Improving Conversations about Parkinson's Dementia.

BACKGROUND: People with Parkinson's disease (PD) have an increased risk of dementia, yet patients and clinicians frequently avoid talking about it due to associated stigma, and the perception that "nothing can be done about it". However, open conversations about PD dementia may allow people with the condition to access treatment and support, and may increase participation in research aimed at understanding PD dementia. OBJECTIVES: To co-produce information resources for patients and healthcare professionals to improve conversations about PD dementia. METHODS: We worked with people with PD, engagement experts, artists, and a PD charity to open up these conversations. 34 participants (16 PD; 6 PD dementia; 1 Parkinsonism, 11 caregivers) attended creative workshops to examine fears about PD dementia and develop information resources. 25 PD experts contributed to the resources. RESULTS: While most people with PD (70%) and caregivers (81%) shared worries about cognitive changes prior to the workshops, only 38% and 30%, respectively, had raised these concerns with a healthcare professional. 91% of people with PD and 73% of caregivers agreed that PD clinicians should ask about cognitive changes routinely through direct questions and perform cognitive tests at clinic appointments. We used insights from the creative workshops, and input from a network of PD experts to co-develop two open-access resources: one for people with PD and their families, and one for healthcare professionals. CONCLUSION: Using artistic and creative workshops, co-learning and striving for diverse voices, we co-produced relevant resources for a wider audience to improve conversations about PD dementia.

Automated Gait Detection in Older Adults during Daily-Living using Self-Supervised Learning of Wrist-Worn Accelerometer Data: Development and Validation of ElderNet.

Progressive gait impairment is common in aging adults. Remote phenotyping of gait during daily living has the potential to quantify gait alterations and evaluate the effects of interventions that may prevent disability in the aging population. Here, we developed ElderNet, a self-supervised learning model for gait detection from wrist-worn accelerometer data. Validation involved two diverse cohorts, including over 1,000 participants without gait labels, as well as 83 participants with labeled data: older adults with Parkinson's disease, proximal femoral fracture, chronic obstructive pulmonary disease, congestive heart failure, and healthy adults. ElderNet presented high accuracy (96.43 ± 2.27), specificity (98.87 ± 2.15), recall (82.32 ± 11.37), precision (86.69 ± 17.61), and F1 score (82.92 ± 13.39). The suggested method yielded superior performance compared to two state-of-the-art gait detection algorithms, with improved accuracy and F1 score (p < 0.05). In an initial evaluation of construct validity, ElderNet identified differences in estimated daily walking durations across cohorts with different clinical characteristics, such as mobility disability (p < 0.001) and parkinsonism (p < 0.001). The proposed self-supervised gait detection method has the potential to serve as a valuable tool for remote phenotyping of gait function during daily living in aging adults.

Delirium is more common and associated with worse outcomes in Parkinson's disease compared to older adult controls: results of two prospective longitudinal cohort studies.

BACKGROUND: Inpatient prevalence of Parkinson's disease (PD) delirium varies widely across the literature. Delirium in general older populations is associated with adverse outcomes, such as increased mortality, dementia, and institutionalisation. However, to date there are no comprehensive prospective studies in PD delirium. This study aimed to determine delirium prevalence in hospitalised PD participants and the association with adverse outcomes, compared to a control group of older adults without PD. METHODS: Participants were hospitalised inpatients from the 'Defining Delirium and its Impact in Parkinson's Disease' and the 'Delirium and Cognitive Impact in Dementia' studies comprising 121 PD participants and 199 older adult controls. Delirium was diagnosed prospectively using the Diagnostic and Statistical Manual of Mental Disorders 5th Edition criteria. Outcomes were determined by medical note reviews and/or home visits 12 months post hospital discharge. RESULTS: Delirium was identified in 66.9% of PD participants compared to 38.7% of controls (p < 0.001). In PD participants only, delirium was associated with a significantly higher risk of mortality (HR = 3.3 (95% confidence interval [CI] = 1.3-8.6), p = 0.014) and institutionalisation (OR = 10.7 (95% CI = 2.1-54.6), p = 0.004) 12 months post-discharge, compared to older adult controls. However, delirium was associated with an increased risk of developing dementia 12 months post-discharge in both PD participants (OR = 6.1 (95% CI = 1.3-29.5), p = 0.024) and in controls (OR = 13.4 (95% CI = 2.5-72.6), p = 0.003). CONCLUSION: Delirium is common in hospitalised PD patients, affecting two thirds of patients, and is associated with increased mortality, institutionalisation, and dementia. Further research is essential to understand how to accurately identify, prevent and manage delirium in people with PD who are in hospital.

