Assessing the efficacy of cell transplantation for Parkinson's Disease: a patient-centered approach

Background: Evidence from a growing number of preclinical studies indicate that recently discovered stem cell lines may be translated into viable cellular therapies for people with Parkinson’s disease. Objectives: In a brief but critical review, we examine the use of primary and secondary outcome measures currently used to evaluate the efficacy of cellular therapies. Methods: The current practice of relying on a single primary outcome measure does not appear to provide the evidence required for demonstrating the robust, life-changing recovery anticipated with the successful implementation of cellular therapies. Results: We propose a 360-degree assessment protocol, which includes co-primary and composite outcome measures to provide accurate and comprehensive evidence of treatment efficacy, from the perspectives of both the researchers and the patients

Rethinking functional outcome measures: the development of an upper limb test to assess basal ganglia dysfunction

The basal ganglia is implicated in a wide range of motor, cognitive and behavioural activities required for normal function. This region is predominantly affected in Huntington’s disease (HD), meaning that functional ability progressively worsens. However, functional outcome measures for HD, particularly those for the upper limb, are limited meaning there is an imperative for well-defined, quantitative measures. Here we describe the development and evaluation of the Moneybox test (MBT). This novel, functional upper limb assessment was developed in accordance with translational neuroscience and physiological principles for people with a broad disease manifestation, such as HD. Participants with HD (n=64) and healthy controls (n=21) performed the MBT, which required subjects to transfer tokens into a container in order of size (Baseline Transfer), value (Complex Transfer) with and without reciting the alphabet (Dual Transfer). Disease specific measures of motor, cognition, behaviour and function were collected. HD patients were grouped into disease stage, from which, discriminative and convergent validity was assessed using Analysis of Variance and Pearson’s correlation respectively. Manifest HD participants were slower than pre-manifest and control participants, and achieved significantly lower MBT total scores. Performance in the Complex Transfer and Dual Transfer tasks were significantly different between pre-manifest and stage 1 HD. All MBT performance variables significantly correlated with routinely used measures of motor, cognition, behaviour and function. The MBT provides a valid, sensitive and affordable functional outcome measure. Unlike current assessments, MBT performance significantly distinguished the subtle differences between the earliest disease stages of HD, which are the populations typically targeted in clinical trials

Motor-cognitive dual-task deficits in individuals with early-mid stage Huntington's disease

Background. Huntington’s disease (HD) results in a range of cognitive and motor impairments that progress throughout the disease stages; however, little research has evaluated specific dual-task abilities in this population, and the degree to which they may be related to functional ability. Objectives. The purpose of this study was to a) examine simple and complex motor-cognitive dual-task performance in individuals with HD, b) determine relationships between dual-task walking ability and disease-specific measures of motor, cognitive and functional ability, and c) examine the relationship of dual-task measures to falls in individuals with HD. Methods. Thirty-two individuals with Huntington’s disease were evaluated for simple and complex dual-task ability using the Walking While Talking Test. Demographics and disease-specific measures of motor, cognitive and functional ability were also obtained. Results. Individuals with HD had impairments in simple and complex dual-task ability. Simple dual-task walking was correlated to disease-specific motor scores as well as cognitive performance, but complex dual-task walking was correlated with total functional capacity, as well as a range of cognitive measures. Number of prospective falls was strongly correlated to dual-task measures. Conclusions. Our results suggest that individuals with HD have impairments in cognitive-motor dual-task ability that are related to disease progression and specifically functional ability. Dual-task measures appear to evaluate a unique construct in individuals with early to mid-stage HD, and may have value in improving the prediction of falls risk in this population

Functional magnetic resonance imaging neurofeedback-guided motor imagery training and motor training for Parkinson's Disease: randomized trial

Objective: Real-time functional magnetic resonance imaging (rt-fMRI) neurofeedback (NF) uses feedback of the patient’s own brain activity to self-regulate brain networks which in turn could lead to a change in behavior and clinical symptoms. The objective was to determine the effect of NF and motor training (MOT) alone on motor and non-motor functions in Parkinson’s Disease (PD) in a 10-week small Phase I randomized controlled trial. Methods: Thirty patients with Parkinson’s disease (PD; Hoehn and Yahr I-III) and no significant comorbidity took part in the trial with random allocation to two groups. Group 1 (NF: 15 patients) received rt-fMRI-NF with MOT. Group 2 (MOT: 15 patients) received MOT alone. The primary outcome measure was the Movement Disorder Society—Unified PD Rating Scale-Motor scale (MDS-UPDRS-MS), administered pre- and post-intervention “off-medication”. The secondary outcome measures were the “on-medication” MDS-UPDRS, the PD Questionnaire-39, and quantitative motor assessments after 4 and 10 weeks. Results: Patients in the NF group were able to upregulate activity in the supplementary motor area (SMA) by using motor imagery. They improved by an average of 4.5 points on the MDS-UPDRS-MS in the “off-medication” state (95% confidence interval: −2.5 to −6.6), whereas the MOT group improved only by 1.9 points (95% confidence interval +3.2 to −6.8). The improvement in the intervention group meets the minimal clinically important difference which is also on par with other non-invasive therapies such as repetitive Transcranial Magnetic Stimulation (rTMS). However, the improvement did not differ significantly between the groups. No adverse events were reported in either group. Interpretation: This Phase I study suggests that NF combined with MOT is safe and improves motor symptoms immediately after treatment, but larger trials are needed to explore its superiority over active control conditions

