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Background: Huntington disease (HD) is a progressive neurodegenerative disease that causes psychiatric and neurological symptoms, including involuntary and irregular muscle movements (chorea). Chorea can disrupt activities of daily living, pose safety issues, and may lead to social withdrawal. The vesicular monoamine transporter 2 inhibitors tetrabenazine, deutetrabenazine, and valbenazine are approved treatments that can reduce chorea., Objective: This post hoc analysis was conducted to evaluate safety and efficacy among participants who received high-dosage deutetrabenazine treatment (> 48 mg/d) in ARC-HD, an open-label study that assessed long-term safety and efficacy of deutetrabenazine for the treatment of chorea in HD in adults., Methods: ARC-HD was a single-arm, two-cohort, open-label study. Participants either successfully completed the First-HD study or switched overnight from tetrabenazine to deutetrabenazine. Participants were dosed with deutetrabenazine in a response-driven manner (maximum 72 mg/d allowed). For the current analysis, exposure-adjusted incidence rates (EAIRs) for adverse events of interest were analyzed according to daily dosage (≤ 48 mg/d versus > 48 mg/d), and total maximal chorea (TMC) scores were analyzed by cohort during the stable-dose period., Results: In total, 116 of the 119 participants enrolled in ARC-HD entered the stable-dose period, where no apparent differences were seen in EAIRs when receiving deutetrabenazine dosages ≤ 48 mg/d (exposure = 177.7 person-years) compared with > 48 mg/d (exposure = 74.1 person-years). Similar results were found among the subset of participants who received deutetrabenazine dosages > 48 mg/d at least once during the study (n = 49, 42%) when their dosage was ≤ 48 mg/d (exposure = 37.9 person-years) versus > 48 mg/d (74.1 person-years). Efficacy analyses were conducted for participants who had TMC scores available (rollover cohort, n = 77; switch cohort, n = 35). For most participants, the lowest deutetrabenazine dosage needed to achieve a TMC response (≥ 30% improvement from baseline) was between 24 and 48 mg/d in both the rollover (n = 57, 74.0%) and switch (n = 16, 46.0%) cohorts. Whereas the dosage needed for a TMC response was independent of baseline TMC score in the rollover cohort, participants with higher baseline TMC scores in the switch cohort required higher dosages to achieve a TMC response during the trial., Conclusions: In this open-label, long-term study, some participants received deutetrabenazine dosing > 48 mg/d to achieve adequate chorea control. There was no new safety concern or incremental change in the safety profile between dosages of ≤ 48 mg/d and > 48 mg/d. These results include dosages that have not been approved for clinical use, however, they increase our understanding of safety and tolerability of deutetrabenazine doses., Clinical Trials Registration: ARC-HD (ClinicalTrials.gov identifier: NCT01897896); First-HD (ClinicalTrials.gov identifier: NCT01795859)., Competing Interests: Declarations. Funding: This study was supported by Teva Branded Pharmaceutical Products R&D, Inc. Conflict of Interest: Samuel Frank and Claudia M. Testa served as co-principal investigators of the First-HD study. Samuel Frank was compensated for his professional role as the chair of the Data and Safety Monitoring Board for the KINECT-HD study. Jody Goldstein, Elise Kayson, Christine O’Neill, and Jacquelyn Whaley report no conflicts of interest. Blair R. Leavitt is an employee of the Department of Medical Genetics and Division of Neurology, Department of Medicine, and a senior scientist at the Centre for Molecular Medicine and Therapeutics, The University of British Columbia, and BC Children’s Hospital. In the last 5 years, he has held or applied for research grants in the area of neurodegenerative disease from the Canadian Institutes of Health Research, The Huntington Society of Canada, Weston Brain Foundation, Brain Canada, uniQure, Triplet Therapeutics, and the Nanomedicines Innovations Network. He has served on advisory boards for sRNAlytics, the Huntington’s Disease Society of America, and the Huntington Society of Canada. In addition, he has acted as a paid consultant for Roche, uniQure, Novartis, PTC Therapeutics, Triplet Therapeutics, Genentech, Takeda, and Ionis. He is also a shareholder, co-founder, and CEO of Incisive Genetics Inc. David Oakes has received research support from Auspex (for the First-HD and related studies), Vaccinex, Prana Pharmaceuticals, Biogen, and the National Institutes of Health, and received honoraria from Raptor Pharmaceuticals and Voyager Inc. Nicholas Gross, Nayla Chaijale, Steve Barash, and Mark Forrest Gordon are employees and shareholders of Teva Pharmaceuticals. Availability of Data and Material: Consistent with the policies of the Huntington Study Group, the corresponding author is confirmed as the guarantor of the work, and all authors had full access to the data. All authors have the right to publish any and all data separate and apart from any sponsor, and we take full responsibility for the data, the analysis and interpretation, and the conduct of the research. Ethics Approval: This article is based on previously conducted studies and does not contain any new studies with human participants. All involved study centers of the original trial (NCT01897896) received approval by local ethics committees and informed consent was received for all participants. Consent to Participate: Consent was obtained during the original clinical study and no new consent forms were required/collected for this analysis. Consent for Publication: Not applicable. Code Availability: Not applicable. Author Contributions: S.F., N.C., and M.F.G. contributed to the drafting/revision of the manuscript for content, including medical writing for content, and had a major role in the conceptualization, data curation, methodology, data analysis, supervision, validation, and reviewing. C.T., J.G., E.K., and J.W. contributed to the drafting/revision of the manuscript for content, including medical writing for content, and had a major role in the acquisition of data and the analysis or interpretation of data. B.R.L. and C.O. had a major role in the acquisition of data. D.O., N.G., and S.B. contributed to the drafting/revision of the manuscript for content, including medical writing for content, and the analysis or interpretation of data. All authors reviewed and approved the final manuscript., (© 2025. The Author(s).)