Early-stage idiopathic Parkinson's disease is associated with reduced circular RNA expression.

Neurodegeneration in Parkinson's disease (PD) precedes diagnosis by years. Early neurodegeneration may be reflected in RNA levels and measurable as a biomarker. Here, we present the largest quantification of whole blood linear and circular RNAs (circRNA) in early-stage idiopathic PD, using RNA sequencing data from two cohorts (PPMI = 259 PD, 161 Controls; ICICLE-PD = 48 PD, 48 Controls). We identified a replicable increase in TMEM252 and LMNB1 gene expression in PD. We identified novel differences in the expression of circRNAs from ESYT2, BMS1P1 and CCDC9, and replicated trends of previously reported circRNAs. Overall, using circRNA as a diagnostic biomarker in PD did not show any clear improvement over linear RNA, minimising its potential clinical utility. More interestingly, we observed a general reduction in circRNA expression in both PD cohorts, accompanied by an increase in RNASEL expression. This imbalance implicates the activation of an innate antiviral immune response and suggests a previously unknown aspect of circRNA regulation in PD.

Mobilise-D insights to estimate real-world walking speed in multiple conditions with a wearable device.

This study aimed to validate a wearable device's walking speed estimation pipeline, considering complexity, speed, and walking bout duration. The goal was to provide recommendations on the use of wearable devices for real-world mobility analysis. Participants with Parkinson's Disease, Multiple Sclerosis, Proximal Femoral Fracture, Chronic Obstructive Pulmonary Disease, Congestive Heart Failure, and healthy older adults (n = 97) were monitored in the laboratory and the real-world (2.5 h), using a lower back wearable device. Two walking speed estimation pipelines were validated across 4408/1298 (2.5 h/laboratory) detected walking bouts, compared to 4620/1365 bouts detected by a multi-sensor reference system. In the laboratory, the mean absolute error (MAE) and mean relative error (MRE) for walking speed estimation ranged from 0.06 to 0.12 m/s and - 2.1 to 14.4%, with ICCs (Intraclass correlation coefficients) between good (0.79) and excellent (0.91). Real-world MAE ranged from 0.09 to 0.13, MARE from 1.3 to 22.7%, with ICCs indicating moderate (0.57) to good (0.88) agreement. Lower errors were observed for cohorts without major gait impairments, less complex tasks, and longer walking bouts. The analytical pipelines demonstrated moderate to good accuracy in estimating walking speed. Accuracy depended on confounding factors, emphasizing the need for robust technical validation before clinical application.Trial registration: ISRCTN - 12246987.

Translating digital healthcare to enhance clinical management: a protocol for an observational study using a digital health technology system to monitor medication adherence and its effect on mobility in people with Parkinson's.

INTRODUCTION: In people with Parkinson's (PwP) impaired mobility is associated with an increased falls risk. To improve mobility, dopaminergic medication is typically prescribed, but complex medication regimens result in suboptimal adherence. Exploring medication adherence and its impact on mobility in PwP will provide essential insights to optimise medication regimens and improve mobility. However, this is typically assessed in controlled environments, during one-off clinical assessments. Digital health technology (DHT) presents a means to overcome this, by continuously and remotely monitoring mobility and medication adherence. This study aims to use a novel DHT system (DHTS) (comprising of a smartphone, smartwatch and inertial measurement unit (IMU)) to assess self-reported medication adherence, and its impact on digital mobility outcomes (DMOs) in PwP. METHODS AND ANALYSIS: This single-centre, UK-based study, will recruit 55 participants with Parkinson's. Participants will complete a range of clinical, and physical assessments. Participants will interact with a DHTS over 7 days, to assess self-reported medication adherence, and monitor mobility and contextual factors in the real world. Participants will complete a motor complications diary (ON-OFF-Dyskinesia) throughout the monitoring period and, at the end, a questionnaire and series of open-text questions to evaluate DHTS usability. Feasibility of the DHTS and the motor complications diary will be assessed. Validated algorithms will quantify DMOs from IMU walking activity. Time series modelling and deep learning techniques will model and predict DMO response to medication and effects of contextual factors. This study will provide essential insights into medication adherence and its effect on real-world mobility in PwP, providing insights to optimise medication regimens. ETHICS AND DISSEMINATION: Ethical approval was granted by London-142 Westminster Research Ethics Committee (REC: 21/PR/0469), protocol V.2.4. Results will be published in peer-reviewed journals. All participants will provide written, informed consent. TRIAL REGISTRATION NUMBER: ISRCTN13156149.

