George Huntington Institute

Abstract Background Huntington’s disease (HD) causes progressive loss of function, cognition, and motor control, with no approved therapy yet shown to slow disease progression. In the PROOF-HD phase 3 trial, pridopidine did not meet the primary or key secondary outcomes in the overall population, but participants who remained off antidopaminergic medications (ADMs) showed benefits compared to placebo during the double-blind phase. Whether such benefits continue with longer duration treatment and how they compare with expected natural-history trajectories remains unknown. Methods We evaluated outcomes through Week 104 from baseline in participants who received continuous pridopidine (45 mg twice daily) and remained off-ADMs throughout the double-blind and open-label extension period (n=90). External comparators from ENROLL-HD and TRACK-HD were constructed using propensity-score weighting methods. Least-squares mean changes from baseline to Week 104 were estimated using mixed-effects models for repeated measures across outcomes. Results At two-years, pridopidine treatment was associated with benefits versus propensity-score weighted natural-history comparators across multiple outcomes. Relative to ENROLL-HD, participants receiving pridopidine showed slowing of progression over 104 weeks, expressed as percent slowing across cUHDRS, TFC, SWR, SDMT, and TMS outcomes (39.5–88.3% slowing). Similar patterns were observed relative to TRACK-HD across the same measures (48.5 – 81.5% slowing), including quantitative motor performance assessed by Q-Motor FT-IOI (77.8% slowing). Exploratory analyses including participants receiving concomitant ADMs showed similar directional patterns as the primary analyses. Conclusions In a two-year follow-up, continuous pridopidine treatment in participants remaining off-ADMs was associated with slower clinical progression relative to expected natural-history trajectories. (Clinical Trials Identifier: NCT04556656 )

BackgroundDigital‐motor outcomes promise better responsiveness than clinician‐reported outcomes in ataxia trials. However, their patient meaningfulness and sensitivity to change remain to be demonstrated, particularly in the upper limb domain.ObjectivesValidation of quantitative motor (Q‐Motor) assessment for upper limb ataxia against patient‐reported outcomes and regarding sensitivity to both longitudinal and treatment‐induced change, the latter in n‐of‐1 treatment settings.MethodsSingle‐center longitudinal assessment of finger tapping, diadochokinesia, grip‐lift, spiral drawing, and target reaching in (1) 36 cross‐genotype ataxia patients and 20 controls, validating digital measures for correlations with patient‐reported outcome measure (PROM)‐ataxia, 2‐weeks test–retest reliability, and sensitivity to change within a trial‐relevant 1‐year follow‐up, anchored in Patient Global Impression of Change (PGI‐C); and (2) two patients with spinocerebellar ataxia type 27B (SCA27B) on versus off treatment with 4‐aminopyridine.ResultsTwenty‐four digital measures correlated with the PROM‐ataxia upper‐limb composite (|ρ| = 0.4–0.7) and had excellent test–retest reliability (ICC = 0.91–0.99). Correlations to individual PROM‐ataxia items were specific for functional impairment the respective measure was hypothesized to capture. Speed of finger tapping and diadochokinesia, and smoothness of target reaching (spectral arc length of movement in three dimensions [SPARC3D]) captured 1‐year progression in ataxia patients (|rprb| = 0.38–0.51), and specifically in patients with worsening PGI‐C. Estimated sample sizes to detect longitudinal change were lower for digital than clinical outcomes (SPARC3D: n = 33, Scale for the Assessment and Rating of Ataxia (SARA): n = 79, nine‐hole peg‐test: n = 214). Speed of diadochokinesia, stability of grip‐lift, and variability of target reaching captured treatment responses to 4‐aminopyridine in SCA27B, exceeding minimal detectable and minimal important change.ConclusionDigital upper limb measures capture patient‐meaningful 1‐year longitudinal and treatment‐induced change, and are therefore promising outcomes for upcoming ataxia trials. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BackgroundQ-Motor measures lack rater-bias and revealed higher sensitivity and consistency than clinical scales in several trials, but little is known about the relationship of treatment responses between Q-Motor and clinical scales. Observational studies and clinical trials show correlation between longitudinal worsening in the objective measures of Q-Motor and worsening in clinical progression as assessed by cUHDRS, TFC, and TMS.ObjectiveTo assess correlations between the benefit of pridopidine in Q-Motor and measures of clinical progression, and to determine the predictive value of early benefits in Q-Motor towards later improvements in measures of clinical progression and function.MethodsIn PROOF-HD, the primary Q-Motor tapping endpoint ‘Inter-Onset-Interval’ (IOI) was analyzed in the ‘finger-tapping’ (digitomotography) and ‘pronate/supinate-hand-tapping’ (dysdiadochomotography) tasks. Correlations between changes in IOI and changes in cUHDRS and TFC at weeks 26, 52, 65 and 78 were calculated. A causal inference model adjusting for natural disease progression and baseline characteristics was applied to assess the relationship of these changes with pridopidine treatment. In addition, we assessed whether early changes to 26 weeks correlate with changes to later visits up to week 78.ResultsChanges in IOI and the cUHDRS were correlated at all visits in finger-tapping [r=-0.26–-0.41, p<0.0001] and pronate/supinate-tapping [r=-0.17–-0.30, p=0.0038–p<0.0001]. Early Q-Motor improvements at 26 weeks were correlated to benefits in cUHDRS at later visits, up to week 78 in finger-tapping [r=-0.17–-0.23, p=0.0048–p=0.00018] and pronate-supinate-tapping [r=-0.12–-0.19, p=0.036–r=0.0057]. The causal-interference-model confirmed these findings with significant relationships detected for treatment induced changes at all visits for both tasks [all p<0.0001]. The model suggests that every 10 msec benefit of pridopidine in finger-tapping is associated with an average of 0.1 less decline in cUHDRS (p<0.0001). Similar observations were seen with the TFC.ConclusionThe correlation of observed changes in Q-Motor measures and cUHDRS and TFC suggest an alignment of objective measures and clinical scales in the assessment of treatment effects in PROOF-HD up to week 78. Furthermore, Q-Motor effects at 26 weeks are highly predictive of changes in cUHDRS and TFC at later visits.