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., (© 2022. The Author(s).)

SIGNAL is a multicenter, randomized, double-blind, placebo-controlled phase 2 study (no. NCT02481674) established to evaluate pepinemab, a semaphorin 4D (SEMA4D)-blocking antibody, for treatment of Huntington's disease (HD). The trial enrolled a total of 265 HD gene expansion carriers with either early manifest (EM, n = 179) or late prodromal (LP, n = 86) HD, randomized (1:1) to receive 18 monthly infusions of pepinemab (n = 91 EM, 41 LP) or placebo (n = 88 EM, 45 LP). Pepinemab was generally well tolerated, with a relatively low frequency of serious treatment-emergent adverse events of 5% with pepinemab compared to 9% with placebo, including both EM and LP participants. Coprimary efficacy outcome measures consisted of assessments within the EM cohort of (1) a two-item HD cognitive assessment family comprising one-touch stockings of Cambridge (OTS) and paced tapping (PTAP) and (2) clinical global impression of change (CGIC). The differences between pepinemab and placebo in mean change (95% confidence interval) from baseline at month 17 for OTS were -1.98 (-4.00, 0.05) (one-sided P = 0.028), and for PTAP 1.43 (-0.37, 3.23) (one-sided P = 0.06). Similarly, because a significant treatment effect was not observed for CGIC, the coprimary endpoint, the study did not meet its prespecified primary outcomes. Nevertheless, a number of other positive outcomes and post hoc subgroup analyses-including additional cognitive measures and volumetric magnetic resonance imaging and fluorodeoxyglucose-positron-emission tomography imaging assessments-provide rationale and direction for the design of a phase 3 study and encourage the continued development of pepinemab in patients diagnosed with EM HD., (© 2022. The Author(s).)

