Distributional data analysis via quantile functions and its application to modeling digital biomarkers of gait in Alzheimer's Disease.

With the advent of continuous health monitoring with wearable devices, users now generate their unique streams of continuous data such as minute-level step counts or heartbeats. Summarizing these streams via scalar summaries often ignores the distributional nature of wearable data and almost unavoidably leads to the loss of critical information. We propose to capture the distributional nature of wearable data via user-specific quantile functions (QF) and use these QFs as predictors in scalar-on-quantile-function-regression (SOQFR). As an alternative approach, we also propose to represent QFs via user-specific L-moments, robust rank-based analogs of traditional moments, and use L-moments as predictors in SOQFR (SOQFR-L). These two approaches provide two mutually consistent interpretations: in terms of quantile levels by SOQFR and in terms of L-moments by SOQFR-L. We also demonstrate how to deal with multi-modal distributional data via Joint and Individual Variation Explained using L-moments. The proposed methods are illustrated in a study of association of digital gait biomarkers with cognitive function in Alzheimers disease. Our analysis shows that the proposed methods demonstrate higher predictive performance and attain much stronger associations with clinical cognitive scales compared to simple distributional summaries.

Promoting independence in Lewy body dementia through exercise: the PRIDE study.

BACKGROUND: Lewy body dementia (LBD) is an aggressive type of dementia of rapid, fluctuating disease trajectory, higher incidence of adverse events, and poorer functional independence than observed in Alzheimer's disease dementia. Non-pharmacological treatments such as progressive, high-intensity exercise are effective in other neurological cohorts but have been scarcely evaluated in LBD. METHODS: The Promoting Independence in Lewy Body Dementia through Exercise (PRIDE) trial was a non-randomised, non-blinded, crossover pilot trial involving older adults with LBD consisting of a baseline assessment, an 8-week wait-list, and an 8-week exercise intervention. The aims of this study were to evaluate the determinants of the primary outcome functional independence, as measured by the Movement Disorder Society Unified Parkinson's Disease Rating Scale, and the feasibility and preliminary efficacy of an exercise intervention on this outcome. Additionally, important clinical characteristics were evaluated to explore associations and treatment targets. The exercise intervention was supervised, clinic-based, high-intensity progressive resistance training (PRT), challenging balance, and functional exercises, 3 days/week. RESULTS: Nine participants completed the baseline cross-sectional study, of which five had a diagnosis of Parkinson's disease dementia (PDD), and four dementia with Lewy Bodies (DLB). Six completed the exercise intervention (three PDD, three DLB). The cohort was diverse, ranging from mild to severe dementia and living in various residential settings. Greater functional independence at baseline was significantly associated with better physical function, balance, cognition, quality of life, muscle mass ratio, walking endurance, faster walking speed and cadence, and lower dementia severity (p < 0.05). Participants declined by clinically meaningful amounts in functional independence, cognition, physical function, muscle mass, and weight over the wait-list period (p < 0.05). Following exercise, participants improved by clinically meaningful amounts in functional independence, cognition, physical function, and strength (p < 0.05). Progressive, high intensity exercise was well-tolerated (> 80% adherence), and only one minor exercise-related adverse event occurred. CONCLUSIONS: PRIDE is the first exercise trial conducted specifically within individuals diagnosed with LBD, and provides important insight for the design of larger, randomized trials for further evaluation of progressive, high-intensity exercise as a valuable treatment in LBD. TRIAL REGISTRATION: The PRIDE trial protocol has previously been prospectively registered (08/04/2016, ANZCTR: ACTRN12616000466448).

Quantification of Daily-Living Gait Quantity and Quality Using a Wrist-Worn Accelerometer in Huntington's Disease.

