Unified Huntington's Disease Research Articles

Antidopaminergic medications in Huntington's disease

Huntington's disease (HD) is a progressive neurodegenerative disorder marked by motor, cognitive, and behavioral impairments. Antidopaminergic medications (ADMs), such as VMAT2 inhibitors and antipsychotics, are commonly used to manage HD motor disturbances and behavioral disorders. For patients and caregivers, ADMs are an important tool for managing symptoms that negatively affect daily life. However, the impact of ADM use in HD is not firmly understood due to a lack of robust, systematic studies that assessed their overall effect on HD disease. A mounting body of evidence suggests these medications may be associated with worse clinical measures of cognitive function and functional impairment. While regulatory guidelines highlight adverse effects like sedation, cognitive dysfunction, and extrapyramidal symptoms, it is unclear whether ADMs directly impact disease progression or if the side effects mimic or exacerbate measures of HD symptoms in clinical trials. Given ADM effects on the central nervous system and biological uncertainty within HD outcomes, clinical trial designs should recognize the impact of ADMs on key outcomes, as measured by acceptable scales including Total Functional Capacity, Stoop Word Reading, Symbol Digit Modality Test, and the composite Unified Huntington's Disease Rating Scale. The development of novel HD interventions requires consideration of concomitant ADM use that may influence measures of disease presentation. In this review, we highlight the role of ADMs in HD management, their symptomatic benefits and potential risks, especially with high dose associated side effects, interactions with CYP2D6 inhibitors, and the individualized need for careful dose monitoring for clinical care and trial design.

Impact of Upper Limb Function on Activities of Daily Living and Quality of Life in Huntington's Disease.

Background/Objectives: Huntington's disease (HD) is a neurodegenerative movement disorder associated with significant disability and impairment of Activities of Daily Living (ADLs). The impact of upper limb disability on quality of life (QoL) and its influence on ADLs is not well known yet. The aim of this study was to describe the manipulative dexterity, strength, and manual eye coordination of patients with manifest and premanifest-HD compared to healthy individuals and to analyze its influence on ADLs and QoL. Methods: We performed an observational, cross-sectional study including 71 ambulatory participants (27 manifest-HD patients, 15 premanifest-HD, and 29 controls). We gathered sociodemographic data, as well as clinical data, including cognition (MMSE), HD motor severity (Unified HD rating scale, UHDRS-TMS), QoL (Neuro-QoL), and ADLs (HD-ADL). Hand dexterity and strength in the dominant and non-dominant hand were assessed with the Nine Hole Peg Test, Ten Neurotest, Nut and Bolt Test, dynamometry, and Late-Life FDI. Analysis of covariance (ANCOVA) models were performed to investigate differences in hand function between manifest-HD, premanifest-HD, and controls. Results: Manifest-HD patients had significantly worse performance in manual and finger dexterity, fine-motor coordination, and poorer handgrip strength than premanifest-HD and controls. Premanifest-HD required more time to complete the test than controls. Significant correlations were found between hand variables and Late-Life FDI, Neuro-QoL, HD-ADL, and UHDRS-TMS. Conclusions: HD affects manipulative dexterity and hand function in premanifest and manifest patients. Therefore, to prevent disability and decreased QoL, evaluating the progression of upper limb dysfunction in HD is important to offer the best possible therapeutic interventions.

The eye movement and gait variability analysis in Chinese patients with Huntington's disease.

Huntington's disease disease (HD) is characterized by motor, cognitive, and neuropsychiatric symptoms. Oculomotor impairments and gait variability have been independently considered as potential markers in HD. But there lacks an integration analysis of eye movement and gait. We assessed multiple examinations of eye movement and gait variability in HTT mutation carriers, analyzed the consistency between these parameters and clinical severity, then examined the association between oculomotor impairments and gait deficits. Seven pre-HD, 30 HD patients and 30 age-matched controls were included. We collected demographics and assessed the Unified Huntington's Disease Rating Scale (UHDRS). Examinations including saccade, smooth pursuit and optokinetic (OPK) test were performed to evaluate eye movement function. The parameters of gait include stride length, walking velocity, step deviation, step length and gait phase. There are significant impairments in HD patients in the latency and velocity of saccades, the gain of smooth pursuit as well as the gain and slow phase velocities (SPV) of OPK tests. Only the speed of saccades has significant difference between pre-HD and controls. There are significant impairments of stride length, walking velocity, step length and gait phase in HD patients. Parameters of eye movement and gait variability in HD patients showed consistency with the scores of UHDRS. There were significant correlations between eye movement and gait parameters. Our results show that eye movement and gait are impaired in HD patients, and speed of saccades is early impaired in pre-HD. Eye movement and gait abnormalities in HD are significantly correlated with clinical disease severities.

