Feasibility and usability of remote monitoring in Alzheimer's disease.

Introduction: Remote monitoring technologies (RMTs) can measure cognitive and functional decline objectively at-home, and offer opportunities to measure passively and continuously, possibly improving sensitivity and reducing participant burden in clinical trials. However, there is skepticism that age and cognitive or functional impairment may render participants unable or unwilling to comply with complex RMT protocols. We therefore assessed the feasibility and usability of a complex RMT protocol in all syndromic stages of Alzheimer's disease and in healthy control participants. Methods: For 8 weeks, participants (N = 229) used two activity trackers, two interactive apps with either daily or weekly cognitive tasks, and optionally a wearable camera. A subset of participants participated in a 4-week sub-study (N = 45) using fixed at-home sensors, a wearable EEG sleep headband and a driving performance device. Feasibility was assessed by evaluating compliance and drop-out rates. Usability was assessed by problem rates (e.g., understanding instructions, discomfort, forgetting to use the RMT or technical problems) as discussed during bi-weekly semi-structured interviews. Results: Most problems were found for the active apps and EEG sleep headband. Problem rates increased and compliance rates decreased with disease severity, but the study remained feasible. Conclusions: This study shows that a highly complex RMT protocol is feasible, even in a mild-to-moderate AD population, encouraging other researchers to use RMTs in their study designs. We recommend evaluating the design of individual devices carefully before finalizing study protocols, considering RMTs which allow for real-time compliance monitoring, and engaging the partners of study participants in the research.

Augmented reality versus standard tests to assess cognition and function in early Alzheimer's disease.

Augmented reality (AR) apps, in which the virtual and real world are combined, can recreate instrumental activities of daily living (IADL) and are therefore promising to measure cognition needed for IADL in early Alzheimer's disease (AD) both in the clinic and in the home settings. The primary aim of this study was to distinguish and classify healthy controls (HC) from participants with AD pathology in an early AD stage using an AR app. The secondary aims were to test the association of the app with clinical cognitive and functional tests and investigate the feasibility of at-home testing using AR. We furthermore investigated the test-retest reliability and potential learning effects of the task. The digital score from the AR app could significantly distinguish HC from preclinical AD (preAD) and prodromal AD (proAD), and preAD from proAD, both with in-clinic and at-home tests. For the classification of the proAD group, the digital score (AUCclinic_visit = 0.84 [0.75-0.93], AUCat_home = 0.77 [0.61-0.93]) was as good as the cognitive score (AUC = 0.85 [0.78-0.93]), while for classifying the preAD group, the digital score (AUCclinic_visit = 0.66 [0.53-0.78], AUCat_home = 0.76 [0.61-0.91]) was superior to the cognitive score (AUC = 0.55 [0.42-0.68]). In-clinic and at-home tests moderately correlated (rho = 0.57, p < 0.001). The digital score was associated with the clinical cognitive score (rho = 0.56, p < 0.001). No learning effects were found. Here we report the AR app distinguishes HC from otherwise healthy Aß-positive individuals, both in the outpatient setting and at home, which is currently not possible with standard cognitive tests.

Correction: Ethical challenges of using remote monitoring technologies for clinical research: A case study of the role of local research ethics committees in the RADAR-AD study.

[This corrects the article DOI: 10.1371/journal.pone.0285807.].

Differences in Life Space Activity Patterns Between Older Adults With Mild Cognitive Impairment Living Alone or as a Couple: Cohort Study Using Passive Activity Sensing.

BACKGROUND: Measuring function with passive in-home sensors has the advantages of real-world, objective, continuous, and unobtrusive measurement. However, previous studies have focused on 1-person homes only, which limits their generalizability. OBJECTIVE: This study aimed to compare the life space activity patterns of participants living alone with those of participants living as a couple and to compare people with mild cognitive impairment (MCI) with cognitively normal participants in both 1- and 2-person homes. METHODS: Passive infrared motion sensors and door contact sensors were installed in 1- and 2-person homes with cognitively normal residents or residents with MCI. A home was classified as an MCI home if at least 1 person in the home had MCI. Time out of home (TOOH), independent life space activity (ILSA), and use of the living room, kitchen, bathroom, and bedroom were calculated. Data were analyzed using the following methods: (1) daily averages over 4 weeks, (2) hourly averages (time of day) over 4 weeks, or (3) longitudinal day-to-day changes. RESULTS: In total, 129 homes with people living alone (n=27, 20.9%, MCI and n=102, 79.1%, no-MCI homes) and 52 homes with people living as a couple (n=24, 46.2%, MCI and n=28, 53.8%, no-MCI homes) were included with a mean follow-up of 719 (SD 308) days. Using all 3 analysis methods, we found that 2-person homes showed a shorter TOOH, a longer ILSA, and shorter living room and kitchen use. In MCI homes, ILSA was higher in 2-person homes but lower in 1-person homes. The effects of MCI status on other outcomes were only found when using the hourly averages or longitudinal day-to-day changes over time, and they depended on the household type (alone vs residing as a couple). CONCLUSIONS: This study shows that in-home behavior is different when a participant is living alone compared to when they are living as a couple, meaning that the household type should be considered when studying in-home behavior. The effects of MCI status can be detected with in-home sensors, even in 2-person homes, but data should be analyzed on an hour-to-hour basis or longitudinally.

