What Huntington's Disease Patients Say About Their Illness: An Online Direct-to-Participant Pilot Study.

Background: Direct-to-participant online reporting facilitates the conduct of clinical research by increasing access and clinically meaningful patient engagement. Objective: We assessed feasibility of online data collection from adults with diagnosed Huntington's disease (HD) who directly reported their problems and impact in their own words. Methods: Data were collected online from consenting United States residents who self-identified as 1) having been diagnosed with Huntington's disease, 2) able to ambulate independently, and 3) self-sufficient for most daily needs. Data for this pilot study were collected using the Huntington Study Group myHDstory online research platform. The Huntington Disease Patient Report of Problems (HD-PROP), an open-ended questionnaire, was used to capture verbatim bothersome problems and functional impact. Natural language processing, human-in-the-loop curation of verbatim reports involving clinical and experience experts, and machine learning classified verbatim-reports into clinically meaningful symptoms. Results: All 8 questionnaires in the online pilot study were completed by 345 participants who were 60.9% men, 34.5±9.9 (mean±SD) years old, and 9.5±8.4 years since HD diagnosis. Racial self-identification was 46.4% Caucasian, 28.7% African American, 15.4% American Indian/Alaska Native, and 9.5% other. Accuracy of verbatim classification was 99%. Non-motor problems were the most frequently reported symptoms; depression and cognitive impairment were the most common. Conclusions: Online research participation was feasible for a diverse cohort of adults who self-reported an HD diagnosis and predominantly non-motor symptoms related to mood and cognition. Online research tools can help inform what bothers HD patients, identify clinically meaningful outcomes, and facilitate participation by diverse and under-represented populations.

Safety and efficacy of valbenazine for the treatment of chorea associated with Huntington's disease (KINECT-HD): a phase 3, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Valbenazine is a highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor approved for treatment of tardive dyskinesia. To address the ongoing need for improved symptomatic treatments for individuals with Huntington's disease, valbenazine was evaluated for the treatment of chorea associated with Huntington's disease. METHODS: KINECT-HD (NCT04102579) was a phase 3, randomised, double-blind, placebo-controlled trial, performed in 46 Huntington Study Group sites in the USA and Canada. The study included adults with genetically confirmed Huntington's disease and chorea (Unified Huntington's Disease Rating Scale [UHDRS] Total Maximal Chorea [TMC] score of 8 or higher) who were randomly assigned (1:1) via an interactive web response system (with no stratification or minimisation) to oral placebo or valbenazine (≤80 mg, as tolerated) for 12 weeks of double-blinded treatment. The primary endpoint was a least-squares mean change in UHDRS TMC score from the screening and baseline period (based on the average of screening and baseline values for each participant) to the maintenance period (based on the average of week 10 and 12 values for each participant) in the full-analysis set using a mixed-effects model for repeated measures. Safety assessments included treatment-emergent adverse events, vital signs, electrocardiograms, laboratory tests, clinical tests for parkinsonism, and psychiatric assessments. The double-blind placebo-controlled period of KINECT-HD has been completed, and an open-label extension period is ongoing. FINDINGS: KINECT-HD was performed from Nov 13, 2019, to Oct 26, 2021. Of 128 randomly assigned participants, 125 were included in the full-analysis set (64 assigned to valbenazine, 61 assigned to placebo) and 127 were included in the safety-analysis set (64 assigned to valbenazine, 63 assigned to placebo). The full-analysis set included 68 women and 57 men. Least-squares mean changes from the screening and baseline period to the maintenance period in the UHDRS TMC score were -4·6 for valbenazine and -1·4 for placebo (least-squares mean difference -3·2, 95% CI -4·4 to -2·0; p<0·0001). The most commonly reported treatment-emergent adverse event was somnolence (ten [16%] with valbenazine, two [3%] with placebo). Serious treatment-emergent adverse events were reported in two participants in the placebo group (colon cancer and psychosis) and one participant in the valbenazine group (angioedema because of allergic reaction to shellfish). No clinically important ch anges in vital signs, electrocardiograms, or laboratory tests were found. No suicidal behaviour or worsening of suicidal ideation was reported in participants treated with valbenazine. INTERPRETATION: In individuals with Huntington's disease, valbenazine resulted in improvement in chorea compared with placebo and was well tolerated. Continued research is needed to confirm the long-term safety and effectiveness of this medication throughout the disease course in individuals with Huntington's disease-related chorea. FUNDING: Neurocrine Biosciences.