Interplay between Sex and Disease Burden in Huntington's Disease: Clinical and Neuroimaging Perspectives.

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a cytosine-adenine-guanine (CAG) repeat expansion in the hungtintin gene. The disease exhibits sex-related differences in symptomatology and disease progression, but the effect on brain structural biomarkers and the interaction between sex and disease burden remain underexplored. To investigate the interplay between sex and disease burden on clinical measures and neuroimaging biomarkers in HD. We retrospectively analyzed data from Enroll-HD, TRACK-HD/ON, PREDICT-HD, and IMAGE-HD studies, including a combined dataset of 19,738 participants with CAG>=40. Linear mixed models were employed to evaluate the influence of sex and the sex-disease burden interaction on clinical evaluations (Unified Huntington's Disease Rating Scale and Problem Behaviors Assessment) and neuroimaging biomarkers (striatal volumes and cortical thickness), with CAG-Age Product Score (CAPS) used as a proxy for disease burden, while controlling for covariates. Female participants exhibited less pronounced striatal atrophy and cortical thinning with increasing CAPS (caudate: β male/female =-3.462/-2.935, p<0.05; putamen: β male/female =-4.775/-3.908, p<0.01). Regarding clinical measures, females experience greater motor decline with increasing CAPS (Total Motor Score: β male/female =3.024/3.244, p<0.0001), greater cognitive decline (Symbol Digit Modalities Test : β male/female =-34.89/-38.91, p<0.0001), and greater functional decline (Total Functional Capacity: β male/female =-6.449/-6.817, p<0.05; Independence Scale: β male/female =-32.44/- 34.99, p<0.001). The sex-CAPS interaction significantly impacts both clinical and neuroimaging biomarkers of HD, underscoring the importance of incorporating sex-specific considerations into the clinical staging and management of HD.

Huntington's disease at work: The effect of profession-specific requirements as related to clinical characteristics on work outcome

Background In most Huntington's disease expanded gene carriers (HDEGC), losing work capacity is the first sign of functional decline. Cognitive deterioration, motor dysfunction, and psychiatric disturbances are associated with or predict work outcomes in HD. The role of profession-specific requirements, however, has not been investigated. Objective This study examines the relationship between work outcomes, clinical characteristics, burnout, and profession-specific requirements in HDEGC. We hypothesize that burnout-like symptoms are associated with mild apathy and that profession-specific requirements influence clinical characteristics affecting work capacity in HD. Methods A cohort of 117 HDEGC (CAG repeat ≥36) participated in the “HD-work” study at Leiden University Medical Center. Participants were 18–67 years old, either, worked at baseline, or had lost their job within two years. The Unified Huntington's Disease Rating Scale assessed motor abilities, global functioning, and cognition. The HD-work questionnaire and the ‘Utrecht Burn Out Scale’ assessed work problems and burnout. Statistical methods included descriptive statistics, Pearson correlations, Cronbachs alpha, t-tests, and logistic regressions. Results Burnout-like symptoms did not differ between those with full and reduced working capacity and were not more prevalent in HD than in the general Dutch population. No significant effect was found between work outcomes and profession-specific requirements, even when adjusted for clinical characteristics. Conclusions Our study suggests that profession-specific requirements do not significantly impact work ability among individuals with HD in early phases of HD. Workplace adjustments should be tailored to individual preferences rather than profession-specific demands. Burnout-like symptoms did not affect work capacity or relate to apathy.

Huntington Disease Health Related Quality of Life, Function and Well Being: The Patient's Perspective.

