An automatic gait analysis pipeline for wearable sensors: a pilot study in Parkinson’s disease

The use of wearable sensors allows continuous recordings of physical activity from participants in free-living or at-home clinical studies. The large amount of data collected demands automatic analysis pipelines to extract gait parameters that can be used as clinical endpoints. We introduce a deep learning-based automatic pipeline for wearables that processes tri-axial accelerometry data and extracts gait events—bout segmentation, initial contact (IC), and final contact (FC)—from a single sensor located at either the lower back (near L5), shin or wrist. The gait events detected are posteriorly used for gait parameter estimation, such as step time, length, and symmetry. We report results from a leave-one-subject-out (LOSO) validation on a pilot study dataset of five participants clinically diagnosed with Parkinson’s disease (PD) and six healthy controls (HC). Participants wore sensors at three body locations and walked on a pressure-sensing walkway to obtain reference gait data. Mean absolute errors (MAE) for the IC events ranged from 22.82 to 33.09 milliseconds (msecs) for the lower back sensor while for the shin and wrist sensors, MAE ranges were 28.56–64.66 and 40.19–72.50 msecs, respectively. For the FC-event detection, MAE ranges were 29.06–48.42, 40.19–72.70 and 36.06–60.18 msecs for the lumbar, wrist and shin sensors, respectively. Intraclass correlation coefficients, ICC(2,k), between the estimated parameters and the reference data resulted in good-to-excellent agreement (ICC ≥ 0.84) for the lumbar and shin sensors, excluding the double support time (ICC = 0.37 lumbar and 0.38 shin) and swing time (ICC = 0.55 lumbar and 0.59 shin). The wrist sensor also showed good agreements, but the ICCs were lower overall than for the other two sensors. Our proposed analysis pipeline has the potential to extract up to 100 gait-related parameters, and we expect our contribution will further support developments in the fields of wearable sensors, digital health, and remote monitoring in clinical trials

Evaluation of Simvastatin as a Disease-Modifying Treatment for Patients With Parkinson Disease: A Randomized Clinical Trial

\ua9 2022 American Medical Association. All rights reserved.Importance: Current treatments manage symptoms of Parkinson disease (PD), but no known treatment slows disease progression. Preclinical and epidemiological studies support the potential use of statins as disease-modifying therapy. Objective: To determine whether simvastatin has potential as a disease-modifying treatment for patients with moderate PD. Design, Setting, and Participants: This randomized clinical trial, a double-blind, parallel-group, placebo-controlled futility trial, was conducted between March 2016 and May 2020 within 23 National Health Service Trusts in England. Participants aged 40 to 90 years with a diagnosis of idiopathic PD, with a modified Hoehn and Yahr stage of 3.0 or less while taking medication, and taking dopaminergic medication with wearing-off phenomenon were included. Data were analyzed from May 2020 to September 2020, with additional analysis in February 2021. Interventions: Participants were allocated 1:1 to simvastatin or matched placebo via a computer-generated random sequence, stratified by site and Hoehn and Yahr stage. In the simvastatin arm, participants entered a 1-month phase of simvastatin, 40 mg daily, followed by 23 months of simvastatin, 80 mg daily, before a 2-month washout period. Main Outcomes and Measures: The prespecified primary outcome was 24-month change in Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) part III score measured while not taking medication (high scores indicate worse outcome). The primary futility analysis included participants who commenced the 80-mg phase and had valid primary outcome data. The safety analysis included all participants who commenced trial treatment and is reported by dose at time of event. Results: Of 332 patients assessed for eligibility, 32 declined and 65 were ineligible. Of 235 recruited participants, 97 (41%) were female, 233 (99%) were White, and the mean (SD) age was 65.4 (9.4) years. A total of 216 patients progressed to the 80-mg dose. Primary outcome analysis (n = 178) indicated the simvastatin group had an additional deterioration in MDS-UPDRS III score while not taking medication at 24 months compared with the placebo group (1.52 points; 2-sided 80% CI, -0.77 to 3.80; 1-sided futility test P =.006). A total of 37 serious adverse events (AEs), including 3 deaths, and 171 AEs were reported for participants receiving 0-mg simvastatin; 37 serious AEs and 150 AEs were reported for participants taking 40 mg or 80 mg of simvastatin. Four participants withdrew from the trial because of an AE. Conclusions and Relevance: In this randomized clinical trial, simvastatin was futile as a disease-modifying therapy in patients with PD of moderate severity, providing no evidence to support proceeding to a phase 3 trial. Trial Registration: ISRCTN Identifier: 16108482