The Safety of Deutetrabenazine for Chorea in Huntington Disease: An Open-Label Extension Study.

BACKGROUND: Deutetrabenazine is approved in the USA, China, Australia, Israel, Brazil, and South Korea for the treatment of chorea associated with Huntington disease. OBJECTIVE: We aimed to evaluate the long-term safety and tolerability of deutetrabenazine for the treatment of Huntington disease. METHODS: This open-label, single-arm, multi-center study included patients who completed a double-blind study (Rollover) and patients who converted overnight from a stable tetrabenazine dose (Switch). Exposure-adjusted incidence rates (adverse events per person-year) were calculated. Efficacy was analyzed using a stable post-titration timepoint (8 weeks). Changes in the Unified Huntington's Disease Rating Scale total motor score and total maximal chorea score from baseline to week 8, as well as those from week 8 to week 145 (or the last visit on the study drug if that occurred earlier), were evaluated as both efficacy and safety endpoints during the study. RESULTS: Of 119 patients (Rollover, n = 82; Switch, n = 37), 100 (84%) completed ≥ 1 year of treatment. End-of-study exposure-adjusted incidence rates for adverse events in Rollover and Switch, respectively, were: any, 2.57 and 4.02; serious, 0.11 and 0.14; leading to dose suspension, 0.05 and 0.04. Common adverse events (≥ 4% either cohort) included somnolence (Rollover, 20%; Switch, 30%), depression (32%; 22%), anxiety (27%; 35%), insomnia (23%; 16%), and akathisia (6%; 11%). Adverse events of interest included suicidality (9%; 5%) and parkinsonism (4%; 8%). Mean dose at week 8 was 38.1 mg (Rollover) and 36.5 mg (Switch). Mean dose across cohorts after titration was 37.6 mg; at the final visit, mean dose across cohorts was 45.7 mg. Patients showed minimal change in the Unified Huntington's Disease Rating Scale total maximal chorea scores with stable dosing from weeks 8-145 or at the end of treatment, but total motor score increased versus week 8 (mean change [standard deviation]: 8.2 [11.9]). There were no unexpected adverse events upon drug withdrawal, and mean (standard deviation) total maximal chorea scores increased 4.7 (4.6) units from week 8 to 1-week follow-up. CONCLUSIONS: Adverse events observed with long-term deutetrabenazine exposure were consistent with previous studies. Reductions in chorea persisted over time. Upon treatment cessation, there was no unexpected worsening of chorea. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01897896.

Empowering the Clinical Research Coordinator in Academic Medical Centers.

OBJECTIVE: To identify factors associated with job satisfaction and retention, we surveyed a large cohort of clinical research coordinators (CRCs). In recent years, the clinical research coordinator has changed from a semi-permanent role to one that has a high turnover rate. The CRCs are integral to clinical research and instability in this role can cause patient stress and increase the burden on clinical teams through unnecessary delegation of resources toward hiring and retraining new talent. The cultural shift toward CRCs as a temporary position may be driven by the perspective that the role positions an individual for other health care careers, but understanding what influences low retention rates are necessary. METHODS: A survey containing 13 multiple choice or open-ended and 32 Likert scale questions was distributed to previous and current CRCs using REDCap. The questionnaires were self-administered and completed over a 12-month period between October 11, 2017, and September 16, 2018. RESULTS: A total of 85 CRCs completed the study. From the 32 potential predictors of retention, we investigated 9 significant predictors: salary, work setting, understanding the role, level of CRC, understanding protocol development, actively engaged principal investigator (PI), having a collaborative role with PI, feeling respected by PI, and having a close relationship with PI. Adequate salary, greater respect, collaboration, and engagement from the PI were significantly associated with higher retention. Surprisingly, greater workload and lack of opportunity for professional growth were not associated with retention. CONCLUSION: The CRCs who feel respected and engaged by the PI and are adequately compensated are more likely to have higher job satisfaction and retention.