Rates of genetic testing in Huntington disease (HD) are lower than was predicted before direct DNA testing became available. Clinicians often do not have in-depth conversations with people at risk who chose not to test. We queried 733 research subjects who chose not to learn their HD gene status when enrolling in the Prospective Huntington At-Risk Observational Study, carried out between 1999 and 2008. Lack of an effective cure or treatment (66% of subjects) and inability to undo knowledge (66%) were the major reasons cited for choosing not to undergo HD DNA testing. Most subjects were not concerned about the length or burden of the testing process (61% and 59%, respectively). Subjects were optimistic that a treatment to improve symptoms or postpone onset would be developed within the next 10 years (56% and 53%, respectively), but they had less certainty about the prospects to prevent HD onset (36%). This is the first large, systematic study of why people at risk for HD choose not to undergo genetic testing. Attitudes about how people at risk for HD approach this life-altering choice should be reassessed as new treatments develop, and as clinical trials now require genetic testing at entry., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To examine phenotype-genotype discrepancies (PGDs) wherein genotype-concealed and prospective judgments of the motor onset of Huntington disease (HD) occurred among at-risk adults who had nonexpanded (<37) cytosine-adenine-guanine (CAG) trinucleotide DNA repeats., Methods: We examined the prospective clinical assessments of investigators who were kept unaware of individual CAG lengths in the Prospective Huntington At-Risk Observational Study (PHAROS) who enrolled and followed undiagnosed adults at risk for HD who chose not to learn their gene status. Subjects ( n  = 1001) at 43 Huntington Study Group research sites in the US and Canada were evaluated prospectively and systematically between 1999 and 2009. At each site, an investigator was designated to perform comprehensive clinic assessments and another investigator to rate only the motor examination. Phenoconversion from a "premanifest" status to a confidently "manifest" status was based on investigator judgment (diagnostic confidence level) of the extrapyramidal motor features of HD., Results: There were 20 PGDs that over time had less severe motor scores than the 101 phenoconversions with CAG ≥37, but more severe motor scores than nonconversions. Following conversion, subjects with CAG ≥37 expansions worsened more motorically and cognitively than PGD subjects in the < 37 group. PGDs were concentrated among three sites and a few investigators, especially raters who only assessed the motor examination., Interpretation: The ability to detect the clinical onset of HD in a timely and reliable fashion remains the key for developing experimental treatments aimed at postponing the clinical onset of HD. Comprehensive clinical evaluation is a more accurate and reliable basis for determining HD clinical onset than sole reliance on judging the extrapyramidal features of HD., Competing Interests: None of the authors report conflicts of interest related to the conduct or reporting of PHAROS.

Background: There is limited understanding of the feasibility of conducting long-term research among undiagnosed (pre-symptomatic) adults at risk to develop Huntington disease (HD), while protecting their emotional well-being and safety., Objective: To assess pre-specified events pertaining to emotional well-being, safety, and feasibility among healthy consenting adults at risk for developing HD who have chosen not to undergo genetic testing., Methods: PHAROS research participants prospectively reported the occurrence of events pertaining to psychological distress (psychiatric evaluations, depression, suicidality) and feasibility (maintaining confidentiality, study attrition). PHAROS enrolled 1001 participants., Results: Events pertaining to psychological distress were reported by 35% of participants. The most common events included heightened suicide risk (26%), new onset depression (12%), and new mental health evaluation (9%); all occurred significantly more frequently among participants with expanded trinucleotide CAG repeats (≥37). Five deaths occurred, none related to suicide. Forty-one percent of participants reported self-disclosure of their HD at-risk status, and 15% reported that someone else (usually a family member) had done so. Confidentiality of CAG test results was maintained by investigators. The withdrawal rate was largely uniform over the study period and did not differ significantly by gender or CAG status., Conclusions: The potentially vulnerable research participants in PHAROS showed good emotional tolerability and safety. Individual CAG data were not disclosed, and confidentiality about disclosure of at-risk HD status was well maintained by others (family, friends, etc.). Long-term research participation of adults at risk for HD who choose not to undergo pre-symptomatic DNA testing is well tolerated, safe and feasible.