Rivastigmine for gait stability in patients with Parkinson's disease (ReSPonD): a randomised, double-blind, placebo-controlled, phase 2 trial

Background Falls are a frequent and serious complication of Parkinson's disease and are related partly to an underlying cholinergic deficit that contributes to gait and cognitive dysfunction in these patients. Gait dysfunction can lead to an increased variability of gait from one step to another, raising the likelihood of falls. In the ReSPonD trial we aimed to assess whether ameliorating this cholinergic deficit with the acetylcholinesterase inhibitor rivastigmine would reduce gait variability. Methods We did this randomised, double-blind, placebo-controlled, phase 2 trial at the North Bristol NHS Trust Hospital, Bristol, UK, in patients with Parkinson's disease recruited from community and hospital settings in the UK. We included patients who had fallen at least once in the year before enrolment, were able to walk 18 m without an aid, had no previous exposure to an acetylcholinesterase inhibitor, and did not have dementia. Our clinical trials unit randomly assigned (1:1) patients to oral rivastigmine or placebo capsules (both taken twice a day) using a computer-generated randomisation sequence and web-based allocation. Rivastigmine was uptitrated from 3 mg per day to the target dose of 12 mg per day over 12 weeks. Both the trial team and patients were masked to treatment allocation. Masking was achieved with matched placebo capsules and a dummy uptitration schedule. The primary endpoint was difference in step time variability between the two groups at 32 weeks, adjusted for baseline age, cognition, step time variability, and number of falls in the previous year. We measured step time variability with a triaxial accelerometer during an 18 m walking task in three conditions: normal walking, simple dual task with phonemic verbal fluency (walking while naming words beginning with a single letter), and complex dual task switching with phonemic verbal fluency (walking while naming words, alternating between two letters of the alphabet). Analysis was by modified intention to treat; we excluded from the primary analysis patients who withdrew, died, or did not attend the 32 week assessment. This trial is registered with ISRCTN, number 19880883. Findings Between Oct 4, 2012 and March 28, 2013, we enrolled 130 patients and randomly assigned 65 to the rivastigmine group and 65 to the placebo group. At week 32, compared with patients assigned to placebo (59 assessed), those assigned to rivastigmine (55 assessed) had improved step time variability for normal walking (ratio of geometric means 0·72, 95% CI 0·58–0·88; p=0·002) and the simple dual task (0·79; 0·62–0·99; p=0·045). Improvements in step time variability for the complex dual task did not differ between groups (0·81, 0·60–1·09; p=0·17). Gastrointestinal side-effects were more common in the rivastigmine group than in the placebo group (p<0·0001); 20 (31%) patients in the rivastigmine group versus three (5%) in the placebo group had nausea and 15 (17%) versus three (5%) had vomiting

Evaluation of Simvastatin as a Disease-Modifying Treatment for Patients With Parkinson Disease: A Randomized Clinical Trial.

Importance: Current treatments manage symptoms of Parkinson disease (PD), but no known treatment slows disease progression. Preclinical and epidemiological studies support the potential use of statins as disease-modifying therapy. Objective: To determine whether simvastatin has potential as a disease-modifying treatment for patients with moderate PD. Design, Setting, and Participants: This randomized clinical trial, a double-blind, parallel-group, placebo-controlled futility trial, was conducted between March 2016 and May 2020 within 23 National Health Service Trusts in England. Participants aged 40 to 90 years with a diagnosis of idiopathic PD, with a modified Hoehn and Yahr stage of 3.0 or less while taking medication, and taking dopaminergic medication with wearing-off phenomenon were included. Data were analyzed from May 2020 to September 2020, with additional analysis in February 2021. Interventions: Participants were allocated 1:1 to simvastatin or matched placebo via a computer-generated random sequence, stratified by site and Hoehn and Yahr stage. In the simvastatin arm, participants entered a 1-month phase of simvastatin, 40 mg daily, followed by 23 months of simvastatin, 80 mg daily, before a 2-month washout period. Main Outcomes and Measures: The prespecified primary outcome was 24-month change in Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) part III score measured while not taking medication (high scores indicate worse outcome). The primary futility analysis included participants who commenced the 80-mg phase and had valid primary outcome data. The safety analysis included all participants who commenced trial treatment and is reported by dose at time of event. Results: Of 332 patients assessed for eligibility, 32 declined and 65 were ineligible. Of 235 recruited participants, 97 (41%) were female, 233 (99%) were White, and the mean (SD) age was 65.4 (9.4) years. A total of 216 patients progressed to the 80-mg dose. Primary outcome analysis (n = 178) indicated the simvastatin group had an additional deterioration in MDS-UPDRS III score while not taking medication at 24 months compared with the placebo group (1.52 points; 2-sided 80% CI, -0.77 to 3.80; 1-sided futility test P = .006). A total of 37 serious adverse events (AEs), including 3 deaths, and 171 AEs were reported for participants receiving 0-mg simvastatin; 37 serious AEs and 150 AEs were reported for participants taking 40 mg or 80 mg of simvastatin. Four participants withdrew from the trial because of an AE. Conclusions and Relevance: In this randomized clinical trial, simvastatin was futile as a disease-modifying therapy in patients with PD of moderate severity, providing no evidence to support proceeding to a phase 3 trial. Trial Registration: ISRCTN Identifier: 16108482