Supporting university students with autism spectrum disorder.

Increasing numbers of students with autism spectrum disorder are entering higher education. Their success can be jeopardized by organizational, social/emotional, and academic challenges if appropriate supports are not in place. Our objective was to evaluate the effectiveness of a support group model for university students with autism spectrum disorder in improving psychological and functional outcomes. A curriculum guided the weekly discussions and consisted of topics such as time and stress management, managing group work, and social communication. Efficacy was assessed through pre- and post self-report measures focused on self-esteem, loneliness, anxiety, and depression. Functional changes in academic and social skills were examined through qualitative analysis of focus groups. Findings from the self-report measures indicated significant reductions in feelings of loneliness and general anxiety, and a significant increase in self-esteem at the end of the program compared to the beginning. Five prominent themes were identified in the focus-group analysis and reflected how the program had positively impacted participants' skills and coping: executive functioning; goal setting; academics and resources; stress and anxiety; and social. Given the cost effectiveness of "in-house" interventions and the potential for improving academic outcomes and retention of students with autism spectrum disorder, further research examining similar program models is warranted.

Safety of Converting From Tetrabenazine to Deutetrabenazine for the Treatment of Chorea.

Importance: Tetrabenazine is efficacious for chorea control; however, tolerability concerns exist. Deutetrabenazine, a novel molecule that reduces chorea, was well tolerated in a double-blind, placebo-controlled study. Objectives: To evaluate the safety and explore the efficacy of conversion from tetrabenazine to deutetrabenazine in patients with chorea associated with Huntington disease (HD). Design, Setting, and Participants: In this ongoing, open-label, single-arm study that started on December 21, 2013, 37 patients at 13 Huntington Study Group sites in the United States and Australia who were taking stable doses of tetrabenazine that provided a therapeutic benefit were switched overnight to deutetrabenazine therapy. After week 1, the deutetrabenazine dose was titrated on a weekly basis for optimal chorea control. Interventions: Deutetrabenazine administration at a dosage thought to provide comparable systemic exposure to the active metabolites of the prior, stable tetrabenazine regimen. Main Outcomes and Measures: Safety measures included adverse events (AEs), clinical laboratory tests, vital signs, electrocardiograms, and validated scales. Changes in the Unified Huntington's Disease Rating Scale total maximal chorea score and total motor score were efficacy end points. Results: Of the 53 patients with HD screened for the study, 37 ambulatory patients with manifest HD (mean [SD] age, 52.4 [11.5] years; 22 [59%] male and 15 [41%] female; 36 white [97.3%]) were enrolled. Deutetrabenazine was generally well tolerated, with low rates of neuropsychiatric AEs. Safety scales did not reveal subclinical toxicity with deutetrabenazine treatment. Rates of dose reduction or suspension attributable to AEs were also low. Chorea control, as measured by the total maximal chorea score, was maintained at week 1 and significantly improved at week 8 (mean [SD] change from baseline, 2.1 [3.2]; P < .001). Conclusions and Relevance: In patients with chorea, overnight conversion to deutetrabenazine therapy provided a favorable safety profile and effectively maintained chorea control.

Evaluating Recall and Recognition Memory Using the Montreal Cognitive Assessment: Applicability for Alzheimer's and Huntington's Diseases.

We sought to investigate whether the Montreal Cognitive Assessment (MoCA) could provide a brief assessment of recall and recognition using Huntington disease (HD) and Alzheimer disease (AD) as disorders characterized by different memory deficits. This study included 80 participants with HD, 64 participants with AD, and 183 community-dwelling control participants. Random-effects hierarchical logistic regressions were performed to assess the relative performance of the normal control (NC), participants with HD, and participants with AD on verbal free recall, cued recall, and multiple-choice recognition on the MoCA. The NC participants performed significantly better than participants with AD at all the 3 levels of assessment. No difference existed between participants with HD and NC for cued recall, but NC participants performed significantly better than participants with HD on free recall and recognition. The participants with HD performed significantly better than participants with AD at all the 3 levels of assessment. The MoCA appears to be a valuable, brief cognitive assessment capable of identifying specific memory deficits consistent with known differences in memory profiles.

Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease: A Randomized Clinical Trial.