Background: Huntington's disease (HD) leads to altered gait patterns and reduced daily-living physical activity. Accurate measurement of daily-living walking that takes into account involuntary movements (e.g. chorea) is needed. Objective: To evaluate daily-living gait quantity and quality in HD, taking into account irregular movements. Methods: Forty-two individuals with HD and fourteen age-matched non-HD peers completed clinic-based assessments and a standardized laboratory-based circuit of functional activities, wearing inertial measurement units on the wrists, legs, and trunk. These activities were used to train and test an algorithm for the automated detection of walking. Subsequently, 29 HD participants and 22 age-matched non-HD peers wore a tri-axial accelerometer on their non-dominant wrist for 7 days. Measures included gait quantity (e.g., steps per day), gait quality (e.g., regularity) metrics, and percentage of walking bouts with irregular movements. Results: Measures of daily-living gait quantity including step counts, walking time and bouts per day were similar in HD participants and non-HD peers (p > 0.05). HD participants with higher clinician-rated upper body chorea had a greater percentage of walking bouts with irregular movements compared to those with lower chorea (p = 0.060) and non-HD peers (p < 0.001). Even after accounting for irregular movements, within-bout walking consistency was lower in HD participants compared to non-HD peers (p < 0.001), while across-bout variability of these measures was higher (p < 0.001). Many of the daily-living measures were associated with disease-specific measures of motor function. Conclusions: Results suggest that a wrist-worn accelerometer can be used to evaluate the quantity and quality of daily-living gait in people with HD, while accounting for the influence of irregular (choreic-like) movements, and that gait features related to within- and across-bout consistency markedly differ in individuals with HD and non-HD peers.

Continuous gait monitoring discriminates community-dwelling mild Alzheimer's disease from cognitively normal controls.

INTRODUCTION: Few studies have explored whether gait measured continuously within a community setting can identify individuals with Alzheimer's disease (AD). This study tests the feasibility of this method to identify individuals at the earliest stage of AD. METHODS: Mild AD (n = 38) and cognitively normal control (CNC; n = 48) participants from the University of Kansas Alzheimer's Disease Center Registry wore a GT3x+ accelerometer continuously for 7 days to assess gait. Penalized logistic regression with repeated five-fold cross-validation followed by adjusted logistic regression was used to identify gait metrics with the highest predictive performance in discriminating mild AD from CNC. RESULTS: Variability in step velocity and cadence had the highest predictive utility in identifying individuals with mild AD. Metrics were also associated with cognitive domains impacted in early AD. DISCUSSION: Continuous gait monitoring may be a scalable method to identify individuals at-risk for developing dementia within large, population-based studies.

A wearable sensor identifies alterations in community ambulation in multiple sclerosis: contributors to real-world gait quality and physical activity.

People with multiple sclerosis (pwMS) often suffer from gait impairments. These changes in gait have been well studied in laboratory and clinical settings. A thorough investigation of gait alterations during community ambulation and their contributing factors, however, is lacking. The aim of the present study was to evaluate community ambulation and physical activity in pwMS and healthy controls and to compare in-lab gait to community ambulation. To this end, 104 subjects were studied: 44 pwMS and 60 healthy controls (whose age was similar to the controls). The subjects wore a tri-axial, lower back accelerometer during usual-walking and dual-task walking in the lab and during community ambulation (1 week) to evaluate the amount, type, and quality of activity. The results showed that during community ambulation, pwMS took fewer steps and walked more slowly, with greater asymmetry, and larger stride-to-stride variability, compared to the healthy controls (p < 0.001). Gait speed during most of community ambulation was significantly lower than the in-lab usual-walking value and similar to the in-lab dual-tasking value. Significant group (pwMS /controls)-by-walking condition (in-lab/community ambulation) interactions were observed (e.g., gait speed). Greater disability was associated with fewer steps and reduced gait speed during community ambulation. In contrast, physical fatigue was correlated with sedentary activity, but was not related to any of the measures of community ambulation gait quality including gait speed. This disparity suggests that more than one mechanism contributes to community ambulation and physical activity in pwMS. Together, these findings demonstrate that during community ambulation, pwMS have marked gait alterations in multiple gait features, reminiscent of dual-task walking measured in the laboratory. Disease-related factors associated with these changes might be targets of rehabilitation.

Tossing and Turning in Bed: Nocturnal Movements in Parkinson's Disease.