Limited information is available on patients' experience living with Huntington's disease (HD). The primary objective of this study was to assess the health-related quality of life and well being of patients with HD. A non-interventional, cross-sectional study was conducted in 17 hospitals-based movement disorders units in Spain. Patients aged≥18years, genetically HD diagnosed [with a diagnostic confidence level score of 4, and an Independence Scale (IS) score≥70] were included. The primary variables were the Huntington's Disease Health-related Quality of Life (HDQLIFE) scores and results of the Satisfaction with Life Scale (SWLS). Secondary outcomes include the Unified HD Rating Scale (UHDRS), Beck Hopelessness Scale (BHS), Stigma Scale for Chronic Illness (SSCI-8), Beck Depression Inventory-Fast Screen (BDI-FS) and Problem Behaviours Assessment for HD short Version (PBA-S). A total of 102 patients were included. The mean age (SD) was 53.1 (12.1) years and 56% were male. Most of the patients (99.0%) showed motor symptoms (87.3%), behavioural and psychiatric disturbances (59.8%), or cognitive impairment (20.6%). HDQLIFE domain score means (SD) includes concern with death and dying 45.97 (9.60) end-of-life planning 37.91 (8.84), and meaning and purpose 44.74 (9.05). SWLS score mean was 24.25 (7.33). Depressive symptoms were found in 37.4% of patients and moderate-to-severe feelings of hopelessness in 32.9%. The prevalence of stigma was 55.9% (n=57). HD impacted quality of life, with prevalent motor, psychiatric symptoms and cognitive impairment. Patient perspectives may provide complementary information to implement specific interventions.

Skin Tau Quantification as a Novel Biomarker in Huntington's Disease.

Emerging research implicates tau protein dysregulation in the pathophysiology of Huntington's disease. This study investigated skin tau quantification as a potential biomarker for Huntington's disease and its correlation with disease burden outcomes. In this cross-sectional study, we measured skin tau levels using enzyme-linked immunosorbent assay in 23 Huntington's disease mutations carriers and eight control subjects, examining group discrimination, correlations with genetic markers, clinical assessments, and neuroimaging data. Brain atrophy was quantified by both volumetric measurements from brain segmentation and a voxel-based morphometry approach. Our findings showed elevated skin tau levels in manifest Huntington's disease compared with premanifest and healthy controls. These levels correlated with CAG repeat length, CAG-Age-Product score, composite Unified Huntington's Disease Rating Scale Total Motor Score, cognitive assessments, and disease-related cortical and subcortical volumes, all independent of age and gender. Using skin tau levels in cluster analysis along with genetic and clinical measures led to improved subject stratification, providing enhanced distinction and validity of clusters. This study not only confirms the feasibility of skin tau quantification in Huntington's disease but also establishes its potential as a biomarker for enhancing group classification and assessing disease severity across the Huntington's disease spectrum, opening new directions in biomarker research. © 2024 International Parkinson and Movement Disorder Society.

Oropharyngeal Dysphagia Phenotypes Across Huntington's Disease Stages: Endoscopic Findings and Tongue Pressure Analysis.

Oropharyngeal dysphagia (OD) is a common symptom in Huntington's disease (HD) and is associated with severe health and psychosocial consequences. Different OD phenotypes are defined on the basis of characteristic patterns at fiberoptic endoscopic evaluation of swallowing (FEES), and they may vary during disease progression. To describe OD phenotypes in different HD stages and to analyze their association with neurological data and tongue pressure measurements. Twenty-four patients with HD at different stages of disease progression underwent a FEES. Data on penetration/aspiration, pharyngeal residue, and OD phenotypes were gained. Neurological examination was performed with the Unified Huntington's Disease Rating Scale (UHDRS). Patient Maximum tongue pressure (MTP) and tongue endurance were measured. We confirmed that the occurrence of penetration/aspiration increased with disease duration and pharyngeal residue increased from 16.7% to 100%, respectively. The most common OD phenotypes were oropharyngeal dyspraxia (91.7%), posterior oral incontinence (87.5%), and delayed pharyngeal phase (87.5%). These types of dysfunctions are already detectable in >80% of patients in the early disease stages. In more advanced stages, we also observed propulsion deficit (66.7%), resistive issue (54.2%), and protective deficit (37.5%). Propulsion deficit was associated with higher disease stage, greater motor dysfunction (UHDRS-I), and lower MTP and tongue endurance (p < 0.05). OD in HD results from a combination of different swallowing phenotypes. Early assessment of swallowing and periodical follow-ups are necessary to monitor OD severity and phenotypes and to revise diet recommendations.

Deciphering Cognitive Impairments in Huntington's Disease: A Comparative Study of Stroop Test Variations.