IMPORTANCE: Deutetrabenazine is a novel molecule containing deuterium, which attenuates CYP2D6 metabolism and increases active metabolite half-lives and may therefore lead to stable systemic exposure while preserving key pharmacological activity. OBJECTIVE: To evaluate efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease. DESIGN, SETTING, AND PARTICIPANTS: Ninety ambulatory adults diagnosed with manifest Huntington disease and a baseline total maximal chorea score of 8 or higher (range, 0-28; lower score indicates less chorea) were enrolled from August 2013 to August 2014 and randomized to receive deutetrabenazine (n = 45) or placebo (n = 45) in a double-blind fashion at 34 Huntington Study Group sites. INTERVENTIONS: Deutetrabenazine or placebo was titrated to optimal dose level over 8 weeks and maintained for 4 weeks, followed by a 1-week washout. MAIN OUTCOMES AND MEASURES: Primary end point was the total maximal chorea score change from baseline (the average of values from the screening and day-0 visits) to maintenance therapy (the average of values from the week 9 and 12 visits) obtained by in-person visits. This study was designed to detect a 2.7-unit treatment difference in scores. The secondary end points, assessed hierarchically, were the proportion of patients who achieved treatment success on the Patient Global Impression of Change (PGIC) and on the Clinical Global Impression of Change (CGIC), the change in 36-Item Short Form- physical functioning subscale score (SF-36), and the change in the Berg Balance Test. RESULTS: Ninety patients with Huntington disease (mean age, 53.7 years; 40 women [44.4%]) were enrolled. In the deutetrabenazine group, the mean total maximal chorea scores improved from 12.1 (95% CI, 11.2-12.9) to 7.7 (95% CI, 6.5-8.9), whereas in the placebo group, scores improved from 13.2 (95% CI, 12.2-14.3) to 11.3 (95% CI, 10.0-12.5); the mean between-group difference was -2.5 units (95% CI, -3.7 to -1.3) (P < .001). Treatment success, as measured by the PGIC, occurred in 23 patients (51%) in the deutetrabenazine group vs 9 (20%) in the placebo group (P = .002). As measured by the CGIC, treatment success occurred in 19 patients (42%) in the deutetrabenazine group vs 6 (13%) in the placebo group (P = .002). In the deutetrabenazine group, the mean SF-36 physical functioning subscale scores decreased from 47.5 (95% CI, 44.3-50.8) to 47.4 (44.3-50.5), whereas in the placebo group, scores decreased from 43.2 (95% CI, 40.2-46.3) to 39.9 (95% CI, 36.2-43.6), for a treatment benefit of 4.3 (95% CI, 0.4 to 8.3) (P = .03). There was no difference between groups (mean difference of 1.0 unit; 95% CI, -0.3 to 2.3; P = .14), for improvement in the Berg Balance Test, which improved by 2.2 units (95% CI, 1.3-3.1) in the deutetrabenazine group and by 1.3 units (95% CI, 0.4-2.2) in the placebo group. Adverse event rates were similar for deutetrabenazine and placebo, including depression, anxiety, and akathisia. CONCLUSIONS AND RELEVANCE: Among patients with chorea associated with Huntington disease, the use of deutetrabenazine compared with placebo resulted in improved motor signs at 12 weeks. Further research is needed to assess the clinical importance of the effect size and to determine longer-term efficacy and safety. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01795859.

Clinical-Genetic Associations in the Prospective Huntington at Risk Observational Study (PHAROS): Implications for Clinical Trials.

