease participants using the Problem Behaviors Assessment for Huntington's disease. Voxelwise regression analysis was performed, controlling for effects of potential confounders, and PET/CT results were corrected for the effects of gray matter atrophy. Apathy was strongly associated with decreased gray matter within a spatially distributed cortico-subcortical network, with major compromise of the bilateral amygdala and temporal cortex. PET metabolism was significantly decreased in frontotemporal and parietal regions. Metabolic uptake and gray matter values in the identified clusters showed significant correlations with multiple clinical measures. Our findings indicate that apathy in Huntington's disease is not exclusively a consequence of basal ganglia and related frontal-executive alterations. It is subserved by a complex cortico-subcortical network where critical reward and emotional-related prefrontal, temporal, and limbic nodes contribute strongly to its severity. This highlights the contribution of damage in regions other than the basal ganglia to the clinical expression of Huntington's disease. © 2018 International Parkinson and Movement Disorder Society.

Alterations in the metabolic and cardiorespiratory response to exercise in Huntington's Disease

BackgroundLimited data suggests that an altered metabolic and cardiorespiratory exercise response may affect exercise performance in individuals with Huntington's disease (HD). There is no clear exploration of the response in individuals at different stages of the disease or in relation to genetic markers. This study aimed to examine the exercise response and recovery of HD participants, and the relationship to genetic and clinical markers. MethodHD gene-positive participants (n = 31; 9 pre-manifest; 22 manifest HD) and a healthy control group (n = 29) performed an incremental exercise test until exhaustion. Performance, cardiorespiratory, metabolic and perceptual responses to exercise were determined from a maximal cycle ergometer test throughout the exercise test and during a recovery period. ResultsDuring sub-maximal exercise, metabolic (lactate levels, oxygen uptake) and cardiorespiratory markers (heart rate) were elevated in HD participants compared to controls. Lactate elevation was specific to pre-manifest HD participants. Work capacity was reduced in both pre-manifest and manifest HD participants with tests terminated with no difference in metabolic, perceptual or cardiorespiratory markers. Submaximal oxygen uptake was correlated with motor score, whilst peak measures were unrelated to genetic or clinical markers. Heart rate recovery was attenuated in pre-manifest and manifest HD participants. ConclusionsOur findings confirm metabolic and cardiorespiratory deficits reduce exercise performance and affect recovery from an early stage in HD, with submaximal deficits related to phenotypic expression. Exercise capacity appears to be limited by an altered movement economy, thus clinicians should consider an altered exercise response and recovery may affect prescription in HD.