Digital endpoints in clinical trials of Alzheimer's disease and other neurodegenerative diseases: challenges and opportunities.

Alzheimer's disease (AD) and other neurodegenerative diseases such as Parkinson's disease (PD) and Huntington's disease (HD) are associated with progressive cognitive, motor, affective and consequently functional decline considerably affecting Activities of Daily Living (ADL) and quality of life. Standard assessments, such as questionnaires and interviews, cognitive testing, and mobility assessments, lack sensitivity, especially in early stages of neurodegenerative diseases and in the disease progression, and have therefore a limited utility as outcome measurements in clinical trials. Major advances in the last decade in digital technologies have opened a window of opportunity to introduce digital endpoints into clinical trials that can reform the assessment and tracking of neurodegenerative symptoms. The Innovative Health Initiative (IMI)-funded projects RADAR-AD (Remote assessment of disease and relapse-Alzheimer's disease), IDEA-FAST (Identifying digital endpoints to assess fatigue, sleep and ADL in neurodegenerative disorders and immune-mediated inflammatory diseases) and Mobilise-D (Connecting digital mobility assessment to clinical outcomes for regulatory and clinical endorsement) aim to identify digital endpoints relevant for neurodegenerative diseases that provide reliable, objective, and sensitive evaluation of disability and health-related quality of life. In this article, we will draw from the findings and experiences of the different IMI projects in discussing (1) the value of remote technologies to assess neurodegenerative diseases; (2) feasibility, acceptability and usability of digital assessments; (3) challenges related to the use of digital tools; (4) public involvement and the implementation of patient advisory boards; (5) regulatory learnings; and (6) the significance of inter-project exchange and data- and algorithm-sharing.

Ethical challenges of using remote monitoring technologies for clinical research: A case study of the role of local research ethics committees in the RADAR-AD study.

INTRODUCTION: Clinical research with remote monitoring technologies (RMTs) has multiple advantages over standard paper-pencil tests, but also raises several ethical concerns. While several studies have addressed the issue of governance of big data in clinical research from the legal or ethical perspectives, the viewpoint of local research ethics committee (REC) members is underrepresented in the current literature. The aim of this study is therefore to find which specific ethical challenges are raised by RECs in the context of a large European study on remote monitoring in all syndromic stages of Alzheimer's disease, and what gaps remain. METHODS: Documents describing the REC review process at 10 sites in 9 European countries from the project Remote Assessment of Disease and Relapse-Alzheimer's Disease (RADAR-AD) were collected and translated. Main themes emerging in the documents were identified using a qualitative analysis approach. RESULTS: Four main themes emerged after analysis: data management, participant's wellbeing, methodological issues, and the issue of defining the regulatory category of RMTs. Review processes differed across sites: process duration varied from 71 to 423 days, some RECs did not raise any issues, whereas others raised up to 35 concerns, and the approval of a data protection officer was needed in half of the sites. DISCUSSION: The differences in the ethics review process of the same study protocol across different local settings suggest that a multi-site study would benefit from a harmonization in research ethics governance processes. More specifically, some best practices could be included in ethical reviews across institutional and national contexts, such as the opinion of an institutional data protection officer, patient advisory board reviews of the protocol and plans for how ethical reflection is embedded within the study.

Physical activity levels in cognitively normal and cognitively impaired oldest-old and the association with dementia risk factors: a pilot study.

BACKGROUND: Research assessing the relationship of physical activity and dementia is usually based on studies with individuals younger than 90 years of age. The primary aim of this study was to determine physical activity levels of cognitively normal and cognitively impaired adults older than 90 years of age (oldest-old). Our secondary aim was to assess if physical activity is associated with risk factors for dementia and brain pathology biomarkers. METHODS: Physical activity was assessed in cognitively normal (N = 49) and cognitively impaired (N = 12) oldest-old by trunk accelerometry for a 7-day period. We tested physical performance parameters and nutritional status as dementia risk factors, and brain pathology biomarkers. Linear regression models were used to examine the associations, correcting for age, sex and years of education. RESULTS: Cognitively normal oldest-old were on average active for a total duration of 45 (SD 27) minutes per day, while cognitively impaired oldest-old seemed less physically active with 33 (SD 21) minutes per day with a lower movement intensity. Higher active duration and lower sedentary duration were related to better nutritional status and better physical performance. Higher movement intensities were related to better nutritional status, better physical performance and less white matter hyperintensities. Longer maximum walking bout duration associated with more amyloid binding. CONCLUSION: We found that cognitively impaired oldest-old are active at a lower movement intensity than cognitively normal oldest-old individuals. In the oldest-old, physical activity is related to physical parameters, nutritional status, and moderately to brain pathology biomarkers.

Assessment of Social Behavior Using a Passive Monitoring App in Cognitively Normal and Cognitively Impaired Older Adults: Observational Study.