Current assessments of fatigue and sleepiness rely on patient reported outcomes (PROs), which are subjective and prone to recall bias. The current study investigated the use of gait variability in the "real world" to identify patient fatigue and daytime sleepiness. Inertial measurement units were worn on the lower backs of 159 participants (117 with six different immune and neurodegenerative disorders and 42 healthy controls) for up to 20 days, whom completed regular PROs. To address walking bouts that were short and sparse, four feature groups were considered: sequence-independent variability (SIV), sequence-dependant variability (SDV), padded SDV (PSDV), and typical gait variability (TGV) measures. These gait variability measures were extracted from step, stride, stance, and swing time, step length, and step velocity. These different approaches were compared using correlations and four machine learning classifiers to separate low/high fatigue and sleepiness.Most balanced accuracies were above 50%, the highest was 57.04% from TGV measures. The strongest correlation was 0.262 from an SDV feature against sleepiness. Overall, TGV measures had lower correlations and classification accuracies.Identifying fatigue or sleepiness from gait variability is extremely complex and requires more investigation with a larger data set, but these measures have shown performances that could contribute to a larger feature set.Clinical relevance- Gait variability has been repeatedly used to assess fatigue in the lab. The current study, however, explores gait variability for fatigue and daytime sleepiness in real-world scenarios with multiple gait-impacted disorders.

Background and ObjectiveWith its relevance for everyday function, upper-limb-coordination is an insufficiently explored domain for digital-motor-outcomes in ataxia. Leveraging the trial-ready quantitative-motor (Q-Motor) system, we developed and validated a comprehensive task battery to capture upper-limb-ataxia.MethodsCross-sectional single-center-study (46 patients with predominantly degenerative cross-genotype cerebellar-ataxias (mean-age: 50 years; mean-SARA: 12 points), and 48 age- and sex-matched controls. Q-Motor assessments with a force transducer and an electromagnetic position sensor comprised both existing bilateral-tasks particularly promising for ataxia (foot-tapping, finger-tapping, diadochokinesia, grip-lift) (47 parameters/side), and tasks newly designed to capture ataxia (multi-directional two-dimensional-target-pointing, spiral-drawing) with the dominant hand (450 parameters, including spatial, temporal, spatiotemporal, and texture measures).ResultsTarget hits per second (AUC: 0.97) and frequency of foot-tapping, finger-tapping or diadochokinesia (AUC: 0.91-0.94) were excellent discriminators between ataxia and controls. Target hits per second and finger-tapping-frequency correlated strongly with the SARA (Spearman rho: -0.87 and -0.81), and even specifically with the sum of its upper limb items (-0.85 and -0.72). For diadochokinesia, temporal variability showed the strongest correlation with SARA (0.71) and its upper-limb composite (0.67, all p<0.001). Parameters in upper-limb tasks had moderate to strong correlations with activities-of-daily-living-function (FARS ADL, |rho|: 0.5-0.6), and dexterity as assessed by the 9-hole peg-test (0.53-0.78, all p<0.001).Discussion and ConclusionSeverity of upper-limb ataxia can be captured by Q-Motor with physiologically interpretable and functionally relevant measures of a finger-tapping, diadochokinesia, and a novel two-dimensional target-pointing-task of interest also for HD. Longitudinal assessments are ongoing to explore their responsiveness to change in a clinical trial setting.