Huntington's disease (HD) is a neurodegenerative disorder marked by cognitive impairment, movement abnormalities, and behavioral disturbances. The Stroop Color Word Test (SCWT) is a widely used tool to detect cognitive decline in HD. Variations in SCWT formats-horizontal (original) and vertical (Golden)-may influence performance, given HD's impact on cognitive and oculomotor abilities. This study aimed to compare the effectiveness of the horizontal and Golden vertical SCWT formats in detecting cognitive decline in HD, and to determine how performance may have been influenced by eye movement abnormalities. Forty-five participants with genetically confirmed HD were recruited. Both SCWT formats were administered to each participant in a counterbalanced fashion. Individual performance of all three sections on each format was standardized across 2 different norms. Raw and normed scores on each variation were compared and correlated with eye movement ratings on the Unified Huntington's Disease Rating Scale. The Golden variation elicited significantly slower responses, particularly in the Word Reading section, across two benchmark norms. Statistical analysis revealed significant performance differences between the two formats. Correlations between vertical eye movement ratings and performance on the Golden SCWT were highly significant, highlighting the impact of oculomotor coordination on cognitive assessments in HD. This study underscores the importance of considering test format in cognitive assessments for HD. The Golden vertical SCWT demonstrates increased sensitivity in detecting deficits in HD, possibly linked to vertical saccade abnormalities. These insights are important for improving the sensitivity of cognitive assessments and monitoring disease progression in HD research and clinical practice.

Using Wearable Sensors and Machine Learning to Assess Upper Limb Function in Huntington's Disease.

Huntington's disease (HD), like many other neurological disorders, affects both lower and upper limb function that is typically assessed in the clinic - providing a snapshot of disease symptoms. Wearable sensors enable the collection of real-world data that can complement such clinical assessments and provide a more comprehensive insight into disease symptoms. In this context, almost all studies are focused on assessing lower limb function via monitoring of gait, physical activity and ambulation. In this study, we monitor upper limb function during activities of daily living in individuals with HD (n = 16), prodromal HD (pHD, n = 7), and controls (CTR, n = 16) using a wrist-worn wearable sensor, called PAMSys ULM, over seven days. The participants were highly compliant in wearing the sensor with an average daily compliance of 99% (100% for HD, 98% for pHD, and 99% for CTR). Goal-directed movements (GDM) of the hand were detected using a deep learning model, and kinematic features of each GDM were estimated. The collected data was used to predict disease groups (i.e., HD, pHD, and CTR) and clinical scores using a combination of statistical and machine learning-based models. Significant differences in GDM features were observed between the groups. HD participants performed fewer GDMs with long duration (> 7.5 seconds) compared to CTR (p-val = 0.021, d = -0.86). In velocity and acceleration metrics, the highest effect size feature was the entropy of the velocity zero-crossing length segments (HD vs CTR p-val <0.001, d = -1.67; HD vs pHD p-val = 0.043, d=-0.98; CTR vs pHD p-val = 0.046, d=0.96). In addition, this same variable showed a strongest correlation with clinical scores. Classification models achieved good performance in distinguishing HD, pHD and CTR individuals with a balanced accuracy of 67% and a 0.72 recall for the HD group, while regression models accurately predicted clinical scores. Notably the explained variance for the upper extremity function subdomain scale of Unified Huntington's Disease Rating Scale (UHDRS) was the highest, with the model capturing 60% of the variance. Our findings suggest the potential of wearables and machine learning for early identification of phenoconversion, remote monitoring in HD, and evaluating new treatments efficacy in clinical trials and medicine.

Atypical Presentations of Huntington Disease-like 2 in South African Individuals.

Huntington disease-like 2 (HDL2) is a neurodegenerative disorder, affecting only individuals of African ancestry. Full penetrance occurs in individuals with 40 repeats or more. To describe the phenotypic variability of HDL2 in a group of mixed ancestry individuals from South Africa. Eight patients were assessed with analysis of repeat size and magnetic resonance brain imaging. We applied the Unified Huntington's Disease Rating Scale (UHDRS), but in deceased patients (4), this was estimated from video material. Cognitive domains were more severely affected than motor; UHDRS motor scores were notable for bradykinesia, and to a slightly lesser extent, for rigidity and dystonia; a single patient had marked chorea. Repeat lengths ranged from 45 to 63 (median, 52). This South African group of mixed ancestry HDL2 individuals presented with severe cognitive and behavioral impairments, with lesser degrees or absence of chorea. This presentation is possibly related to large repeat sizes.