BACKGROUND: Sleep disturbances and nocturnal hypokinesia are common in Parkinson's disease (PD). Recent work using wearable technologies showed fewer nocturnal movements in PD when compared with controls. However, it is unclear how these manifest across the disease spectrum. OBJECTIVES: We assessed the prevalence of sleep disturbances and nocturnal hypokinesia in early and advanced PD and their relation to nonmotor symptoms and dopaminergic medication. METHODS: A total of 305 patients with PD with diverse disease severity (Hoehn and Yahr [H&Y] stage 1 = 47, H&Y stage 2 = 181, H&Y stage 3 = 77) and 205 healthy controls continuously wore a tri-axial accelerometer on the lower back for at least 2 days. Lying, turning, and upright -time at night were extracted from the acceleration signals. Percent upright time and nighttime walking were classified as sleep interruptions. The number, velocity, time, side, and degree of rotations in bed were used to evaluate nocturnal movements. RESULTS: Nocturnal lying time was similar among all groups (healthy controls, 7.5 ± 1.2 hours; H&Y stage 1, 7.3 ± 0.9 hours; H&Y stage 2, 7.2 ± 1.3 hours; H&Y stage 3, 7.4 ± 1.6 hours; P = 0.501). However, patients with advanced PD had more upright periods, whereas the number and velocity of their turns were reduced (P ≤ 0.021). Recently diagnosed patients (<1 year from diagnosis) were similar to controls in the number of nocturnal turns (P = 0.148), but showed longer turning time (P = 0.001) and reduced turn magnitude (P = 0.002). Reduced nocturnal movements were associated with increased PD motor severity and worse dysautonomia and cognition and with dopaminergic medication. CONCLUSIONS: Using wearable sensors for continuous monitoring of movement at night may offer an unbiased measure of disease severity that could enhance optimal nighttime dopaminergic treatment and utilization of turning strategies. © 2020 International Parkinson and Movement Disorder Society.

Is every-day walking in older adults more analogous to dual-task walking or to usual walking? Elucidating the gaps between gait performance in the lab and during 24/7 monitoring.

BACKGROUND: The traditional evaluation of gait in the laboratory during structured testing has provided important insights, but is limited by its "snapshot" character and observation in an unnatural environment. Wearables enable monitoring of gait in real-world environments over a week. Initial findings show that in-lab and real-world measures differ. As a step towards better understanding these gaps, we directly compared in-lab usual-walking (UW) and dual-task walking (DTW) to daily-living measures of gait. METHODS: In-lab gait features (e.g., gait speed, step regularity, and stride regularity) derived from UW and DTW were compared to the same gait features during daily-living in 150 elderly fallers (age: 76.5 ± 6.3 years, 37.6% men). In both settings, features were extracted from a lower-back accelerometer. In the real-world setting, subjects were asked to wear the device for 1 week and pre-processing detected 30-s daily-living walking bouts. A histogram of all walking bouts was determined for each walking feature for each subject and then each subject's typical (percentile 50, median), worst (percentile 10) and the best (percentile 90) values over the week were determined for each feature. Statistics of reliability were assessed using Intra-Class correlations and Bland-Altman plots. RESULTS: As expected, in-lab gait speed, step regularity, and stride regularity were worse during DTW, compared to UW. In-lab gait speed, step regularity, and stride regularity during UW were significantly higher (i.e., better) than the typical daily-living values (p < 0.001) and different (p < 0.001) from the worst and best values. DTW values tended to be similar to typical daily-living values (p = 0.205, p = 0.053, p = 0.013 respectively). ICC assessment and Bland-Altman plots indicated that in-lab values do not reliably reflect the daily-walking values. CONCLUSIONS: Gait values measured during relatively long (30-s) daily-living walking bouts are more similar to the corresponding values obtained in the lab during dual-task walking, as compared to usual walking. Still, gait performance during most daily-living walking bouts is worse than that measured during usual and dual-tasking in the lab. The values measured in the lab do not reliably reflect daily-living measures. That is, an older adult's typical daily-living gait cannot be estimated by simply measuring walking in a structured, laboratory setting.

Using wearables to assess bradykinesia and rigidity in patients with Parkinson's disease: a focused, narrative review of the literature.

The potential of using wearable technologies for the objective assessment of motor symptoms in Parkinson's disease (PD) has gained prominence recently. Nonetheless, compared to tremor and gait impairment, less emphasis has been placed on the quantification of bradykinesia and rigidity. This review aimed to consolidate the existing research on objective measurement of bradykinesia and rigidity in PD through the use of wearables, focusing on the continuous monitoring of these two symptoms in free-living environments. A search of PubMed was conducted through a combination of keyword and MeSH searches. We also searched the IEEE, Google Scholar, Embase, and Scopus databases to ensure thorough results and to minimize the chances of missing relevant studies. Papers published after the year 2000 with sample sizes greater than five were included. Studies were assessed for quality and information was extracted regarding the devices used and their location on the body, the setting and duration of the study, the "gold standard" used as a reference for validation, the metrics used, and the results of each paper. Thirty-one and eight studies met the search criteria and evaluated bradykinesia and rigidity, respectively. Several studies reported strong associations between wearable-based measures and the gold-standard references for bradykinesia, and, to a lesser extent, rigidity. Only a few, pilot studies investigated the measurement of bradykinesia and rigidity in the home and free-living settings. While the current results are promising for the future of wearables, additional work is needed on their validation and adaptation in ecological, free-living settings. Doing so has the potential to improve the assessment and treatment of motor fluctuations and symptoms of PD more generally through real-time objective monitoring of bradykinesia and rigidity.