Background: In Huntington's disease, 60% of the variance in onset age is not explained by the huntingtin gene mutation. Huntington's disease onset was earlier in caffeine users., Objective: The objective of this study was to assess the relationship of lifestyle factors with motor phenoconversion among persons at risk for Huntington's disease., Methods: The associations of motor phenoconversion and exposure to selected lifestyle and health factors were examined using Cox proportional hazards analyses adjusted for age, gender, and repeat length., Results: Of 247 participants, 36 (14.6%) phenoconverted. Mean follow-up was 4.2 years. Greater caffeinated soda use was associated with an increased hazard of phenoconversion: moderate use hazard ratio 2.26 (95% confidence interval 0.59-8.71), high use hazard ratio 4.05 (95% confidence interval 1.18-13.96)., Conclusions: Huntington's disease onset was earlier among consumers of caffeinated soda, but not other caffeinated beverages. This finding may be spurious or not related to caffeine. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

Objective: To investigate whether creatine administration could slow progressive functional decline in adults with early symptoms of Huntington disease., Methods: We conducted a multicenter, randomized, double-blind, placebo-controlled study of up to 40 g daily of creatine monohydrate in participants with stage I and II HD treated for up to 48 months. The primary outcome measure was the rate of change in total functional capacity (TFC) between baseline and end of follow-up. Secondary outcome measures included changes in additional clinical scores, tolerability, and quality of life. Safety was assessed by adverse events and laboratory studies., Results: At 46 sites in North America, Australia, and New Zealand, 553 participants were randomized to creatine (275) or placebo (278). The trial was designed to enroll 650 patients, but was halted for futility after the first interim analysis. The estimated rates of decline in the primary outcome measure (TFC) were 0.82 points per year for participants on creatine, 0.70 points per year for participants on placebo, favoring placebo (nominal 95% confidence limits -0.11 to 0.35). Adverse events, mainly gastrointestinal, were significantly more common in participants on creatine. Serious adverse events, including deaths, were more frequent in the placebo group. Subgroup analysis suggested that men and women may respond differently to creatine treatment., Conclusions: Our data do not support the use of creatine treatment for delaying functional decline in early manifest HD., Clinicaltrialsgov Identifier: NCT00712426., Classification of Evidence: This study provides Class II evidence that for patients with early symptomatic HD, creatine monohydrate is not beneficial for slowing functional decline., (Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

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.

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.

Background: The cohort-level risk of Huntington disease (HD) is related to the age and symptom level of the cohort, but this relationship has not been made precise., Objective: To predict the evolving likelihood of carrying the Huntington disease (HD) gene for at-risk adults using age and sign level., Methods: Using data from adults with early signs and symptoms of HD linked to information on genetic status, we use Bayes' theorem to calculate the probability that an undiagnosed individual of a certain age and sign level has an expanded CAG repeat., Results: Both age and sign levels have substantial influence on the likelihood of HD onset, and the probability of eventual diagnosis changes as those at risk age and exhibit (or fail to exhibit) symptoms. For example, our data suggest that in a cohort of individuals age 26 with a Unified Huntington's Disease Rating Scale (UHDRS) motor score of 7-10 70% of them will carry the HD mutation. For individuals age 56, the same motor score suggests only a 40% chance of carrying the mutation. Early motor signs of HD, overall and the chorea subscore, were highly predictive of disease onset at any age. However, body mass index (BMI) and cognitive performance scores were not as highly predictive., Conclusions: These results suggest that if researchers or clinicians are looking for early clues of HD, it may be more foretelling to look at motor rather than cognitive signs. Application of similar approaches could be used with other adult-onset genetic conditions.