Functional Magnetic Resonance Imaging Neurofeedback-guided Motor Imagery Training and Motor Training for Parkinson’s Disease: Randomized Trial

Objective: Real-time functional magnetic resonance imaging (rt-fMRI) neurofeedback (NF) uses feedback of the patient’s own brain activity to self-regulate brain networks which in turn could lead to a change in behaviour and clinical symptoms. The objective was to determine the effect of neurofeedback and motor training and motor training (MOT) alone on motor and non-motor functions in Parkinson’s disease (PD) in a 10-week small Phase I randomised controlled trial. Methods: 30 patients with PD (Hoehn & Yahr I-III) and no significant comorbidity took part in the trial with random allocation to two groups. Group 1 (NF: 15 patients) received rt-fMRI-NF with motor training. Group 2 (MOT: 15 patients) received motor training alone. The primary outcome measure was the Movement Disorder Society – Unified Parkinson’s Disease Rating Scale-Motor scale (MDS-UPDRS-MS), administered pre- and post-intervention ‘off-medication’. The secondary outcome measures were the ‘on-medication’ MDS-UPDRS, the Parkinson’s disease Questionnaire-39, and quantitative motor assessments after 4 and 10 weeks. Results: Patients in the NF group were able to upregulate activity in the supplementary motor area by using motor imagery. They improved by an average of 4.5 points on the MDS-UPDRS-MS in the ‘off-medication’ state (95% confidence interval: -2.5 to -6.6), whereas the MOT group improved only by 1.9 points (95% confidence interval +3.2 to -6.8). However, the improvement did not differ significantly between the groups. No adverse events were reported in either group. Interpretation: This Phase I study suggests that NF combined with motor training is safe and improves motor symptoms immediately after treatment, but larger trials are needed to explore its superiority over active control conditions. Clinical Trial website : Unique Identifier: NCT01867827 URL: https://clinicaltrials.gov/ct2/show/NCT01867827?term=NCT01867827&rank=

Applying an integrated knowledge translation framework approach to develop a tablet-based rhythmic movement training intervention for people with Huntington’s disease

Background: Huntington’s Disease (HD) is an incurable neurodegenerative disease that leads to the progressive loss of cognitive and motor functions and mood disturbances, largely due to basal ganglia atrophy. Currently, there are no therapeutic interventions tailored to address cognitive and motor impairment in people with HD. Using an integrated knowledge translation (IKT) framework we developed the HD-DRUM intervention, a tablet-based rhythmic movement training application, with the aim to stimulate basal ganglia reliant cognitive and motor abilities in people with HD. Objective: The primary aim was to develop the HD-DRUM intervention for people with HD. Here we describe the IKT-based process, involving knowledge user engagement, co-design, and iterative usability testing for design refinement. Methods: The IKT framework was applied to iteratively refine the design of the HD-DRUM application. This process involved three phases of knowledge user engagement and co-design including an online survey into the use of digital technologies and usability testing for design refinement in people with HD. The developed HD-DRUM intervention was described according to the template for intervention description and replication (TIDieR) checklist. Results: Barriers and facilitators of using digital technologies were identified. Tablets with touch screens were identified as a feasible and accessible platform to deliver the application. Key elements to ensure that the application design and build met the needs of people with HD were identified. The developed tablet-based HD-DRUM intervention can be used at home and allows the quantification of performance changes, remote monitoring of adherence, matching of training difficulty to users’ performance levels using gamification, and future scaling-up for reaching a wide range of interested users. Conclusions: Applying iterative usability testing within the IKT framework allowed the refinement of the design and build of a novel tablet-based intervention to target cognitive and motor functions in people with HD. Mapping the intervention against the TIDieR framework for describing complex interventions, allowed the detailed description of the HD-DRUM intervention and identification of areas that required refinement prior to finalising the intervention protocol

Protocol for a randomised controlled feasibility trial of HD-DRUM, a rhythmic movement training application for cognitive and motor symptoms in people with Huntington?s disease.

Introduction Huntington’s disease (HD) is an inherited neurodegenerative disease causing progressive cognitive and motor decline, largely due to basal ganglia (BG) atrophy. Rhythmic training offers promise as therapy to counteract BG-regulated deficits. We have developed HD-DRUM, a tablet-based app to enhance movement synchronization skills and improve cognitive and motor abilities in people with HD. This paper outlines a randomised controlled trial protocol to determine the feasibility of a larger effectiveness trial for HD-DRUM. Additionally, the trial investigates cognitive and motor function measures, along with brain microstructure, aiming to advance our understanding of the neural mechanisms underlying training effects. Methods, Design & Analysis Fifty individuals with HD, confirmed by genetic testing, and a Total Functional Capacity (TFC) score of 9-13, will be recruited into a two-arm randomised controlled feasibility trial. Consenting individuals with HD will be randomised to the intervention group, which entails eight weeks of at-home usage of HD-DRUM, or a usual- activity control group. All participants will undergo cognitive and motor assessments, alongside ultra-strong gradient (300mT/m) brain microstructural magnetic resonance imaging (MRI) before and after the eight-week period. The feasibility assessment will encompass recruitment, retention, adherence, and acceptability of HD-DRUM following pre- specified criteria. The study will also evaluate variations in cognitive and motor performance and brain microstructure changes resulting from the intervention to determine effect size estimates for future sample size calculations

Cell therapy for Huntington's disease: learning from failure

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