Associations between daily-living physical activity and laboratory-based assessments of motor severity in patients with falls and Parkinson's disease.

INTRODUCTION: Recent work suggests that wearables can augment conventional measures of Parkinson's disease (PD). We evaluated the relationship between conventional measures of disease and motor severity (e.g., MDS-UPDRS part III), laboratory-based measures of gait and balance, and daily-living physical activity measures in patients with PD. METHODS: Data from 125 patients (age: 71.7 ±â€¯6.5 years, Hoehn and Yahr: 1-3, 60.5% men) were analyzed. The MDS-UPDRS-part III was used as the gold standard of motor symptom severity. Gait and balance were quantified in the laboratory. Daily-living gait and physical activity metrics were extracted from an accelerometer worn on the lower back for 7 days. RESULTS: In multivariate analyses, daily-living physical activity and gait metrics, laboratory-based balance, demographics and subject characteristics together explained 46% of the variance in MDS-UPDRS-part III scores. Daily-living measures accounted for 62% of the explained variance, laboratory measures 30%, and demographics and subject characteristics 7% of the explained variance. Conversely, demographics and subject characteristics, laboratory-based measures of gait symmetry, and motor symptom severity together explained less than 30% of the variance in total daily-living physical activity. MDS-UPDRS-part III scores accounted for 13% of the explained variance, i.e., <4% of all the variance in total daily-living activity. CONCLUSIONS: Our findings suggest that conventional measures of motor symptom severity do not strongly reflect daily-living activity and that daily-living measures apparently provide important information that is not captured in a conventional one-time, laboratory assessment of gait, balance or the MDS-UPDRS. To provide a more complete evaluation, wearable devices should be considered.

Home monitoring of sleep with a temporary-tattoo EEG, EOG and EMG electrode array: a feasibility study.

OBJECTIVE: Circadian and sleep dysfunction have long been symptomatic hallmarks of a variety of devastating neurodegenerative conditions. The gold standard for sleep monitoring is overnight sleep in a polysomnography (PSG) laboratory. However, this method has several limitations such as availability, cost and being labour-intensive. In recent years there has been a heightened interest in home-based sleep monitoring via wearable sensors. Our objective was to demonstrate the use of printed electrode technology as a novel platform for sleep monitoring. APPROACH: Printed electrode arrays offer exciting opportunities in the realm of wearable electrophysiology. In particular, soft electrodes can conform neatly to the wearer's skin, allowing user convenience and stable recordings. As such, soft skin-adhesive non-gel-based electrodes offer a unique opportunity to combine electroencephalography (EEG), electromyography (EMG), electrooculography (EOG) and facial EMG capabilities to capture neural and motor functions in comfortable non-laboratory settings. In this investigation temporary-tattoo dry electrode system for sleep staging analysis was designed, implemented and tested. MAIN RESULTS: EMG, EOG and EEG were successfully recorded using a wireless system. Stable recordings were achieved both at a hospital environment and a home setting. Sleep monitoring during a 6 h session shows clear differentiation of sleep stages. SIGNIFICANCE: The new system has great potential in monitoring sleep disorders in the home environment. Specifically, it may allow the identification of disorders associated with neurological disorders such as rapid eye movement (REM) sleep behavior disorder.

Everyday Stepping Quantity and Quality Among Older Adult Fallers With and Without Mild Cognitive Impairment: Initial Evidence for New Motor Markers of Cognitive Deficits?