IMPORTANCE: Identifying measures that are associated with the cytosine-adenine-guanine (CAG) expansion in individuals before diagnosis of Huntington disease (HD) has implications for designing clinical trials. OBJECTIVE: To identify the earliest features associated with the motor diagnosis of HD in the Prospective Huntington at Risk Observational Study (PHAROS). DESIGN, SETTING, AND PARTICIPANTS: A prospective, multicenter, longitudinal cohort study was conducted at 43 US and Canadian Huntington Study Group research sites from July 9, 1999, through December 17, 2009. Participants included 983 unaffected adults at risk for HD who had chosen to remain unaware of their mutation status. Baseline comparability between CAG expansion (≥37 repeats) and nonexpansion (<37 repeats) groups was assessed. All participants and investigators were blinded to individual CAG analysis. A repeated-measures analysis adjusting for age and sex was used to assess the divergence of the linear trend between the expanded and nonexpanded groups. Data were analyzed from April 27, 2010, to September 3, 2013. EXPOSURE: Huntington disease mutation status in individuals with CAG expansion vs without CAG expansion. MAIN OUTCOMES AND MEASURES: Unified Huntington's Disease Rating Scale motor (score range, 0-124; higher scores indicate greater impairment), cognitive (symbol digits modality is the total number of correct responses in 90 seconds; lower scores indicate greater impairment), behavioral (score range, 0-176; higher scores indicate greater behavioral symptoms), and functional (Total Functional Capacity score range, 0-13; lower scores indicate reduced functional ability) domains were assessed at baseline and every 9 months up to a maximum of 10 years. RESULTS: Among the 983 research participants at risk for HD in the longitudinal cohort, 345 (35.1%) carried the CAG expansion and 638 (64.9%) did not. The mean (SD) duration of follow-up was 5.8 (3.0) years. At baseline, participants with expansions had more impaired motor (3.0 [4.2] vs 1.9 [2.8]; P < .001), cognitive (P < .05 for all measures except Verbal Fluency, P = .52), and behavioral domain scores (9.4 [11.4] vs 6.5 [8.5]; P < .001) but not significantly different measures of functional capacity (12.9 [0.3] vs 13.0 [0.2]; P = .23). With findings reported as mean slope (95% CI), in the longitudinal analyses, participants with CAG expansions showed significant worsening in motor (0.84 [0.73 to 0.95] vs 0.03 [-0.05 to 0.11]), cognitive (-0.54 [-0.67 to -0.40] vs 0.22 [0.12 to 0.32]), and functional (-0.08 [-0.09 to -0.06] vs -0.01 [-0.02 to 0]) measures compared with those without expansion (P < .001 for all); behavioral domain scores did not diverge significantly between groups. CONCLUSIONS AND RELEVANCE: Using these prospectively accrued clinical data, relatively large treatment effects would be required to mount a randomized, placebo-controlled clinical trial involving premanifest HD individuals who carry the CAG expansion.

The functional implications of motor, cognitive, psychiatric, and social problem-solving states in Huntington's disease.

OBJECTIVE: Huntington's disease (HD) is a genetic, neurodegenerative disorder characterized by motor, cognitive, and psychiatric dysfunction. In HD, the inability to solve problems successfully affects not only disease coping, but also interpersonal relationships, judgment, and independent living. The aim of the present study was to examine social problem-solving (SPS) in well-characterized HD and at-risk (AR) individuals and to examine its unique and conjoint effects with motor, cognitive, and psychiatric states on functional ratings. METHOD: Sixty-three participants, 31 HD and 32 gene-positive AR, were included in the study. Participants completed the Social Problem-Solving Inventory-Revised: Long (SPSI-R:L), a 52-item, reliable, standardized measure of SPS. Items are aggregated under five scales (Positive, Negative, and Rational Problem-Solving; Impulsivity/Carelessness and Avoidance Styles). Participants also completed the Unified Huntington's Disease Rating Scale functional, behavioral, and cognitive assessments, as well as additional neuropsychological examinations and the Symptom Checklist-90-Revised (SCL-90R). A structural equation model was used to examine the effects of motor, cognitive, psychiatric, and SPS states on functionality. RESULTS: The multifactor structural model fit well descriptively. Cognitive and motor states uniquely and significantly predicted function in HD; however, neither psychiatric nor SPS states did. SPS was, however, significantly related to motor, cognitive, and psychiatric states, suggesting that it may bridge the correlative gap between psychiatric and cognitive states in HD. CONCLUSION: SPS may be worth assessing in conjunction with the standard gamut of clinical assessments in HD. Suggestions for future research and implications for patients, families, caregivers, and clinicians are discussed.

Usefulness of the Montreal Cognitive Assessment (MoCA) in Huntington's disease.