Evaluation of Simvastatin as a Disease-Modifying Treatment for Patients With Parkinson Disease: A Randomized Clinical Trial

This is the final version. Available on open access from the American Medical Association via the DOI in this recordData Sharing Statement Stevens. Evaluation of Simvastatin as a Neuroprotective Treatment for Patients With Parkinson Disease. JAMA Neurol. Published October 31, 2022. doi:10.1001/jamaneurol.2022.3718 Data Data available: Yes Data types: Deidentified participant data How to access data: By request to the data custodian/sponsor representative ([email protected] ). When available: With publication Supporting Documents Document types: None Additional Information Who can access the data: Researchers undertaking ethically approved purposes and on execution of a valid data sharing agreement. Types of analyses: Specified ethically approved purpose. Mechanisms of data availability: With a signed valid data sharing agreement.mportance Current treatments manage symptoms of Parkinson disease (PD), but no known treatment slows disease progression. Preclinical and epidemiological studies support the potential use of statins as disease-modifying therapy. Objective To determine whether simvastatin has potential as a disease-modifying treatment for patients with moderate PD. Design, Setting, and Participants This randomized clinical trial, a double-blind, parallel-group, placebo-controlled futility trial, was conducted between March 2016 and May 2020 within 23 National Health Service Trusts in England. Participants aged 40 to 90 years with a diagnosis of idiopathic PD, with a modified Hoehn and Yahr stage of 3.0 or less while taking medication, and taking dopaminergic medication with wearing-off phenomenon were included. Data were analyzed from May 2020 to September 2020, with additional analysis in February 2021. Interventions Participants were allocated 1:1 to simvastatin or matched placebo via a computer-generated random sequence, stratified by site and Hoehn and Yahr stage. In the simvastatin arm, participants entered a 1-month phase of simvastatin, 40 mg daily, followed by 23 months of simvastatin, 80 mg daily, before a 2-month washout period. Main Outcomes and Measures The prespecified primary outcome was 24-month change in Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) part III score measured while not taking medication (high scores indicate worse outcome). The primary futility analysis included participants who commenced the 80-mg phase and had valid primary outcome data. The safety analysis included all participants who commenced trial treatment and is reported by dose at time of event. Results Of 332 patients assessed for eligibility, 32 declined and 65 were ineligible. Of 235 recruited participants, 97 (41%) were female, 233 (99%) were White, and the mean (SD) age was 65.4 (9.4) years. A total of 216 patients progressed to the 80-mg dose. Primary outcome analysis (n = 178) indicated the simvastatin group had an additional deterioration in MDS-UPDRS III score while not taking medication at 24 months compared with the placebo group (1.52 points; 2-sided 80% CI, −0.77 to 3.80; 1-sided futility test P = .006). A total of 37 serious adverse events (AEs), including 3 deaths, and 171 AEs were reported for participants receiving 0-mg simvastatin; 37 serious AEs and 150 AEs were reported for participants taking 40 mg or 80 mg of simvastatin. Four participants withdrew from the trial because of an AE. Conclusions and Relevance In this randomized clinical trial, simvastatin was futile as a disease-modifying therapy in patients with PD of moderate severity, providing no evidence to support proceeding to a phase 3 trial. Trial Registration ISRCTN Identifier: 16108482JP Moulton Charitable FoundationCure Parkinson’s Trus

Towards a multi-arm multi-stage platform trial of disease modifying approaches in Parkinson’s disease