Background: Recent work demonstrated that the gait of people with mild cognitive impairment (MCI) differs from that of age-matched controls and, in general, that walking ability, as measured in the clinic, does not necessarily reflect actual, daily performance. We evaluated if the quantity and quality of everyday walking (ie, community ambulation) differs in older adults with MCI, compared to age-matched controls. Methods: Inclusion criteria included: age 65-90 years, able to walk at least 5 minutes unassisted, and ≥2 falls in the past 6 months. Subjects with MCI were included if they scored 0.5 on the Clinical Dementia Rating Scale. To assess stepping quantity and quality, subjects wore a tri-axial accelerometer on the lower-back for 7 days. Results: Age and gender were similar (p > .10) in MCI (n = 36, 77.8 ± 6.4 years; 27.8% men) and controls (n = 100, 76.0 ± 6.2 years; 22.0% men). As expected, Montreal Cognitive Assessment scores were lower (p < .001) in MCI (21.31 ± 4.05), compared to controls (25.81 ± 2.64). Walking time was lower (p = .016) in MCI (0.74 ± 0.48 hours/d), compared to controls (1.05 ± 0.66 hours/d). Within-bout walking (eg, stride regularity) was less consistent (p = .024) in MCI (0.51 ± 0.14), compared to controls (0.58 ± 0.14). Changes in stride regularity across bouts were lower (p < .001) in MCI (0.13 ± 0.04), compared to controls (0.17 ± 0.01). Conclusions: Older adults with MCI walk less and with a more variable within-bout and less variable across-bout walking pattern, as compared to cognitively-intact subjects matched with respect to age and gender. These findings extend previous clinical work and suggest that MCI affects both the quantity and quality of community ambulation.

Monitoring of Cellular Changes in the Bone Marrow following PTH(1-34) Treatment of OVX Rats Using a Portable Stray-Field NMR Scanner.

Osteoporosis is characterized by reduction in trabecular bone in conjunction with increased marrow cell adiposity. While these changes occur within weeks, monitoring of treatment efficacy as performed by DEXA is sensitive only to long-term changes. MRI is sensitive to bone marrow changes but is less affordable. In a recent study, we have shown that a stray-field NMR can monitor bone marrow cellular changes that are related to osteoporosis. Objectives. To demonstrate sensitivity of a low-field tabletop NMR scanner to bone marrow dynamics following hormonal treatment in rats. Methods. Two-month-old female rats (n = 36) were ovariectomized (OVX) and dosed for the ensuing 3 or 5 weeks with 20 mg/kg of PTH(1-34). Hind limbs femurs and tibiae were isolated and underwent ex vivo microradiography and histology and NMR relaxometry at 6 weeks (preventive experiment) and 11 weeks (therapeutic treatment experiment) after OVX. Results. OVX rats developed osteoporotic changes including adipogenic marrow compared to Sham and PTH treated rats. T2 and ADC NMR relaxation coefficients were found to correlate with marrow composition. Conclusions. This study suggests that stray-field NMR, an affordable method that is sensitive to the rapid cellular changes in bone marrow, may have a clinical value in monitoring hormonal treatment for osteoporosis.

Detection of bone marrow changes related to estrogen withdrawal in rats with a tabletop stray-field NMR scanner.

PURPOSE: Osteoporosis is characterized by a decrease in bone mineral density (BMD). A preliminary stage of the disease is progressive bone marrow adiposity, caused by imbalance between osteogenesis and adipogenesis in the marrow. Detection of osteoporosis relies on the quantification of BMD with techniques such as dual-energy X-ray absorptiometry. This work aimed to detect bone marrow changes in an experimental model of osteopenia using a low-field tabletop NMR scanner. METHODS: An experiment was performed on 32 female rats, 3 months old, 16 of which were ovariectomized (OVX) and 16 were sham-operated (sham). The femur and tibia from both hind limbs were isolated and underwent ex vivo NMR scans at four time points after the OVX and sham operations. NMR scans were complemented by BMD measurements and histology. RESULTS: Significant changes in the bone marrow of ovariectomized rats, relative to sham operated rats, were observed after 3.5 and 4.5 months. Bone marrow adiposity was detected by significant changes in T1 and T2 relaxation times, and in the diffusion coefficient. CONCLUSIONS: This study suggests a potential detection of changes to the bone marrow using a tabletop NMR device. Clinical translation may facilitate screening, early detection of bone weakening as a result of estrogen withdrawal, and monitoring of treatment efficacy. Magn Reson Med 78:860-870, 2017. © 2016 International Society for Magnetic Resonance in Medicine.