BACKGROUND: The Montreal Cognitive Assessment (MoCA) is a brief screening instrument for dementia that is sensitive to executive dysfunction. This study examined its usefulness for assessing cognitive performance in mild, moderate, and severe Huntington's disease (HD), compared with the use of the Mini-Mental State Examination (MMSE). METHODS: We compared MoCA and MMSE total scores and the number of correct answers in 5 cognitive-specific domains in 104 manifest HD patients and 100 matched controls. RESULTS: For the total HD sample, and for the moderate and severe patients, significant differences between both MoCA and MMSE total scores and almost all cognitive-specific domains emerged. Even mild HD subjects showed significant differences with regard to total score and several cognitive domains on both instruments. CONCLUSIONS: We conclude that the MoCA, although not necessarily superior to the MMSE, is a useful instrument for assessing cognitive performance over a broad level of functioning in HD.

Cognitive performance on the mini-mental state examination and the montreal cognitive assessment across the healthy adult lifespan.

OBJECTIVE: We sought to compare age-related performance on the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) across the adult lifespan in an asymptomatic, presumably normal, sample. BACKGROUND: The MMSE is the most commonly used brief cognitive screening test; however, the MoCA may be better at detecting early cognitive dysfunction. METHODS: We gave the MMSE and MoCA to 254 community-dwelling participants ranging in age from 20 to 89, stratified by decade, and we compared their scores using the Wilcoxon signed rank test. RESULTS: For the total sample, the MMSE and MoCA differed significantly in total scores as well as in visuospatial, language, and memory domains (for all of these scores, P<0.001). Mean MMSE scores declined only modestly across the decades; mean MoCA scores declined more dramatically. There were no consistent domain differences between the MMSE and MoCA during the third and fourth decades; however, significant differences in memory (P<0.05) and language (P<0.001) emerged in the fifth through ninth decades. CONCLUSIONS: We conclude that the MoCA may be a better detector of age-related decrements in cognitive performance than the MMSE, as shown in this community-dwelling adult population.

Difficulty modifying a sustained motor response in prodromal Huntington's disease.

We investigated the nature of motor symptoms in the preclinical stage of Huntington's disease. Individuals with the CAG expanded repeat of Huntington's disease (prHD) and two control groups were tested on a task requiring a releasing movement (releasing a depressed button) followed by a ballistic movement (pressing a different button). Movement times were measured separately for releasing and ballistic movements. The mean reaction time of the prHD group was significantly longer when releasing a movement than that of the other groups. The groups, however, did not differ significantly on movement time for ballistic movements. Our results show that motor slowing is evident prior to the clinical diagnosis of Huntington's disease and may reflect difficulty in modifying a sustained motor program.

Postural limits of stability in premanifest and manifest Huntington's disease.

BACKGROUND: Huntington's disease (HD) is associated with neuronal death in basal ganglia circuits important for postural control. Despite evidence of postural instability associated with HD, postural control at the limits of stability has not been investigated in this disease. OBJECTIVE: To use computerized dynamic posturography to measure postural control at the limits of stability during the premanifest and manifest stages of HD. METHODS: Patients with manifest HD, premanifest gene carriers, and matched controls stood on mechanically locked force plates while viewing a computer screen. The participant's estimated center of gravity was represented on the screen as a cursor along with eight target icons arranged in a circular pattern at the theoretical edge of limits of stability. On each trial, one of the eight targets was highlighted and the participant was instructed to control the cursor by rapidly shifting his/her weight in the direction of the target. Measures included reaction time, movement velocity, endpoint excursion, maximum excursion, and directional control. RESULTS: Analysis of variance revealed significant impairment on endpoint excursion, maximum excursion, and directional control (p≤0.001) in the Huntington's disease group, but not in the premanifest gene carrier group as compared to controls. No differences were found on reaction time or movement velocity measures. Group signal to noise ratios also were examined for the measures. CONCLUSIONS: HD patients, but not premanifest gene carriers, showed impaired postural control at the limits of stability. Impaired performance in HD patients has potential functional consequences including increased risk of falling during weight-shifting activities.

