Physical activity and exercise outcomes in Huntington's disease (PACE-HD): results of a 12-month trial-within-cohort feasibility study of a physical activity intervention in people with Huntington's disease

Introduction While physical activity (PA) is recognized as important in Huntington's disease (HD) disease management, there has been no long-term evaluation undertaken. We aimed to evaluate the feasibility of a nested (within cohort) randomized controlled trial (RCT) of a physical therapist-led PA intervention. Methods Participants were recruited from six HD specialist centers participating in the Enroll-HD cohort study in Germany, Spain and U.S. Assessments were completed at baseline and 12 months and linked to Enroll-HD cohort data. Participants at three sites (cohort) received no contact between baseline and 12 month assessments. Participants at three additional sites (RCT) were randomized to PA intervention or control group. The intervention consisted of 18 sessions delivered over 12 months; control group participants received no intervention, however both groups completed monthly exercise/falls diaries and 6-month assessments. Results 274 participants were screened, 204 met inclusion criteria and 116 were enrolled (59 in cohort; 57 in RCT). Retention rates at 12-months were 84.7% (cohort) and 79.0% (RCT). Data completeness at baseline ranged from 42.3 to 100% and at 12-months 19.2–85.2%. In the RCT, there was 80.5% adherence, high intervention fidelity, and similar adverse events between groups. There were differences in fitness, walking endurance and self-reported PA at 12 months favoring the intervention group, with data completeness >60%. Participants in the cohort had motor and functional decline at rates comparable to previous studies. Conclusion Predefined progression criteria indicating feasibility were met. PACE-HD lays the groundwork for a future, fully-powered within cohort trial, but approaches to ensure data completeness must be considered

New hyperekplexia mutations provide insight into glycine receptor assembly, trafficking, and activation mechanisms

Background: Hyperekplexia mutations have provided much information about glycine receptor structure and function. Results: Weidentified and characterized nine new mutations. Dominant mutations resulted in spontaneous activation, whereas recessive mutations precluded surface expression. Conclusion: These data provide insight into glycine receptor activation mechanisms and surface expression determinants. Significance: The results enhance our understanding of hyperekplexia pathology and glycine receptor structure-function. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A

Considerations for clinical trial design and conduct in the evaluation of novel advanced therapeutics in neurodegenerative disease

The recent advances in the development of potentially disease modifying cell and gene therapies for neurodegenerative disease has resulted in the production of a number of promising novel therapies which are now moving forward to clinical evaluation. The robust evaluation of these therapies pose a significant number of challenges when compared to more traditional evaluations of pharmacotherapy, which is the current mainstay of neurodegenerative disease symptom management. Indeed, there is an inherent complexity in the design and conduct of these trials at multiple levels. Here we discuss specific aspects requiring consideration in the context of investigating novel cell and gene therapies for neurodegenerative disease. This extends to overarching trial designs that could be employed and the factors that underpin design choices such outcome assessments, participant selection and methods for delivery of cell and gene therapies. We explore methods of data collection that may improve efficiency in trials of cell and gene therapy to maximize data sharing and collaboration. Lastly, we explore some of the additional context beyond efficacy evaluations that should be considered to ensure implementation across relevant healthcare settings

F21 Co-design of a lifestyle intervention to improve quality of life in Huntington's disease

Background Healthy lifestyle behaviours are important in reducing the impact of Huntington’s Disease (HD). However, evidence to date is limited to singular lifestyle domains. The DOMINO-HD project is focussed on understanding the interplay between lifestyle factors in HD through the conduct of a longitudinal observational study in 100 people with HD. Aim The next project stage centres on the development of a personalised, data driven, lifestyle intervention that can be used to improve quality of life and reduce disease burden in people with HD. Firstly, we need to understand fundamental aspects governing intervention development in terms of content, delivery, training and measurement. Methods We will conduct a scoping review to identify physical activity, diet and sleep interventions typically implemented in HD populations. A conceptual synthesis along with a list of statements (for each individual lifestyle domain and any combined domains) describing common intervention components, related outcomes and research design and implementation approaches will be produced. A range of stakeholders (patients, family members and allied health professionals) will be invited to participate in a modified eDelphi process to establish consensus best practice in facilitating feasible lifestyle interventions in HD. Stakeholders will be asked to rank importance of the statements established from the scoping review with due consideration of the emerging DOMINO HD data. A final series of focus groups will be conducted to support the mapping of a lifestyle intervention based on the eDelphi results