The prevalence of sarcopenia in Parkinson's disease and related disorders- a systematic review.

BACKGROUND: The prevalence of sarcopenia (reduced skeletal muscle strength and mass), Parkinson's disease (PD) and Parkinson's related disorders (PRD) all increase with age. They also share risk factors and pathogenetic features. An increased prevalence of sarcopenia in PD and PRD than the general population was thus postulated. METHODS: Four databases were searched using predefined literature search strategies. Studies conducted in participants with PD or PRD reporting the prevalence of sarcopenia and those providing data to compute the prevalence were included. Pre-sarcopenia, probable/possible sarcopenia and confirmed sarcopenia were defined according to the main sarcopenia working groups. Risk of bias was assessed using the AXIS tool. RESULTS: 1978 studies were identified; 97 assessed in full; 14 met inclusion criteria. The median study quality score was 15/20. The range of probable sarcopenia was 23.9 to 66.7%, and it did not change after excluding PRD participants. The prevalence of confirmed sarcopenia in participants with any parkinsonian disorder ranged from 2 to 31.4%. Including just PD participants, the range was 10.9 to 31.4%. In studies with controls, sarcopenia was more prevalent in PD and PRD. There was a positive non-significant trend between severity of motor symptoms and prevalence of sarcopenia or components of sarcopenia. High heterogeneity precluded meta-analysis, therefore there was insufficient evidence to conclude whether sarcopenia is more prevalent in PD or PRD. CONCLUSIONS: Probable and confirmed sarcopenia are common in PD and PRD and they may be associated with disease severity. This co-occurrence supports the value of screening for sarcopenia in parkinsonian populations.

Can Digital Mobility Assessment Enhance the Clinical Assessment of Disease Severity in Parkinson's Disease?

BACKGROUND: Real-world walking speed (RWS) measured using wearable devices has the potential to complement the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS III) for motor assessment in Parkinson's disease (PD). OBJECTIVE: Explore cross-sectional and longitudinal differences in RWS between PD and older adults (OAs), and whether RWS was related to motor disease severity cross-sectionally, and if MDS-UPDRS III was related to RWS, longitudinally. METHODS: 88 PD and 111 OA participants from ICICLE-GAIT (UK) were included. RWS was evaluated using an accelerometer at four time points. RWS was aggregated within walking bout (WB) duration thresholds. Between-group-comparisons in RWS between PD and OAs were conducted cross-sectionally, and longitudinally with mixed effects models (MEMs). Cross-sectional association between RWS and MDS-UPDRS III was explored using linear regression, and longitudinal association explored with MEMs. RESULTS: RWS was significantly lower in PD (1.04 m/s) in comparison to OAs (1.10 m/s) cross-sectionally. RWS significantly decreased over time for both cohorts and decline was more rapid in PD by 0.02 m/s per year. Significant negative relationship between RWS and the MDS-UPDRS III only existed at a specific WB threshold (30 to 60 s, ß= - 3.94 points, p = 0.047). MDS-UPDRS III increased significantly by 1.84 points per year, which was not related to change in RWS. CONCLUSION: Digital mobility assessment of gait may add unique information to quantify disease progression remotely, but further validation in research and clinical settings is needed.

The Role of Wearable Sensors to Monitor Physical Activity and Sleep Patterns in Older Adult Inpatients: A Structured Review.