Clinical severity of Huntington's disease does not always correlate with neuropathologic stage.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by a triplet-repeat, CAG expansion mutation. Although CAG repeat length is thought to correlate with pathologic burden and disease severity, considerable variability in clinical phenotype remains. This study examined whether neuropathologic burden at autopsy corresponded with severity of clinical phenotype in HD. The brains of 24 patients with a clinical and genetic diagnosis of HD were analyzed at autopsy. Subjects were stratified on the basis of Vonsattel staging as mild/moderate (stage 1-2; n = 7) or severe (stage 3-4; n = 17). Clinical severity was assessed on the basis of the Mini-Mental State Examination (MMSE; 0-30) and two Unified Huntington's Disease Rating Scale (UHDRS) functional components: the Independence Scale (10-100) and the Total Functional Capacity (0-13). Mild/moderate subjects were significantly older, had lower CAG repeat lengths, and greater fixed brain weights than those classified as severe. Patients who were pathologically classified as severe at autopsy were, on average, younger at age of onset and death and less well educated. Despite obvious clinical and pathological differences between mild-moderate and severe HD subjects at autopsy, mean MMSE scores of the two groups before death were surprisingly similar. Correlations between Vonsattel stage and functional assessment scores before death were low and not statistically significant. Our results suggest that the extent of striatal changes in HD may not always correlate with clinical disease severity as measured by UHDRS functional scales.

Basal ganglia atrophy in prodromal Huntington's disease is detectable over one year using automated segmentation.

Future clinical trials of neuroprotection in prodromal Huntington's (known as preHD) will require sensitive in vivo imaging biomarkers to track disease progression over the shortest period. Since basal ganglia atrophy is the most prominent structural characteristic of Huntington's pathology, systematic assessment of longitudinal subcortical atrophy holds great potential for future biomarker development. We studied 36 preHD and 22 age-matched controls using a novel method to quantify regional change from T(1) -weighted structural images acquired 1 year apart. We assessed cross-sectional volume differences and longitudinal volumetric change in 7 subcortical structures-the accumbens, amygdala, caudate, hippocampus, pallidum, putamen, and thalamus. At baseline, accumbens, caudate, pallidum, and putamen volumes were reduced in preHD versus controls (all P < .01). Longitudinally, atrophy was greater in preHD than controls in the caudate, pallidum, and putamen (all P < .01). Each structure showed a large between-group effect size, especially the pallidum where Cohen's d was 1.21. Using pallidal atrophy as a biomarker, we estimate that a hypothetical 1-year neuroprotection study would require only 35 preHD per arm to detect a 50% slowing in atrophy and only 138 preHD per arm to detect a 25% slowing in atrophy. The effect sizes calculated for preHD basal ganglia atrophy over 1 year are some of the largest reported to date. Consequently, this translates to strikingly small sample size estimates that will greatly facilitate any future neuroprotection study. This underscores the utility of this automatic image segmentation and longitudinal nonlinear registration method for upcoming studies of preHD and other neurodegenerative disorders.

Behavioral measures of saccade latency and inhibition in manifest and premanifest Huntington's disease.

Initiation and inhibition of saccadic eye movements has been shown to be impaired in patients with Huntington's disease (HD) and premanifest gene carriers (PMGC), and may provide biomarkers useful in tracking phenotypic change. Computerized behavioral tests of prosaccade latency and disinhibition presented to 31 non-gene carriers (NGC), 25 PMGC, and 12 HD patients. These tests provided quantitative performance measures without use of eye-tracking equipment. Significant differences on saccade tests were found, with PMGC intermediate between NGC and HD patients. Saccade latency discriminated PMGC from NGC, whereas saccade disinhibition discriminated PMGC from HD patients. Results suggest utility of behavioral saccade measures as premanifest indicators of phenoconversion in HD.

Automated structural imaging analysis detects premanifest Huntington's disease neurodegeneration within 1 year.