Importance: Adherence to Mediterranean-type diet (MeDi) may delay onset of Alzheimer and Parkinson diseases. Whether adherence to MeDi affects time to phenoconversion in Huntington disease (HD), a highly penetrant, single-gene disorder, is unknown., Objectives: To determine if MeDi modifies the time to clinical onset of HD (phenoconversion) in premanifest carriers participating in Prospective Huntington at Risk Observational Study (PHAROS), and to examine the effects of body mass index and caloric intake on time to phenoconversion., Design, Setting, and Participants: A prospective cohort study of 41 Huntington study group sites in the United States and Canada involving 1001 participants enrolled in PHAROS between July 1999 and January 2004 who were followed up every 9 months until 2010. A total of 211 participants aged 26 to 57 years had an expanded CAG repeat length (≥ 37)., Exposure: A semiquantitative food frequency questionnaire was administered 33 months after baseline. We calculated daily gram intake for dairy, meat, fruit, vegetables, legumes, cereals, fish, monounsaturated and saturated fatty acids, and alcohol and constructed MeDi scores (0-9); higher scores indicate higher adherence. Demographics, medical history, body mass index, and Unified Huntington's Disease Rating Scale (UHDRS) score were collected., Main Outcome and Measure: Cox proportional hazards regression models to determine the association of MeDi and phenoconversion. RESULTS Age, sex, caloric intake, education status, and UHDRS motor scores did not differ among MeDi tertiles (0-3, 4-5, and 6-9). The highest body mass index was associated with the lowest adherence to MeDi. Thirty-one participants phenoconverted. In a model adjusted for age, CAG repeat length, and caloric intake, MeDi was not associated with phenoconversion (P for trend = 0.14 for tertile of MeDi, and P = .22 for continuous MeDi). When individual components of MeDi were analyzed, higher dairy consumption (hazard ratio, 2.36; 95% CI, 1.0-5.57; P = .05) and higher caloric intake (P = .04) were associated with risk of phenoconversion., Conclusions and Relevance: MeDi was not associated with phenoconversion; however, higher consumption of dairy products had a 2-fold increased risk and may be a surrogate for lower urate levels (associated with faster progression in manifest HD). Studies of diet and energy expenditure in premanifest HD may provide data for interventions to modify specific components of diet that may delay the onset of HD.

Objective: We measured the levels of mutant huntingtin (mtHtt) and total huntingtin (tHtt) in blood leukocytes from Prospective Huntington At-Risk Observational Study (PHAROS) subjects at 50% risk of carrying the Huntington disease mutation using a homogeneous time-resolved fluorescence (HTRF) assay to assess its potential as a biomarker., Methods: Peripheral blood mononuclear cells from consenting PHAROS subjects were analyzed by HTRF using antibodies that simultaneously measured mtHtt and tHtt. mtHtt levels were normalized to tHtt, double-stranded DNA, or protein and analyzed according to cytosine-adenine-guanine repeat length (CAGn), demographics, predicted time to clinical onset or known time since clinical onset, and available clinical measures., Results: From 363 assayed samples, 342 met quality control standards. Levels of mtHtt and mt/tHtt were higher in 114 subjects with expanded CAG repeats (CAG ≥ 37) compared with 228 subjects with nonexpanded CAG repeats (CAG <37) (p < 0.0001). Analysis of relationships to predicted time to onset or to phenoconversion suggested that the HTRF signal could mark changes during the Huntington disease prodrome or after clinical onset., Conclusions: The HTRF assay can effectively measure mtHtt in multicenter sample sets and may be useful in trials of therapies targeting huntingtin.

Objectives: We aimed to describe the clinical phenotype conferred by the intermediate-length huntingtin allele CAG repeat expansion in a population-based study., Methods: The Prospective Huntington At Risk Observational Study (PHAROS) enrolled adults at risk for Huntington disease (HD). They were assessed approximately every 9 months with the Unified Huntington's Disease Rating Scale (UHDRS) by investigators unaware of participants' gene status. UHDRS scores were compared according to the Huntingtin gene CAG repeat number: expanded >36, intermediate 27-35, and nonexpanded controls <26., Results: Fifty (5.1%) of the 983 participants had an intermediate allele (IA). They were similar to controls on UHDRS motor, cognitive, and functional measures, but significantly worse behaviorally on apathy and suicidal ideation. On 5 of the 9 other behavioral items and on total behavior, the IA group's scores were worse than those of controls and expanded participants, who themselves scored significantly worse than controls on 6 behavioral measures. Retention rates at 4 years were 48% for the IA group compared to 58% and 60% for the expanded and control groups., Conclusions: In a cohort at risk for HD, the IA was associated with significant behavioral abnormalities but normal motor and cognition. This behavioral phenotype may represent a prodromal stage of HD, with the potential for subsequent clinical manifestations, or be part of a distinct phenotype conferred by pathology independent of the CAG expansion length.