Low levels of physical activity (PA) and sleep disruption are commonly seen in older adult inpatients and are associated with poor health outcomes. Wearable sensors allow for objective continuous monitoring; however, there is no consensus as to how wearable sensors should be implemented. This review aimed to provide an overview of the use of wearable sensors in older adult inpatient populations, including models used, body placement and outcome measures. Five databases were searched; 89 articles met inclusion criteria. We found that studies used heterogenous methods, including a variety of sensor models, placement and outcome measures. Most studies reported the use of only one sensor, with either the wrist or thigh being the preferred location in PA studies and the wrist for sleep outcomes. The reported PA measures can be mostly characterised as the frequency and duration of PA (Volume) with fewer measures relating to intensity (rate of magnitude) and pattern of activity (distribution per day/week). Sleep and circadian rhythm measures were reported less frequently with a limited number of studies providing both physical activity and sleep/circadian rhythm outcomes concurrently. This review provides recommendations for future research in older adult inpatient populations. With protocols of best practice, wearable sensors could facilitate the monitoring of inpatient recovery and provide measures to inform participant stratification and establish common objective endpoints across clinical trials.

Predicting cognitive decline using neuropsychiatric symptoms in prodromal Lewy body dementia: A longitudinal study.

INTRODUCTION: Neuropsychiatric symptoms (NPS) in Lewy body dementias (LBD) occur frequently and early in disease progression. Such symptoms are associated with worse quality of life, caregiver burden and functional limitations. Limited evidence exists, however, outlining the longitudinal relationship between NPS and cognitive decline in prodromal LBD. METHODS: 123 participants were derived from three cohort studies. Patients with mild cognitive impairment (MCI) relating to probable dementia with Lewy bodies (MCI-LB, n = 67) and Parkinson's disease (PD-MCI, n = 56) completed comprehensive cognitive and neuropsychiatric assessment and were followed up longitudinally. Linear regression and mixed effects models assessed the relationship between baseline NPS and cognition at baseline and over time. RESULTS: In MCI-LB, overall NPS burden was associated with declines over time in executive function (p = 0.026) and processing speed (p = 0.028) and baseline aberrant motor behaviour was associated with declines in attention (p < 0.025). Anxiety was significantly associated with poorer visuospatial functioning (p = 0.016) at baseline and poorer attention both at baseline (p = 0.017) and across time points (p = 0.024). In PD-MCI, psychosis was associated with poorer executive functioning at baseline (p = 0.008) and across time points (p = 0.002) but had no association with changes longitudinally. CONCLUSIONS: Core neuropsychiatric components of LBD are not strongly associated with cognition in prodromal disease. This may suggest that neuropathological mechanisms underlying NPS may not be the same as those underlying cognitive impairment. Non-core NPS, however, may be more directly associated with cognitive change. Future studies utilising neuroimaging techniques are needed to explore the neuropathological basis of NPS in prodromal LBD.

Assessing real-world gait with digital technology? Validation, insights and recommendations from the Mobilise-D consortium.

BACKGROUND: Although digital mobility outcomes (DMOs) can be readily calculated from real-world data collected with wearable devices and ad-hoc algorithms, technical validation is still required. The aim of this paper is to comparatively assess and validate DMOs estimated using real-world gait data from six different cohorts, focusing on gait sequence detection, foot initial contact detection (ICD), cadence (CAD) and stride length (SL) estimates. METHODS: Twenty healthy older adults, 20 people with Parkinson's disease, 20 with multiple sclerosis, 19 with proximal femoral fracture, 17 with chronic obstructive pulmonary disease and 12 with congestive heart failure were monitored for 2.5 h in the real-world, using a single wearable device worn on the lower back. A reference system combining inertial modules with distance sensors and pressure insoles was used for comparison of DMOs from the single wearable device. We assessed and validated three algorithms for gait sequence detection, four for ICD, three for CAD and four for SL by concurrently comparing their performances (e.g., accuracy, specificity, sensitivity, absolute and relative errors). Additionally, the effects of walking bout (WB) speed and duration on algorithm performance were investigated. RESULTS: We identified two cohort-specific top performing algorithms for gait sequence detection and CAD, and a single best for ICD and SL. Best gait sequence detection algorithms showed good performances (sensitivity > 0.73, positive predictive values > 0.75, specificity > 0.95, accuracy > 0.94). ICD and CAD algorithms presented excellent results, with sensitivity > 0.79, positive predictive values > 0.89 and relative errors < 11% for ICD and < 8.5% for CAD. The best identified SL algorithm showed lower performances than other DMOs (absolute error < 0.21 m). Lower performances across all DMOs were found for the cohort with most severe gait impairments (proximal femoral fracture). Algorithms' performances were lower for short walking bouts; slower gait speeds (< 0.5 m/s) resulted in reduced performance of the CAD and SL algorithms. CONCLUSIONS: Overall, the identified algorithms enabled a robust estimation of key DMOs. Our findings showed that the choice of algorithm for estimation of gait sequence detection and CAD should be cohort-specific (e.g., slow walkers and with gait impairments). Short walking bout length and slow walking speed worsened algorithms' performances. Trial registration ISRCTN - 12246987.

