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Background: 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). Objective: The present study examined the predictive utility of graphomotor measures handwriting and drawing movements. Methods: 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. Results: 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. Conclusion: 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.

The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is a brief, standardized neuropsychological test that assesses several areas of cognitive function. Recent studies, although sparse, have examined the use of the RBANS to detect cognitive deficits in individuals with manifest Huntington disease (HD); however, no studies have investigated its utility to detect cognitive deficits in individuals with premanifest HD (PreHD), where cognitive symptoms are thought to be more subtle.To assess cognitive deficits in individuals with HD, particularly in individuals with PreHD, using an easily administered, brief but comprehensive, neuropsychological test.We administered the RBANS to 31 individuals with HD, 29 individuals with PreHD, and 22 healthy controls (HC) at an academic HD clinical research center and collected RBANS Total, Index, and subtest scores for group comparisons.The HD group had significantly lower RBANS Total, Index, and subtest scores than the HC. The PreHD group had significantly lower RBANS Total scores and Coding subtest scores than the HC, but no other significant group differences were identified.Our results substantiate previous findings of significant impairment on the RBANS in individuals with HD. In addition, we are the first to demonstrate that, although the RBANS can identify deficits in psychomotor speed and information processing in individuals with PreHD, it does not appear to have the ability to detect impairment in any additional cognitive domains in individuals with PreHD.

IntroductionMeasuring Huntingtin (Htt) protein in peripheral cells represents an essential step in biomarker discovery for Huntington’s Disease (HD), however to date, investigations into the salivary expression of Htt has been lacking.MethodIn the current study, we quantified total Htt (tHtt) and mutant Htt (mHtt) protein in matched blood and saliva samples using single molecule counting (SMC) immunoassays: 2B7-D7F7 (tHtt) and 2B7-MW1 (mHtt). Matched samples, and clinical data, were collected from 95 subjects: n=19 manifest HD, n=34 premanifest HD (PM), and n=42 normal controls (NC). ResultsTotal Htt and mHtt levels were not correlated in blood and saliva. Plasma tHtt was significantly associated with age, and participant sex; whereas salivary mHtt was significantly correlated with age, CAG repeat length and CAP score. Plasma and salivary tHtt did not differ across cohorts. Salivary and plasma mHtt were significantly increased in PM compared to NC; salivary mHtt was also significantly increased in HD compared to NC. Only salivary tHtt and mHtt were significantly correlated with clinical measures.Conclusions Salivary Htt is uniquely associated with clinical measures of HD and offers significant promise as a relevant, non-invasive HD biomarker. Its use could be immediately implemented into both translational and clinical research applications.

ObjectiveTo investigate whether plasma NfL levels correlate with clinical symptom severity in premanifest (PM) and manifest HD (HD) individuals, and whether a NfL cut-point could distinguish PM from HD patients with reasonable accuracy.Method98 participants (33 control, 26 PM, 39 HD), underwent blood sample collection and clinical assessment, using both UHDRS and non-UHDRS measures, at one academic HD Center. Years to onset (YTO), probability of disease onset in 5 years, and predicted years until 60% onset probability were also calculated. NfL levels were measured using a Meso Scale Discovery assay.ResultsCohorts differed by age. NfL levels differed significantly across diagnostic groups and were significantly correlated with age. Age-adjusted NfL levels were not correlated with clinical measures in either HD or PM cohorts, but were correlated when cohorts were combined. In PM subjects, NfL levels correlated with YTO, probability of onset in 5 years, and years until 60% onset probability. Using ROC analysis, a NfL cut-point of

IntroductionThe inclusion of premanifest Huntington's Disease (Pre-HD) subjects in clinical trials necessitates selecting those who are near transition to manifest Huntington's disease (Man-HD). We previously determined that plasma neurofilament light (NfL) levels are significantly correlated with predicted years to Man-HD onset, using established formulae. Recently, a new normalized prognostic index (PIN) score for predicting Pre-HD disease progression has been validated. Our objective was to determine whether plasma NfL levels are similarly associated with PIN score and PIN score-derived years to Man-HD onset (PIN-YTO).Method112 individuals (46 Pre-HD, 66 Man-HD) underwent blood sample collection and clinical assessment, inclusive of the Symbol Digit Modalities Test and Unified Huntington's Disease Rating Scale Total Motor Score. Plasma NfL levels were measured using a Meso Scale Discovery assay.ResultsPre-HD and Man-HD cohorts differed by age (p10 predicted years from Man-HD onset, compared to those ≤10 predicted years.ConclusionsWe have extensively shown that plasma NfL levels are associated with predicted years to manifest HD onset in Pre-HD participants, and present a plasma NfL cut-point that may help exclude far-from-onset Pre-HD patients from clinical trials.