Background: Neurofilaments are major structural elements of neuronal cells. The light subunit of neurofilament triplet protein (NFL) has been shown to be increased in several neurological diseases (e.g. vascular, infectious, neurodegenerative), indicating axonal damage., Methods: In this study we analyzed the NFL levels in all (N=35) available cerebrospinal fluid (CSF) samples from a clinical trial in Huntington's disease (HD) and compared them to age and gender matched controls., Results: The CSF-NFL levels were significantly higher in HD subjects compared with age and genders matched controls, and were correlated with scores on the Unified Huntington's Disease Rating Scale Total Functional Capacity assessment. The potential of CSF-NFL levels as a disease activity marker in HD needs to be further investigated.

Genetic testing in Huntington disease, an inherited ultimately fatal neurodegenerative disorder, is infrequent despite wide availability. Factors influencing the decision to pursue testing are largely unknown. We conducted a prospective longitudinal observational study of 1,001 individuals in North America who were at risk for Huntington disease who had not pursued genetic testing prior to enrollment. We evaluated the rationale for remaining untested at baseline, determined the concerns of those who eventually pursued testing, and assessed the population's psychological attributes. We contrasted responses between those who did and did not pursue testing, and between United States and Canadian residents. The principal reasons for remaining untested were comfort with risk and uncertainty and the inability to "undo" knowledge gained. After enrollment, 83 individuals [8.3%] pursued genetic testing. Their greatest concern was losing health insurance, and 41.6% of them [vs. 6.7% of those who did not pursue testing; P < 0.001] reported paying out of pocket for testing or other medical services to conceal their genetic risk from their insurer/employer. Among individuals who were tested, more United States residents [46.1%] than Canadian residents [0.0%; P = 0.02] paid out of pocket for health services or genetic testing. Psychological attributes were similar among individuals who did and did not pursue testing. Individuals at risk for Huntington disease who pursued genetic testing feared losing medical insurance, and many paid out of pocket for medical services. Alleviating the fear of health insurance loss may help those who want to pursue genetic testing for many other conditions. [ClinicalTrials.gov number, NCT0052143]., (Copyright 2008 Wiley-Liss, Inc.)

Objective: To assess tetrabenazine (TBZ) efficacy by evaluating the change in Huntington disease-associated chorea resulting from TBZ treatment withdrawal., Methods: Thirty patients treated in the long term were randomized to 1 of 3 groups assigned to withdraw from TBZ in a double-blind, staggered fashion during a 5-day period., Results: The chorea scores of subjects withdrawn from TBZ treatment increased by 5.3 units from days 1 to 3, whereas the scores of the group with partial or no withdrawal of TBZ treatment increased by 3.0 units (P = 0.0773). A post hoc analysis of the linear trend was positive for reemergent chorea (P = 0.0486). No serious adverse events were reported after abrupt withdrawal of TBZ treatment., Conclusions: The trend for reemergence of chorea in patients with Huntington disease who were withdrawn from TBZ treatment is consistent with the findings from previous studies, thus showing the effectiveness of TBZ in reducing chorea.

Previous studies of emotion recognition suggest that detection of disgust relies on processing within the basal ganglia and insula. Research involving individuals with symptomatic and pre-diagnostic Huntington's disease (HD), a disease with known basal ganglia atrophy, has generally indicated a relative impairment in recognizing disgust. However, some data have suggested that recognition of other emotions (particularly fear and anger) may also be affected in HD, and a recent study found fear recognition deficits in the absence of other emotion-recognition impairments, including disgust. To further examine emotion recognition in HD, we administered a computerized facial emotion recognition task to 475 individuals with the HD CAG expansion and 57 individuals without. Logistic regression was used to examine associations of emotion recognition performance with estimated proximity to clinical diagnosis (based on CAG repeat length and current age) and striatal volumes. Recognition of anger, disgust, fear, sadness and surprise (but not happiness) was associated with estimated years to clinical diagnosis; performance was unrelated to striatal volumes. Compared to a CAG-normal control group, the CAG-expanded group demonstrated significantly less accurate recognition of all negative emotions (anger, disgust, fear, sadness). Additionally, participants with more pronounced motor signs of HD were significantly less accurate at recognizing negative emotions than were individuals with fewer motor signs. Findings indicate that recognition of all negative emotions declines early in the disease process, and poorer performance is associated with closer proximity to clinical diagnosis. In contrast to previous results, we found no evidence of relative impairments in recognizing disgust or fear, and no evidence to support a link between the striatum and disgust recognition.