A multi-sensor wearable system for the assessment of diseased gait in real-world conditions.

Introduction: Accurately assessing people's gait, especially in real-world conditions and in case of impaired mobility, is still a challenge due to intrinsic and extrinsic factors resulting in gait complexity. To improve the estimation of gait-related digital mobility outcomes (DMOs) in real-world scenarios, this study presents a wearable multi-sensor system (INDIP), integrating complementary sensing approaches (two plantar pressure insoles, three inertial units and two distance sensors). Methods: The INDIP technical validity was assessed against stereophotogrammetry during a laboratory experimental protocol comprising structured tests (including continuous curvilinear and rectilinear walking and steps) and a simulation of daily-life activities (including intermittent gait and short walking bouts). To evaluate its performance on various gait patterns, data were collected on 128 participants from seven cohorts: healthy young and older adults, patients with Parkinson's disease, multiple sclerosis, chronic obstructive pulmonary disease, congestive heart failure, and proximal femur fracture. Moreover, INDIP usability was evaluated by recording 2.5-h of real-world unsupervised activity. Results and discussion: Excellent absolute agreement (ICC >0.95) and very limited mean absolute errors were observed for all cohorts and digital mobility outcomes (cadence ≤0.61 steps/min, stride length ≤0.02 m, walking speed ≤0.02 m/s) in the structured tests. Larger, but limited, errors were observed during the daily-life simulation (cadence 2.72-4.87 steps/min, stride length 0.04-0.06 m, walking speed 0.03-0.05 m/s). Neither major technical nor usability issues were declared during the 2.5-h acquisitions. Therefore, the INDIP system can be considered a valid and feasible solution to collect reference data for analyzing gait in real-world conditions.

Feasibility and usability of a digital health technology system to monitor mobility and assess medication adherence in mild-to-moderate Parkinson's disease.

Introduction: Parkinson's disease (PD) is a neurodegenerative disorder which requires complex medication regimens to mitigate motor symptoms. The use of digital health technology systems (DHTSs) to collect mobility and medication data provides an opportunity to objectively quantify the effect of medication on motor performance during day-to-day activities. This insight could inform clinical decision-making, personalise care, and aid self-management. This study investigates the feasibility and usability of a multi-component DHTS to remotely assess self-reported medication adherence and monitor mobility in people with Parkinson's (PwP). Methods: Thirty participants with PD [Hoehn and Yahr stage I (n = 1) and II (n = 29)] were recruited for this cross-sectional study. Participants were required to wear, and where appropriate, interact with a DHTS (smartwatch, inertial measurement unit, and smartphone) for seven consecutive days to assess medication adherence and monitor digital mobility outcomes and contextual factors. Participants reported their daily motor complications [motor fluctuations and dyskinesias (i.e., involuntary movements)] in a diary. Following the monitoring period, participants completed a questionnaire to gauge the usability of the DHTS. Feasibility was assessed through the percentage of data collected, and usability through analysis of qualitative questionnaire feedback. Results: Adherence to each device exceeded 70% and ranged from 73 to 97%. Overall, the DHTS was well tolerated with 17/30 participants giving a score > 75% [average score for these participants = 89%, from 0 (worst) to 100 (best)] for its usability. Usability of the DHTS was significantly associated with age (ρ = -0.560, BCa 95% CI [-0.791, -0.207]). This study identified means to improve usability of the DHTS by addressing technical and design issues of the smartwatch. Feasibility, usability and acceptability were identified as key themes from PwP qualitative feedback on the DHTS. Conclusion: This study highlighted the feasibility and usability of our integrated DHTS to remotely assess medication adherence and monitor mobility in people with mild-to-moderate Parkinson's disease. Further work is necessary to determine whether this DHTS can be implemented for clinical decision-making to optimise management of PwP.