Pridopidine is a highly selective Sigma-1 receptor (S1R) agonist, being evaluated in the PROOF-HD Ph3 trial. Pooled safety data from 22 trials assessing pridopidine at doses 10-112.5 mg bid was analyzed, encompassing safety data from 1300 patients (~1300 patient-years of exposure, including long-term data >5 years); 1100/1300 (85%) HD patients, and 981/1300 (75%) treated with 45 mg bid, the dose assessed in PROOF-HD. Due to different placebo and pridopidine exposures, AE rate analyses, corrected for patient-years of exposure, were performed. The rate of common AEs was similar for placebo vs. 45 mg bid (rate=2.35 vs.1.82 events/patient years). Serious adverse events (SAEs) were reported in placebo and 45 mg bid groups (rate=0.07 and 0.18, respectively). Most SAEs were common for HD; 1 case of subdural hematoma was considered drug-related. Concentration-QTc analysis was performed using PK sampling and ECG monitoring data from 402 PRIDE-HD Ph2 trial participants, for 52 weeks. Pridopidine shows a concentration dependent effect on QTcF interval (slope=0.012 ms/ng/mL; 90% CI: 0.0109-0.0127). The, predicted QTc effect at 45 mg bid is 6.6 ms, with a two-sided 90% CI below 8 ms, that is of no regulatory concern (FDA considers QTc <10 ms low risk for Torsade de Pointes, TdP). Across the integrated safety database, the rate of AEs for QT prolongation was higher in placebo vs 45 mg bid (rate=0.013 vs. 0.005). No cases of TdP, and no increased risk for pro-arrhythmic events reported at the clinical dose. As of June 16th, 2022, PROOF-HD has low dropout (23/499, 4.6%) and discontinuation (19/499, 3.8%) rates. In February 2022, an independent safety monitoring committee reported no safety signals of concern, and recommended PROOF-HD continue as planned.

BackgroundEfficient cognitive tasks sensitive to longitudinal deterioration in small cohorts of Huntington’s disease (HD) patients are lacking in HD research. We thus developed and assessed the digitized arithmetic task (DAT), which combines inner language and executive functions in approximately 4 minutes.MethodsWe assessed the psychometric properties of DAT in three languages, across four European sites, in 77 early-stage HD patients (age: 52 ± 11 years; 27 females), and 57 controls (age: 50 ± 10, 31 females). Forty-eight HD patients and 34 controls were followed up to one year with 96 participants who underwent MRI brain imaging (HD patients = 46) at baseline and 50 participants (HD patients = 22) at one year. Linear mixed models and Pearson correlations were used to assess associations with clinical assessment.ResultsAt baseline, HD patients were less accurate (p = 0.0002) with increased response time (p<0.0001) when compared to DAT in controls. Test-retest reliability in HD patients ranged from good to excellent for response time (range: 0.63–0.79) and from questionable to acceptable for accuracy (range: r = 0.52–0.69). Only DAT, the Mattis Dementia Rating Scale, the Symbol Digit Modalities Test, and Total Functional Capacity scores were able to detect a decline within a one-year follow-up in HD patients (all p< 0.05). In contrast with all the other cognitive tasks, DAT correlated with striatal atrophy over time (p = 0.037) but not with motor impairment.ConclusionsDAT is fast, reliable, motor-free, applicable in several languages, and able to unmask cognitive decline correlated with striatal atrophy in small cohorts of HD patients. This likely makes it a useful endpoint in future trials for HD and other neurodegenerative diseases.

Non-invasive methods, such as neurofeedback training, could support cognitive symptom management in Huntington’s disease by targeting brain regions whose function is impaired. The aim of our single-blind, sham-controlled study was to collect rigorous evidence regarding the feasibility of neurofeedback training in Huntington’s disease by examining two different methods, activity and connectivity real-time functional MRI neurofeedback training. Thirty-two Huntington’s disease gene-carriers completed 16 runs of neurofeedback training, using an optimized real-time functional MRI protocol. Participants were randomized into four groups, two treatment groups, one receiving neurofeedback derived from the activity of the supplementary motor area, and another receiving neurofeedback based on the correlation of supplementary motor area and left striatum activity (connectivity neurofeedback training), and two sham control groups, matched to each of the treatment groups. We examined differences between the groups during neurofeedback training sessions and after training at follow-up sessions. Transfer of training was measured by measuring the participants’ ability to upregulate neurofeedback training target levels without feedback (near transfer), as well as by examining change in objective, a priori defined, behavioural measures of cognitive and psychomotor function (far transfer) before and at 2 months after training. We found that the treatment group had significantly higher neurofeedback training target levels during the training sessions compared to the control group. However, we did not find robust evidence of better transfer in the treatment group compared to controls, or a difference between the two neurofeedback training methods. We also did not find evidence in support of a relationship between change in cognitive and psychomotor function and learning success. We conclude that although there is evidence that neurofeedback training can be used to guide participants to regulate the activity and connectivity of specific regions in the brain, evidence regarding transfer of learning and clinical benefit was not robust.