Individuals with Huntington's disease (HD) commonly experience anosognosia, a lack of awareness of deficits. Thus, it is important to examine the accuracy of patient vs caregiver ratings on the basis of objective performance-based measures.The Anosognosia Scale (AS) was given to 33 patients with manifest HD and their caregivers. The AS consists of 8 items in which individuals rate their global abilities relative to same-aged peers. Scores range from very impaired to excellent. Caregiver and patient ratings were then correlated with objective measures.Caregivers' evaluations of patients' cognitive and motoric abilities were more highly correlated with objective measures than patients' ratings. Specifically, caregivers' AS item scores were highly correlated with objective measures of walking (Unified Huntington Disease Rating Scale (UHDRS) tandem walking score [r = 0.57, p = .001] vs. patient [r = 0.39, p = .031]); dexterity (UHDRS pronation supination score [r = 0.55, p = .011] vs. patient [r = 0.18, p = .393]); speech (UHDRS dysarthria score [r = 0.55, p = .004] vs. patient [r = 0.03, p = .854]); memory (MoCA score [r = -.45, p = .048] vs. patient [r = -.11, p = .963]); attention (Trails Making Test A score [r = 0.58, p = .004] vs. patient [r = 0.08, p = .686]); and word retrieval (category fluency ([r = -.58, p = .004] vs. patient [r = -.02, p = 1.00]). Moreover, both the UHDRS total motor score (TMS) (F(1,29) = 7.50, p = .010) and the Mini Mental Status Exam (MMSE) (F(1,31) = 5.40, p = .027) were significant predictors of patient levels of anosognosia.Our findings indicate that caregivers may be better able to rate HD patients' cognitive and motor abilities than patients themselves. Both cognitive and motor severity are significant predictors of levels of anosognosia in HD.

BACKGROUND: Several studies have suggested that cognitive processing speed may be useful for assessing early cognitive change in premanifest Huntington's disease (HD); however, current measures lack the ability to control for the effects of motor dysfunction commonly found in HD. The Computerized Test of Information Processing (CTiP) is a rapidly administered computerized tool that allows for the examination of central cognitive processing speed by using motor‐corrected scores to account for motor dysfunction. OBJECTIVE: To examine central cognitive processing speed as an early marker of HD onset using the CTiP. METHODS: The CTiP and other measures were administered to 102 HD gene carriers and 55 healthy adults (HA). Gene carriers included presymptomatic HD (pre‐HD; n = 33), prodromal HD (pro‐HD; ie, individuals close to disease onset; n = 23), and mild–moderate HD (HD; n = 46). RESULTS: The HD group performed significantly slower than all other groups (HA, pre‐HD, and pro‐HD) on most subtests (Ps

Background Kinematic measures of handwriting movements are sensitive to mild subclinical motor abnormalities stemming from a wide range of disorders involving the basal ganglia including Huntington's disease (HD). Prior research has not investigated handwriting movements in at-risk individuals in the premanifest stage of HD. Objectives The purpose of this study was to examine whether handwriting movement abnormalities are present prior to clinically manifest chorea in HD. Methods A total of 38 symptomatic HD, 30 gene-positive premanifest, and 25 healthy control participants completed handwriting tasks consisting of circles, loops, sentences, and spirals with a noninking pen on a digitizing tablet. Multiple measures of pen stroke kinematics and pressure were measured along with the cognitive and motor status of each participant. Burden of pathology and CAG × age product scores were obtained from each participant with HD. Results Participants with HD exhibited significantly longer and more variable stroke durations, decreased handwriting smoothness, and increased and more variable pen pressures when compared with the healthy controls. We found significant positive associations between stroke duration and both burden of pathology and CAG × age product. Results from a discriminant function analysis revealed a 7-factor model that distinguished premanifest from healthy controls with 85% accuracy. Factors in the model included greater variability in stroke amplitude, velocity and pen pressure, higher levels of pen pressure, longer stroke durations, and lower velocities for combinations of handwritten circles, sentences, and spirals. Conclusions These findings support the clinical utility of dynamic measures of handwriting kinematics as a potential early behavioral biomarker in HD.