Safety and tolerability of adjunct non-invasive vagus nerve stimulation in people with parkinson's: a study protocol.

BACKGROUND: Parkinson's disease (PD) is the fastest growing neurological condition worldwide. Recent theories suggest that symptoms of PD may arise due to spread of Lewy-body pathology where the process begins in the gut and propagate transynaptically via the vagus nerve to the central nervous system. In PD, gait impairments are common motor manifestations that are progressive and can appear early in the disease course. As therapies to mitigate gait impairments are limited, novel interventions targeting these and their consequences, i.e., reducing the risk of falls, are urgently needed. Non-invasive vagus nerve stimulation (nVNS) is a neuromodulation technique targeting the vagus nerve. We recently showed in a small pilot trial that a single dose of nVNS improved (decreased) discrete gait variability characteristics in those receiving active stimulation relative to those receiving sham stimulation. Further multi-dose, multi-session studies are needed to assess the safety and tolerability of the stimulation and if improvement in gait is sustained over time. DESIGN: This will be an investigator-initiated, single-site, proof-of-concept, double-blind sham-controlled randomised pilot trial in 40 people with PD. Participants will be randomly assigned on a 1:1 ratio to receive either active or sham transcutaneous cervical VNS. All participants will undergo comprehensive cognitive, autonomic and gait assessments during three sessions over 24 weeks, in addition to remote monitoring of ambulatory activity and falls, and exploratory analyses of cholinergic peripheral plasma markers. The primary outcome measure is the safety and tolerability of multi-dose nVNS in PD. Secondary outcomes include improvements in gait, cognition and autonomic function that will be summarised using descriptive statistics. DISCUSSION: This study will report on the proportion of eligible and enrolled patients, rates of eligibility and reasons for ineligibility. Adverse events will be recorded informing on the safety and device tolerability in PD. This study will additionally provide us with information for sample size calculations for future studies and evidence whether improvement in gait control is enhanced when nVNS is delivered repeatedly and sustained over time. TRIAL REGISTRATION: This trial is prospectively registered at www.isrctn.com/ISRCTN19394828 . Registered August 23, 2021.

Documentation and diagnosis of delirium in Parkinson's disease.

OBJECTIVE: To assess the accuracy of documentation of the symptoms and diagnosis of delirium in medical notes of inpatients with Parkinson's disease (PD). METHODS: The DETERMINE-PD pilot study assessed PD inpatients over 4-months. Delirium prevalence was classified prospectively using a standardized assessment at a single visit on the basis of Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-5) criteria. Incident delirium was diagnosed retrospectively using detailed clinical vignettes and validated consensus method. Inpatient medical notes and discharge summaries of those with delirium were reviewed for documentation of symptoms, diagnosis and follow-up. RESULTS: Forty-four PD patients consented to take part in the study, accounting for 53 admissions. We identified 30 cases (56.6%) of delirium during the participants' stay in hospital. Of those with delirium identified by the research team, delirium symptoms were documented in the clinical notes of 72.3%; 37.9% had a delirium diagnosis documented. Older patients were more likely to have delirium (p = 0.027) and have this diagnosis documented (p = 0.034). Time from documentation of symptoms to diagnosis ranged from <24 h to 7 days (mean 1.6 ± 4.4 days). Hypoactive delirium was significantly less likely to have been identified and formally diagnosed (63% of not documented were hypoactive vs. 37% hyperactive, mixed or unclear, p = 0.016). Only 11.5% of discharge summaries included diagnosis of delirium. CONCLUSION: Delirium in PD is common. Documentation of symptoms of delirium was common; however, fails to lead to a documentation of diagnosis in over half of admissions with delirium and was even less commonly communicated in the Primary Care discharge summaries. This highlights the need for increased education about delirium symptomatology and diagnosis in PD.