Cerebrospinal fluid glial fibrillary acidic protein, in contrast to amyloid beta protein, is associated with disease symptoms in Huntington's disease

IntroductionHuntington's disease (HD) is a hereditary neurodegenerative disease, currently lacking disease-modifying treatments. Biomarkers are needed for objective assessment of disease progression. Evidence supports both complex protein aggregation and astrocyte activation in HD. This study assesses the 42 amino acid long amyloid beta (Aβ42) and glial fibrillary acidic protein (GFAP) as potential biomarkers in the cerebrospinal fluid (CSF) of HD mutation carriers. MethodsCSF from participants was obtained from three sites in Sweden. Clinical symptoms were graded with the composite Unified Huntington's disease rating scale (cUHDRS). Protein concentrations were measured using ELISA. Pearson correlations were calculated to assess disease progression association. Results were adjusted for age and collection site. ResultsThe study enrolled 28 manifest HD patients (ManHD), 13 premanifest HD gene-expansion carriers (PreHD) and 20 controls. Aβ42 levels did not differ between groups and there was no correlation with measures of disease progression.GFAP concentration was higher in ManHD (424 ng/l, SD 253) compared with both PreHD (266 ng/l, SD 92.4) and controls (208 ng/l, SD 83.7). GFAP correlated with both cUHDRS (r = −0.77, p < 0.001), and 5-year risk of disease onset (r = 0.70, p = 0.008). ConclusionWe provide evidence that indicates CSF Aβ42 has limited potential as a biomarker for HD. GFAP is a potential biomarker of progression in HD. Validation in larger cohorts measuring GFAP in blood and CSF would be of interest.

Language-Independent Acoustic Biomarkers for Quantifying Speech Impairment in Huntington's Disease.

Changes in voice and speech are characteristic symptoms of Huntington's disease (HD). Objective methods for quantifying speech impairment that can be used across languages could facilitate assessment of disease progression and intervention strategies. The aim of this study was to analyze acoustic features to identify language-independent features that could be used to quantify speech dysfunction in English-, Spanish-, and Polish-speaking participants with HD. Ninety participants with HD and 83 control participants performed sustained vowel, syllable repetition, and reading passage tasks recorded with previously validated methods using mobile devices. Language-independent features that differed between HD and controls were identified. Principal component analysis (PCA) and unsupervised clustering were applied to the language-independent features of the HD data set to identify subgroups within the HD data. Forty-six language-independent acoustic features that were significantly different between control participants and participants with HD were identified. Following dimensionality reduction using PCA, four speech clusters were identified in the HD data set. Unified Huntington's Disease Rating Scale (UHDRS) total motor score, total functional capacity, and composite UHDRS were significantly different for pairwise comparisons of subgroups. The percentage of HD participants with higher dysarthria score and disease stage also increased across clusters. The results support the application of acoustic features to objectively quantify speech impairment and disease severity in HD in multilanguage studies. https://doi.org/10.23641/asha.25447171.

High Levels of Mutant Huntingtin Protein in Tear Fluid From Huntington's Disease Gene Expansion Carriers.

Huntington's disease (HD) is an autosomal dominant, fully penetrant, neurodegenerative disease that most commonly affects middle-aged adults. HD is caused by a CAG repeat expansion in the HTT gene, resulting in the expression of mutant huntingtin (mHTT). Our aim was to detect and quantify mHTT in tear fluid, which, to our knowledge, has never been measured before. We recruited 20 manifest and 13 premanifest HD gene expansion carriers, and 20 age-matched controls. All patients underwent detailed assessments, including the Unified Huntington's Disease Rating Scale (UHDRS) total motor score (TMS) and total functional capacity (TFC) score. Tear fluid was collected using paper Schirmer's strips. The level of tear mHTT was determined using single-molecule counting SMCxPRO technology. The average tear mHTT levels in manifest (67,223 ± 80,360 fM) and premanifest patients (55,561 ± 45,931 fM) were significantly higher than those in controls (1,622 ± 2,179 fM). We noted significant correlations between tear mHTT levels and CAG repeat length, "estimated years to diagnosis," disease burden score and UHDRS TMS and TFC. The receiver operating curve demonstrated an almost perfect score (area under the curve [AUC] = 0.9975) when comparing controls to manifest patients. Similarly, the AUC between controls and premanifest patients was 0.9846. The optimal cutoff value for distinguishing between controls and manifest patients was 4,544 fM, whereas it was 6,596 fM for distinguishing between controls and premanifest patients. Tear mHTT has potential for early and noninvasive detection of alterations in HD patients and could be integrated into both clinical trials and clinical diagnostics.

