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

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 of HD morbidity preceding an HD diagnosis.

Development and Psychometric Properties of a New Brief, Yet Comprehensive, Behavioral Questionnaire for Huntington's Disease.

Background: Individuals with Huntington's disease (HD) experience motoric, cognitive, and psychiatric dysfunction. These difficulties can cause maladaptive behaviors that can be very distressing to family and caregivers. Capturing these behaviors in clinical and research settings is crucial. Objectives: To develop and evaluate the psychometric properties of an instrument that is brief, yet comprehensive, in assessing a broad range of behaviors in HD. Methods: A pool of 30 items encompassing common behaviors in HD was generated. Items were scored on a 4-point Likert scale ranging from completely disagree to completely agree, with higher scores indicating greater dysfunction. The self-report measure was piloted on a small sample of individuals with HD. Reliability (test-retest, internal consistency) and validity (convergent, discriminant, criterion) were evaluated. Results: The HD-Behavioral Questionnaire (HD-BQ) demonstrated evidence for reliability with a test-retest correlation coefficient of r = 0.81 and an internal consistency of 0.96. Validity was established with evidence for good convergent, divergent, and criterion validity. A receiver operating characteristic curve showed that the HD-BQ outperformed a similar commonly used measure in diagnostic capability of behaviors in HD. Conclusions: The HD-BQ, a patient self-report measure, was created to more fully explore behavioral issues that people with HD experience in response to limitations of commonly used instruments in the field. Psychometric evidence supports that the HD-BQ is a valid and reliable instrument for the brief, yet comprehensive, assessment of problematic behaviors in HD.

Salivary Huntingtin protein is uniquely associated with clinical features of Huntington's disease.

Measuring 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. In 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). Total 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. 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.

Anosognosia in HD: Comparison of self-report and caregiver ratings with objective performance measures.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

The Repeatable Battery for the Assessment of Neuropsychological Status, While Useful for Measuring Cognitive Changes in Manifest Huntington Disease, May Show Limited Utility in Premanifest Disease.

BACKGROUND: 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. OBJECTIVE: To assess cognitive deficits in individuals with HD, particularly in individuals with PreHD, using an easily administered, brief but comprehensive, neuropsychological test. METHOD: 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. RESULTS: 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. CONCLUSION: 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.

Associations between prognostic index scores and plasma neurofilament light in Huntington's disease.

INTRODUCTION: The 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). METHOD: 112 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. RESULTS: Pre-HD and Man-HD cohorts differed by age (p < .0001), and CAG repeat number (p = .004), but not education level or gender. Plasma NfL levels were significantly correlated with PIN scores (r = 0.69, p < .0001) and PIN-YTO (r = -0.69, p < .0001). Plasma NfL levels were similarly correlated with predicted years to onset scores determined using Langbehn and colleague's formula (r = -0.68, p < .0001). All significant correlations endured corrections for age and CAG repeat number. A plasma NfL cut-point of <45.0 pg/ml distinguished Pre-HD participants >10 predicted years from Man-HD onset, compared to those ≤10 predicted years. CONCLUSIONS: We 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.

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

OBJECTIVE: To 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. METHOD: 98 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. RESULTS: Cohorts differed by age. NfL levels differed significantly across diagnostic groups and were significantly correlated with age. Age-adjusted NfL levels were not correlated with clinical measures in either HD or PM cohorts, but were correlated when cohorts were combined. In PM subjects, NfL levels correlated with YTO, probability of onset in 5 years, and years until 60% onset probability. Using ROC analysis, a NfL cut-point of <53.15 pg/ml distinguished HD from control; <74.84 pg/ml distinguished HD from PM. CONCLUSIONS: These findings implicate plasma NfL as a peripheral prognostic marker for premanifest-HD. Notably, we show that significant correlations between NfL and clinical symptoms are detected only when PM + HD subjects are combined, but not within HD subjects alone. To date, prior studies have investigated the clinical usefulness of NfL exclusively in merged PM + HD cohorts. Our data suggests a biasing of these previous correlations, and hence potentially limited usefulness of plasma NfL in monitoring HD symptom progression, for example, in clinical trials.

Central Cognitive Processing Speed Is an Early Marker of Huntington's Disease Onset.