Free-water imaging of the cholinergic basal forebrain and pedunculopontine nucleus in Parkinson's disease.

Free-water imaging can predict and monitor dopamine system degeneration in people with Parkinson's disease. It can also enhance the sensitivity of traditional diffusion tensor imaging (DTI) metrics for indexing neurodegeneration. However, these tools are yet to be applied to investigate cholinergic system degeneration in Parkinson's disease, which involves both the pedunculopontine nucleus and cholinergic basal forebrain. Free-water imaging, free-water-corrected DTI and volumetry were used to extract structural metrics from the cholinergic basal forebrain and pedunculopontine nucleus in 99 people with Parkinson's disease and 46 age-matched controls. Cognitive ability was tracked over 4.5 years. Pearson's partial correlations revealed that free-water-corrected DTI metrics in the pedunculopontine nucleus were associated with performance on cognitive tasks that required participants to make rapid choices (behavioural flexibility). Volumetric, free-water content and DTI metrics in the cholinergic basal forebrain were elevated in a sub-group of people with Parkinson's disease with evidence of cognitive impairment, and linear mixed modelling revealed that these metrics were differently associated with current and future changes to cognition. Free water and free-water-corrected DTI can index cholinergic degeneration that could enable stratification of patients in clinical trials of cholinergic interventions for cognitive decline. In addition, degeneration of the pedunculopontine nucleus impairs behavioural flexibility in Parkinson's disease, which may explain this region's role in increased risk of falls.

Connecting real-world digital mobility assessment to clinical outcomes for regulatory and clinical endorsement-the Mobilise-D study protocol.

BACKGROUND: The development of optimal strategies to treat impaired mobility related to ageing and chronic disease requires better ways to detect and measure it. Digital health technology, including body worn sensors, has the potential to directly and accurately capture real-world mobility. Mobilise-D consists of 34 partners from 13 countries who are working together to jointly develop and implement a digital mobility assessment solution to demonstrate that real-world digital mobility outcomes have the potential to provide a better, safer, and quicker way to assess, monitor, and predict the efficacy of new interventions on impaired mobility. The overarching objective of the study is to establish the clinical validity of digital outcomes in patient populations impacted by mobility challenges, and to support engagement with regulatory and health technology agencies towards acceptance of digital mobility assessment in regulatory and health technology assessment decisions. METHODS/DESIGN: The Mobilise-D clinical validation study is a longitudinal observational cohort study that will recruit 2400 participants from four clinical cohorts. The populations of the Innovative Medicine Initiative-Joint Undertaking represent neurodegenerative conditions (Parkinson's Disease), respiratory disease (Chronic Obstructive Pulmonary Disease), neuro-inflammatory disorder (Multiple Sclerosis), fall-related injuries, osteoporosis, sarcopenia, and frailty (Proximal Femoral Fracture). In total, 17 clinical sites in ten countries will recruit participants who will be evaluated every six months over a period of two years. A wide range of core and cohort specific outcome measures will be collected, spanning patient-reported, observer-reported, and clinician-reported outcomes as well as performance-based outcomes (physical measures and cognitive/mental measures). Daily-living mobility and physical capacity will be assessed directly using a wearable device. These four clinical cohorts were chosen to obtain generalizable clinical findings, including diverse clinical, cultural, geographical, and age representation. The disease cohorts include a broad and heterogeneous range of subject characteristics with varying chronic care needs, and represent different trajectories of mobility disability. DISCUSSION: The results of Mobilise-D will provide longitudinal data on the use of digital mobility outcomes to identify, stratify, and monitor disability. This will support the development of widespread, cost-effective access to optimal clinical mobility management through personalised healthcare. Further, Mobilise-D will provide evidence-based, direct measures which can be endorsed by regulatory agencies and health technology assessment bodies to quantify the impact of disease-modifying interventions on mobility. TRIAL REGISTRATION: ISRCTN12051706.