Characterizing differences in retinal and choroidal microvasculature and structure in individuals with Huntington's Disease compared to healthy controls: A cross-sectional prospective study.

To characterize retinal and choroidal microvascular and structural changes in patients who are gene positive for mutant huntingtin protein (mHtt) with symptoms of Huntington's Disease (HD). This study is a cross-sectional comparison of patients who are gene positive for mHtt and exhibit symptoms of HD, either motor manifest or prodromal (HD group), and cognitively normal individuals without a family history of HD (control group). HD patients were diagnosed by Duke movement disorder neurologists based on the Unified Huntington's Disease Rating Scale (UHDRS). Fovea and optic nerve centered OCT and OCTA images were captured using Zeiss Cirrus HD-5000 with AngioPlex. Outcome metrics included central subfield thickness (CST), peripapillary retinal nerve fiber layer (pRNFL) thickness, ganglion cell-inner plexiform layer (GCIPL) thickness, and choroidal vascularity index (CVI) on OCT, and foveal avascular zone (FAZ) area, vessel density (VD), perfusion density (PD), capillary perfusion density (CPD), and capillary flux index (CFI) on OCTA. Generalized estimating equation (GEE) models were used to account for inter-eye correlation. Forty-four eyes of 23 patients in the HD group and 77 eyes of 39 patients in the control group were analyzed. Average GCIPL thickness and FAZ area were decreased in the HD group compared to controls (p = 0.001, p < 0.001). No other imaging metrics were significantly different between groups. Patients in the HD group had decreased GCIPL thickness and smaller FAZ area, highlighting the potential use of retinal biomarkers in detecting neurodegenerative changes in HD.

Reflexive and voluntary saccadic eye movements as biomarker of Huntington's Disease.

Subtle abnormalities in the preclinical stage of Huntington's Disease (HD) can be detected using saccadic eye movement assessment reflecting disease progression. This study was aimed to evaluate abnormalities in saccade parameters in asymptomatic carriers and symptomatic HD patients at various stages of HD. The study enrolled 104 participants, including 14 asymptomatic carriers of HTT mutations, 44 symptomatic HD patients, and 46 control subjects. HD severity was measured using the Unified Huntington's Disease Rating Scale Total Motor Score (UHDRS-TMS) and Total Functional Capacity Scale (TFC). The evaluation of rapid eye movements (reflexive saccades, anti-saccades, memory-guided saccades) was carried out using 'Saccadometer Research'. Measures of reflexive and volitional saccades did not differ between the asymptomatic carriers and controls. Significant latency prolongation and increased physiological variability of latency times, as well as higher error rates among HD patients, were found in all saccade tasks (p < 0.001) compared to the controls. Abnormalities in saccade parameters were more pronounced in the advanced stages of the disease. Latency of saccades and error rate of volitional saccades correlated with the UHDRS-TMS and TFC scores. The saccade parameters in asymptomatic HD carriers with a long time to disease development were similar to those in the control group. Saccade abnormalities appeared in symptomatic patients at the beginning of the disease, and correlated with HD severity.

Baseline Large-Scale Network Dynamics Associated with Disease Progression in Huntington's Disease.

Huntington's disease (HD) is a genetically determined disease with motor, cognitive, and neuropsychiatric disorders. However, the links between clinical progression and disruptions to dynamics in motor and cognitive large-scale networks are not well established. To investigate changes in dynamic and static large-scale networks using an established tool of disease progression in Huntington's disease, the composite Unified Huntington's Disease Rating Scale (cUHDRS). Sixty-four mutation carriers were included. Static and dynamic baseline functional connectivity as well as topological features were correlated to 2-year follow-up clinical assessments using the cUHDRS. Decline in cUHDRS scores was associated with higher connectivity between frontal default-mode and motor networks, whereas higher connectivity in posterior, mainly visuospatial regions was associated with a smaller decline in cUHDRS scores. Structural disruptions in HD were evident both in posterior parietal/occipital and frontal motor regions, with reciprocal increases in functional connectivity. However, although higher visuospatial network connectivity was tied to a smaller cUHDRS decline, increased motor and frontal default-mode connections were linked to a larger cUHDRS decreases. Therefore, divergent functional compensation mechanisms might be at play in the clinical evolution of HD.