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 < .05). Moreover, the pro-HD group performed significantly slower than the HA group on both motor-corrected subtests (Ps < 0.05). Effect sizes associated with significant group differences between the pro-HD and HA groups on motor-corrected CTiP subtests (d = 0.73 and 0.84) were similar to effect sizes associated with group differences on the Symbol Digit Modalities Test (d = .82) and other traditional cognitive assessments (Montreal Cognitive Assessment, d = .75; Mini-Mental State Examination, d = .84). CONCLUSIONS: The CTiP may be a useful marker of deficits in central cognitive processing speed in individuals close to manifest onset of HD.

Levels of Interleukin-6 in Saliva, but Not Plasma, Correlate with Clinical Metrics in Huntington's Disease Patients and Healthy Control Subjects.

Growing evidence suggests that inflammatory responses, in both the brain and peripheral tissues, contribute to disease pathology in Huntington's disease (HD), an inherited, progressive neurodegenerative disorder typically affecting adults in their 30-40 s. Hence, studies of inflammation-related markers in peripheral fluids might be useful to better characterize disease features. In this study, we measured levels of C-reactive protein (CRP), Interleukin-6 (IL-6), interleukin 1 beta (IL-1B), and alpha-amylase (AA) in saliva and plasma from n = 125 subjects, including n = 37 manifest HD patients, n = 36 premanifest patients, and n = 52 healthy controls, using immunoassays. We found increases in salivary levels of IL-6, IL-1B and CRP across different disease groups and increased levels of IL-6 in the plasma of HD patients as compared to premanifest patients and controls. The levels of salivary IL-6 were significantly correlated with each of the other salivary markers, as well as with IL-6 levels measured in plasma. Further, salivary IL-6 and IL-1B levels were significantly positively correlated with Total Motor Score (TMS) and chorea scores and negatively correlated with Total Functional Capacity (TFC) in HD patients, whereby in healthy control subjects, IL-6 was significantly negatively correlated with Montreal Cognitive Assessment (MoCA) and the Symbol Digit Modalities test (SDM). Interestingly, the plasma levels of IL-6 did not show similar correlations to any clinical measures in either HD or control subjects. These findings suggest that salivary IL-6 is particularly relevant as a potential non-invasive biomarker for HD symptoms. The advent of an effective, dependable salivary biomarker would meet the urgent need for a less invasive means of identifying and monitoring HD disease progression.

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

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Subtle memory deficits can be observed during the premanifest stage of HD with use of a subset of indices from the CVLT-II.

Uric Acid as a Potential Peripheral Biomarker for Disease Features in Huntington's Patients.

Oxidative stress has long been implicated in the pathophysiology and progression of Huntington's disease (HD). Uric acid (UA) is a naturally occurring antioxidant that is present in the brain and periphery. Growing evidence has implicated UA as a molecular biomarker for several neurodegenerative diseases, most notably Parkinson's disease (PD). In this study, we investigated UA levels in clinical samples from HD patients and normal controls (NCs) and assessed potential relationships between UA levels and disease and clinical data. UA levels were measured in plasma (n = 107) and saliva (n = 178) samples from premanifest (pre-HD) and manifest HD patients and control subjects. Gender effects of UA levels were observed in both biofluids, with male patients showing higher UA levels compared to female patients. Comparisons of UA levels across diagnostic groups, separated by gender, revealed that both plasma and salivary UA levels were significantly lower in female pre-HD and manifest HD patients compared to NCs. Salivary levels of UA were also significantly lower in male manifest HD patients versus controls, but not in plasma. Correlations of peripheral UA levels to clinical data also showed differences according to gender. In male HD patients, both plasma and salivary UA levels were significantly negatively correlated with total functional capacity (TFC), while positive correlations were observed with total motor score (TMS). Female HD patients showed a significant positive correlation between plasma UA levels and TMS, while salivary UA levels from female patients were significantly correlated to disease burden. Finally, in a separate cohort, we show that UA levels are decreased in postmortem prefrontal cortical samples (n = 20) from HD subjects compared to matched controls. These findings suggest that decreased levels of UA in the brains of HD patients can be reflected in peripheral fluids, with salivary measures of UA particularly offering significant promise as a potentially relevant, non-invasive biomarker of disease symptoms and burden. Our findings further highlight the impact of sexual dimorphism in HD pathophysiology.

Handwriting Movement Abnormalities in Symptomatic and Premanifest Huntington's Disease.

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.