\ua9 The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.An increase in the efficiency of clinical trial conduct has been successfully demonstrated in the oncology field, by the use of multi-arm, multi-stage trials allowing the evaluation of multiple therapeutic candidates simultaneously, and seamless recruitment to phase 3 for those candidates passing an interim signal of efficacy. Replicating this complex innovative trial design in diseases such as Parkinson’s disease is appealing, but in addition to the challenges associated with any trial assessing a single potentially disease modifying intervention in Parkinson’s disease, a multiarm platform trial must also specifically consider the heterogeneous nature of the disease, alongside the desire to potentially test multiple treatments with different mechanisms of action. In a multi-arm trial, there is a need to appropriately stratify treatment arms to ensure each are comparable with a shared placebo/standard of care arm; however, in Parkinson’s disease there may be a preference to enrich an arm with a subgroup of patients that may be most likely to respond to a specific treatment approach. The solution to this conundrum lies in having clearly defined criteria for inclusion in each treatment arm as well as an analysis plan that takes account of predefined subgroups of interest, alongside evaluating the impact of each treatment on the broader population of Parkinson’s disease patients. Beyond this, there must be robust processes of treatment selection, and consensus derived measures to confirm target engagement and interim assessments of efficacy, as well as consideration of the infrastructure needed to support recruitment, and the long-term funding and sustainability of the platform. This has to incorporate the diverse priorities of clinicians, triallists, regulatory authorities and above all the views of people with Parkinson’s disease

Comprehensive in vivo Mapping of the Human Basal Ganglia and Thalamic Connectome in Individuals Using 7T MRI

Basal ganglia circuits are affected in neurological disorders such as Parkinson's disease (PD), essential tremor, dystonia and Tourette syndrome. Understanding the structural and functional connectivity of these circuits is critical for elucidating the mechanisms of the movement and neuropsychiatric disorders, and is vital for developing new therapeutic strategies such as deep brain stimulation (DBS). Knowledge about the connectivity of the human basal ganglia and thalamus has rapidly evolved over recent years through non-invasive imaging techniques, but has remained incomplete because of insufficient resolution and sensitivity of these techniques. Here, we present an imaging and computational protocol designed to generate a comprehensive in vivo and subject-specific, three-dimensional model of the structure and connections of the human basal ganglia. High-resolution structural and functional magnetic resonance images were acquired with a 7-Tesla magnet. Capitalizing on the enhanced signal-to-noise ratio (SNR) and enriched contrast obtained at high-field MRI, detailed structural and connectivity representations of the human basal ganglia and thalamus were achieved. This unique combination of multiple imaging modalities enabled the in-vivo visualization of the individual human basal ganglia and thalamic nuclei, the reconstruction of seven white-matter pathways and their connectivity probability that, to date, have only been reported in animal studies, histologically, or group-averaged MRI population studies. Also described are subject-specific parcellations of the basal ganglia and thalamus into sub-territories based on their distinct connectivity patterns. These anatomical connectivity findings are supported by functional connectivity data derived from resting-state functional MRI (R-fMRI). This work demonstrates new capabilities for studying basal ganglia circuitry, and opens new avenues of investigation into the movement and neuropsychiatric disorders, in individual human subjects

N-Acetyl Cysteine May Support Dopamine Neurons in Parkinson\u27s Disease: Preliminary Clinical and Cell Line Data.

BACKGOUND: The purpose of this study was to assess the biological and clinical effects of n-acetyl-cysteine (NAC) in Parkinson\u27s disease (PD). METHODS: The overarching goal of this pilot study was to generate additional data about potentially protective properties of NAC in PD, using an in vitro and in vivo approach. In preparation for the clinical study we performed a cell tissue culture study with human embryonic stem cell (hESC)-derived midbrain dopamine (mDA) neurons that were treated with rotenone as a model for PD. The primary outcome in the cell tissue cultures was the number of cells that survived the insult with the neurotoxin rotenone. In the clinical study, patients continued their standard of care and were randomized to receive either daily NAC or were a waitlist control. Patients were evaluated before and after 3 months of receiving the NAC with DaTscan to measure dopamine transporter (DAT) binding and the Unified Parkinson\u27s Disease Rating Scale (UPDRS) to measure clinical symptoms. RESULTS: The cell line study showed that NAC exposure resulted in significantly more mDA neurons surviving after exposure to rotenone compared to no NAC, consistent with the protective effects of NAC previously observed. The clinical study showed significantly increased DAT binding in the caudate and putamen (mean increase ranging from 4.4% to 7.8%; p CONCLUSIONS: The results of this preliminary study demonstrate for the first time a potential direct effect of NAC on the dopamine system in PD patients, and this observation may be associated with positive clinical effects. A large-scale clinical trial to test the therapeutic efficacy of NAC in this population and to better elucidate the mechanism of action is warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT02445651