Previous studies of verbal episodic memory in pre-diagnostic Huntington's disease (HD) have yielded mixed results; some evidence suggests that memory decline is evident prior to the onset of pronounced neurological signs of HD, whereas other data indicate that memory function remains normal throughout the pre-diagnostic period. This study examines verbal episodic memory in a sample of CAG expanded individuals who have not yet been clinically diagnosed, and who represent a wide range of points along the continuum from health to disease. The Hopkins Verbal Learning Test-Revised (HVLT-R) was administered to 479 participants (428 with the HD CAG expansion and 51 without), and performance was compared to neurobiological indices of disease progression, including a DNA-based estimate of proximity to clinical diagnosis, magnetic resonance imaging (MRI) measures of striatal volume, and neurologist ratings of motor signs. Lower HVLT-R scores were associated with closer proximity to clinical diagnosis and smaller striatal volumes; these relationships were found even in groups with no neurological signs of HD. The CAG expanded groups, including those with only minimal neurological signs, had significantly lower HVLT-R scores than the control group, and performance was worse in sub-groups that had more neurological signs consistent with HD. These findings indicate that verbal episodic memory is affected in early pre-diagnostic HD and may decline as striatal volumes decrease and individuals approach the motor diagnostic threshold.

Background: The optimal design and outcome measures for preventive clinical trials in neurodegenerative diseases are unknown., Objective: To examine measures that may be associated with disease in the largest cohort ever recruited of prediagnosed individuals carrying the gene expansion for Huntington disease (HD)., Design: The Predict-HD study is a multicenter observational research study in progress at 17 sites in the United States, 4 in Canada, and 3 in Australia., Setting: Genetics and HD outpatient clinics., Participants: Five hundred five at-risk individuals who had previously undergone elective DNA analyses for the CAG expansion in the HD gene (predictive testing) and did not currently have a clinical diagnosis of HD., Main Outcome Measures: Basal ganglia volumes on magnetic resonance images, estimated probability of diagnosis (based on CAG repeat length), performances on 21 standardized cognitive tasks, total scores on 3 scales of psychiatric distress, and motor diagnosis based on the Unified Huntington's Disease Rating Scale., Results: Several variables showed progressive decline as the diagnostic ratings advanced toward manifest disease. Estimated probability of diagnosis was associated with Unified Huntington's Disease Rating Scale prediagnostic stages and varied from 15% in persons with no motor abnormalities to nearly 40% in those with abnormalities suggestive of probable disease. Striatal volumes, cognitive performances, and even psychiatric ratings declined significantly with motor manifestations of disease., Conclusions: The documentation of biological and refined clinical markers suggests several clinical end points for preventive clinical trials. Longitudinal study is critical to further validate possible markers for prediagnosed HD.

With prospects improving for experimental therapeutics aimed at postponing the onset of illness in preclinical carriers of the Huntington's disease (HD) gene, we assessed agreement among experienced clinicians with respect to the motor manifestations of HD, a relevant outcome measure for preventive trials in this population. Seventy-five clinicians experienced in the evaluation of patients with early HD and six non-clinicians were shown a videotape compiled from the film archives of the United States-Venezuela Collaborative HD Research Project. Observers were asked to rate a 2-3-minute segment of the motor examination for each of 17 at-risk subjects. The rating scale ranged from 0 (normal) to 4 (unequivocal extrapyramidal movement disorder characteristic of HD). As measured by a weighted kappa statistic, there was substantial agreement among the 75 clinicians in the judgment of unequivocal motor abnormalities comparing scale ratings of 4 with ratings that were not 4 (weighted kappa = 0.67; standard error (SE) = 0.09). Agreement among the non-clinicians was only fair (weighted kappa = 0.28; SE = 0.10). Even under the artificial conditions of a videotape study, experienced clinicians show substantial agreement about the signs that constitute the motor manifestations of illness in subjects at risk for HD. We expect these findings to translate to a similar level of interobserver agreement in the clinical trial setting involving experienced investigators examining live patients., (2005 Movement Disorder Society.)