Evaluating motor progression of juvenile-onset Huntington's Disease: An Enroll-HD analysis

IntroductionJuvenile-onset Huntington's disease (JOHD) is characterized by a unique motor phenotype relative to patients with adult-onset Huntington's Disease (AOHD). This study characterized motor progression of JOHD to propose improved outcome measures for this group. MethodsWe used linear mixed effect regression models to compare progression of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score (TMS) and the chorea score between patients with JOHD and AOHD. We then evaluated all 31 subscales that make up the UHDRS over time within patients with JOHD to identify measures that may be used to track motor progression most reliably. ResultsThe JOHD cohort had faster TMS progression compared to AOHD (p = 0.006) but no group difference in the rate of change of chorea. Patients with JOHD did not show significant change in any of the chorea subscales. The subscales that changed most reliably over time amongst patients with JOHD were dysarthria, upper extremity dystonia, tandem walking, gait, bilateral pronate/supinate, bilateral finger-tapping, and tongue protrusion. When these subscales were summed, they progressed at a faster rate (7.07%, 95% CI [5.96–8.18]) than the TMS (4.92%, 95% CI [3.95–5.89]). ConclusionWhile the TMS changes at a significant rate in JOHD subjects, not all subscales that make up the TMS accurately represent the unique motor features of JOHD. A JOHD-specific scale performed better at tracking motor progression relative to the TMS. This scale may improve clinical care for patients with JOHD and allow for the development of more efficient clinical trials.

Graphomotor Dysfluency as a Predictor of Disease Progression in Premanifest Huntington's Disease.

Prior studies have relied on conventional observer-based severity ratings such as the Unified Huntington's Disease Rating Scale (UHDRS) to identify early motor markers of decline in Huntington's disease (HD). The present study examined the predictive utility of graphomotor measures handwriting and drawing movements. Seventeen gene-positive premanifest HD subjects underwent comprehensive clinical, cognitive, motor, and graphomotor assessments at baseline and at follow-up intervals ranging from 9-36 months. Baseline graphomotor assessments were subjected to linear multiple regression procedures to identify factors associated with change on the comprehensive UHDRS index. Subjects were followed for an average of 21.2 months. Three multivariate regression models based on graphomotor variables derived from a complex loop task, a maximum speed circle drawing task and a combined task returned adjusted R2 coefficients of 0.76, 0.71, and 0.80 respectively accounting for a significant portion of the variability in cUHDRS change score. The best-fit model based on the combined tasks indicated that greater decline on the cUHDRS was associated with increased pen movement dysfluency and stroke-stroke variability at baseline. Performance on multiple measures of graphomotor dysfluency assessed during the premanifest or prodromal stage in at-risk HD individuals was associated with decline on a multidimensional index on HD morbidity preceding an HD diagnosis.

Validity, diagnostics and feasibility of the Italian version of the Montreal Cognitive Assessment (MoCA) in Huntington's disease.

This study is aimed at assessing the clinimetric properties and feasibility of the Italian version of the Montreal Cognitive Assessment (MoCA) in patients with Huntington's disease (HD). N = 39 motor-manifest HD patients, N = 74 Parkinson's disease (PD) patients and N = 92 matched HCs were administered the MoCA. HD patients further underwent the Unified Huntington's Disease Rating Scale (UHDRS), self-report questionnaires for anxiety and depression and a battery of first- and second-level cognitive tests. Construct validity was tested against cognitive and behavioural/psychiatric measures, whereas ecological validity against motor-functional subscales of the UHDRS. Sensitivity to disease severity was tested, via a logistic regression, by exploring whether the MoCA discriminated between patients in Shoulson-Fahn stage ≤ 2 vs. > 2. The same analysis was employed to test its ability to discriminate HD patients from HCs and PD patients. The MoCA converged towards cognitive and behavioural measures but diverged from psychiatric ones, being also associated with motor/functional measures from the UHDRS. In identifying patients with cognitive impairment, adjusted MoCA scores were highly accurate (AUC = .92), yielding optimal diagnostics at the cut-off of < 19.945 (J = .78). The MoCA was able to discriminate patients in the middle-to-advanced from those in the early-to-middle stages of the disease (p = .037), as well as to differentiate HD patients from both HCs (p < .001) and PD patients (p < .001). The MoCA is a valid, diagnostically sound and feasible cognitive screener in motor-manifest HD patients, whose adoption is thus encouraged in clinical practice and research.