F62 Validation of digital assessment of physical activity in Huntington’s disease: comparing fitbit charge 4 step count with research-grade accelerometers

Background Physical activity has been implicated in improving symptom management and quality of life in Huntington’s disease (HD). Verifying the role of physical activity in HD requires accurate quantification of exercise metrics. Aim To assess the reliability and validity of Fitbit® Charge 4 step-count compared to research accelerometers and observer count in HD patients. Methods 17 manifest HD participants completed two indoor 2-minute walking tests (2MWT) while wearing a Fitbit® charge 4, and an ActiGraph GTX9 on their non-dominant wrist, ActivPAL4™ on both anterior thighs, and ActiGraph GTX9 on both anterior shanks. Steps were manually counted from video recordings of the 2MWTs. Step-counts for devices were obtained from their proprietary software. Intraclass correlation coefficients (ICC) determined Fitbit and observer reliability, whilst Bland-Altman (B-A) analysis demonstrated monitor agreement. Results Intra-rater reliability of researcher count from repeat trials was excellent (ICC 0.95/n = 17) meanwhile, Fitbit yielded good reliability (ICC 0.81/n = 16). B-A plots displayed greatest agreement between Fitbit and manual count (bias -4.7/SD 36.2). Average monitor count revealed largest consistencies with ActivPAL4 and Fitbit (bias -3.4/SD 37.4) whereas, wrist-worn ActiGraph deviated markedly (bias 4.9/SD 66.9). Motor symptom severity did not influence average Fitbit count although, upper extremity devices occasionally underestimated steps produced. Conclusions Whilst superior step-count accuracy was seen with devices placed on lower limbs, these data show that Fitbit charge 4 may be a reliable device for monitoring steps in manifest HD

HD-DRUM – a novel computerised drumming training for movement and cognitive abilities in people with Huntington’s disease – app development and protocol of a randomised controlled feasibility study

Background Huntington’s Disease (HD) causes cell loss in the basal ganglia (BG) that are important for cognitive and motor functions. Learning novel drumming sequences requires BG abilities of attention, multi-tasking, and the planning and execution of motor sequences, all of which are affected in HD. Previously, we observed that rhythmic Bongo drumming improved attention and motor abilities and strengthened callosal white matter pathways in people with HD. Aims To assess the feasibility of HD-DRUM, a novel computerised drumming training app that optimises the training difficulty for each user with an automatic stair-case procedure. To obtain estimates of effects of HD-DRUM on cognitive and motor abilities and on white and grey matter microstructure in motor and executive networks of the brain. Methods We will assess the feasibility (recruitment, retention, acceptability, adherence) of three months of HD-DRUM (15 min per day, 5 days a week) in 50 people with HD at premanifest to mild-moderate manifest stages recruited from five clinics in the UK. They will be randomly allocated to the training or a standard-care control group. Further, 25 healthy control participants will be recruited who will also use HD-DRUM. All participants will undergo cognitive and motor assessment (ENROLL protocol) and magnetic resonance imaging of the brain with diffusion-weighted and quantitative magnetization transfer imaging at the beginning and the end of the study. Anticipated Outcomes If feasible, HD-DRUM may provide a remotely accessible training tool to help improve motor and cognitive symptoms in HD without the risk of harmful side-effects in the future

Chronic treatment with 13-cis-retinoic acid changes aggressive behaviours in the resident–intruder paradigm in rats

Retinoids, vitamin A related compounds, have an established role in the development of the nervous system and are increasingly recognized to play a role in adult brain function. The synthetic retinoid, 13-cis-retinoic acid (13-cis-RA, Roaccutane) is widely used to treat severe acne but has been linked to an increased risk of neuropsychiatric side effects, including depression. Here we report that chronic administration with 13-cis-RA (1 mg/kg i.p. daily, 7–14 days) in adult rats reduced aggression- and increased flight-related behaviours in the resident–intruder paradigm. However, in the forced swim, sucrose consumption and open field tests treatment for up to 6 weeks with 13-cis-RA did not modify behaviour in adult or juvenile animals. The behavioural change observed in the resident–intruder paradigm is directly opposite to that observed with chronic antidepressant administration. These findings indicate that when a suitably sensitive behavioural test is employed then chronic administration of 13-cis-RA in adult rats induces behavioural changes consistent with a pro-depressant action