Intense efforts are underway to evaluate neuroimaging measures as biomarkers for neurodegeneration in premanifest Huntington's disease (preHD). We used a completely automated longitudinal analysis method to compare structural scans in preHD individuals and controls. Using a 1-year longitudinal design, we analyzed T(1) -weighted structural scans in 35 preHD individuals and 22 age-matched controls. We used the SIENA (Structural Image Evaluation, using Normalization, of Atrophy) software tool to yield overall percentage brain volume change (PBVC) and voxel-level changes in atrophy. We calculated sample sizes for a hypothetical disease-modifying (neuroprotection) study. We found significantly greater yearly atrophy in preHD individuals versus controls (mean PBVC controls, -0.149%; preHD, -0.388%; P = .031, Cohen's d = .617). For a preHD subgroup closest to disease onset, yearly atrophy was more than 3 times that of controls (mean PBVC close-to-onset preHD, -0.510%; P = .019, Cohen's d = .920). This atrophy was evident at the voxel level in periventricular regions, consistent with well-established preHD basal ganglia atrophy. We estimated that a neuroprotection study using SIENA would only need 74 close-to-onset individuals in each arm (treatment vs placebo) to detect a 50% slowing in yearly atrophy with 80% power. Automated whole-brain analysis of structural MRI can reliably detect preHD disease progression in 1 year. These results were attained with a readily available imaging analysis tool, SIENA, which is observer independent, automated, and robust with respect to image quality, slice thickness, and different pulse sequences. This MRI biomarker approach could be used to evaluate neuroprotection in preHD.

Postural deficits in Huntington's disease when performing motor skills involved in daily living.

Previous studies of Huntington's disease (HD) have reported motor control deficits for selected fine and gross motor skills. However, no studies have metrically assessed postural control in this clinical group when performing motor skills involved in daily living. Therefore, the purpose of the present study was to evaluate and compare postural control of individuals with confirmed Huntington's disease and non-gene carriers when completing three functional postural tasks. Eleven individuals with HD (mean age=47.1 years: UHDRS mean=34.5: mean age of HD onset 34.6 years: mean CAG repeat=44.1) and 17 non-gene carriers (NGC) (mean age=39.2 years: UHDRS mean=0.13: mean CAG repeat=20.5) completed three tests on a force plate interfaced with a computer. The tests were a step up and over an obstacle (SUO) test, a sit-to-stand (STS) test, and a step and turn (ST) test. Selected kinematic and kinetic variables were used to quantify postural control. Data were analyzed using MANOVA procedures and discriminant function analysis. HD patients were significantly slower in completing all three tests (HD SUO=2.3 s vs. NGC SUO=1.6 s; HD STS=0.8 s vs. NGC STS=0.5 s; HD ST=1.7 s vs. NGC ST=0.9 s) and developed less rising force during the step up and over test (HD=25.8% body weight vs. NGC=39.4% body weight) but not for the sit-to-stand test. Additionally, sway velocity of the center of gravity (COG) was significantly higher for HD patients when performing the sit-to-stand (HD=4.1°/s vs. NGC=2.9°/s) and step and turn tests (HD=33.7°/s vs. NGC=21.7°/s). HD patients manifest significant postural control deficits when performing motor skills typical of daily living activities.

Evaluating imaging biomarkers for neurodegeneration in pre-symptomatic Huntington's disease using machine learning techniques.

The development of MRI measures as biomarkers for neurodegenerative disease could prove extremely valuable for the assessment of neuroprotective therapies. Much current research is aimed at developing such biomarkers for use in people who are gene-positive for Huntington's disease yet exhibit few or no clinical symptoms of the disease (pre-HD). We acquired structural (T1), diffusion weighted and functional MRI (fMRI) data from 39 pre-HD volunteers and 25 age-matched controls. To determine whether it was possible to decode information about disease state from neuroimaging data, we applied multivariate pattern analysis techniques to several derived voxel-based and segmented region-based datasets. We found that different measures of structural, diffusion weighted, and functional MRI could successfully classify pre-HD and controls using support vector machines (SVM) and linear discriminant analysis (LDA) with up to 76% accuracy. The model producing the highest classification accuracy used LDA with a set of six volume measures from the basal ganglia. Furthermore, using support vector regression (SVR) and linear regression models, we were able to generate quantitative measures of disease progression that were significantly correlated with established measures of disease progression (estimated years to clinical onset, derived from age and genetic information) from several different neuroimaging measures. The best performing regression models used SVR with neuroimaging data from regions within the grey matter (caudate), white matter (corticospinal tract), and fMRI (insular cortex). These results highlight the utility of machine learning analyses in addition to conventional ones. We have shown that several neuroimaging measures contain multivariate patterns of information that are useful for the development of disease-state biomarkers for HD.