BACKGROUND: In people with cognitive impairment, loss of social interactions has a major impact on well-being. Therefore, patients would benefit from early detection of symptoms of social withdrawal. Current measurement techniques such as questionnaires are subjective and rely on recall, in contradiction to smartphone apps, which measure social behavior passively and objectively. OBJECTIVE: This study uses the remote monitoring smartphone app Behapp to assess social behavior, and aims to investigate (1) the association between social behavior, demographic characteristics, and neuropsychiatric symptoms in cognitively normal (CN) older adults, and (2) if social behavior is altered in cognitively impaired (CI) participants. In addition, we explored in a subset of individuals the association between Behapp outcomes and neuropsychiatric symptoms. METHODS: CN, subjective cognitive decline (SCD), and CI older adults installed the Behapp app on their own Android smartphone for 7 to 42 days. CI participants had a clinical diagnosis of mild cognitive impairment (MCI) or Alzheimer-type dementia. The app continuously measured communication events, app use and location. Neuropsychiatric Inventory (NPI) total scores were available for 20 SCD and 22 CI participants. Linear models were used to assess group differences on Behapp outcomes and to assess the association of Behapp outcomes with the NPI. RESULTS: We included CN (n=209), SCD (n=55) and CI (n=22) participants. Older cognitively normal participants called less frequently and made less use of apps (P<.05). No sex effects were found. Compared to the CN and SCD groups, CI individuals called less unique contacts (ß=-0.7 [SE 0.29], P=.049) and contacted the same contacts relatively more often (ß=0.8 [SE 0.25], P=.004). They also made less use of apps (ß=-0.83 [SE 0.25], P=.004). Higher total NPI scores were associated with further traveling (ß=0.042 [SE 0.015], P=.03). CONCLUSIONS: CI individuals show reduced social activity, especially those activities that are related to repeated and unique behavior, as measured by the smartphone app Behapp. Neuropsychiatric symptoms seemed only marginally associated with social behavior as measured with Behapp. This research shows that the Behapp app is able to objectively and passively measure altered social behavior in a cognitively impaired population.

Remote monitoring technologies in Alzheimer's disease: design of the RADAR-AD study.

BACKGROUND: Functional decline in Alzheimer's disease (AD) is typically measured using single-time point subjective rating scales, which rely on direct observation or (caregiver) recall. Remote monitoring technologies (RMTs), such as smartphone applications, wearables, and home-based sensors, can change these periodic subjective assessments to more frequent, or even continuous, objective monitoring. The aim of the RADAR-AD study is to assess the accuracy and validity of RMTs in measuring functional decline in a real-world environment across preclinical-to-moderate stages of AD compared to standard clinical rating scales. METHODS: This study includes three tiers. For the main study, we will include participants (n = 220) with preclinical AD, prodromal AD, mild-to-moderate AD, and healthy controls, classified by MMSE and CDR score, from clinical sites equally distributed over 13 European countries. Participants will undergo extensive neuropsychological testing and physical examination. The RMT assessments, performed over an 8-week period, include walk tests, financial management tasks, an augmented reality game, two activity trackers, and two smartphone applications installed on the participants' phone. In the first sub-study, fixed sensors will be installed in the homes of a representative sub-sample of 40 participants. In the second sub-study, 10 participants will stay in a smart home for 1 week. The primary outcome of this study is the difference in functional domain profiles assessed using RMTs between the four study groups. The four participant groups will be compared for each RMT outcome measure separately. Each RMT outcome will be compared to a standard clinical test which measures the same functional or cognitive domain. Finally, multivariate prediction models will be developed. Data collection and privacy are important aspects of the project, which will be managed using the RADAR-base data platform running on specifically designed biomedical research computing infrastructure. RESULTS: First results are expected to be disseminated in 2022. CONCLUSION: Our study is well placed to evaluate the clinical utility of RMT assessments. Leveraging modern-day technology may deliver new and improved methods for accurately monitoring functional decline in all stages of AD. It is greatly anticipated that these methods could lead to objective and real-life functional endpoints with increased sensitivity to pharmacological agent signal detection.

A long-term effect of distal radius fracture on the sensorimotor control of the wrist joint in older adults.

INTRODUCTION: Sensorimotor control can be disturbed because of pain and trauma. There is scarce comprehension about which component of the sensorimotor system would benefit the most from treatment in distal radius fracture (DRF). PURPOSE OF THE STUDY: The purpose of this study was to determine whether the sensorimotor control of subjects with a history of DRF impaired compared with healthy subjects. If so, which component of the sensorimotor system is most affected. METHODS: Nine healthy participants and 11 participants with a DRF history executed posture and reproduction tasks in interaction with a robotic wrist manipulator. A posture task with force perturbations assess sensorimotor control. Position and force reproduction tasks assessed sensory feedback. Electromyography recorded the muscle activity to study the motor part of the sensorimotor system. STUDY DESIGN: Cross-sectional case-control. RESULTS: The results showed that the motor responses to the perturbations during the posture task did not differ significantly, whereas the position reproduction did significantly differ between the 2 groups. Moreover, participants with a DRF history did not adapt to the changed dynamics of the environment during the posture task, whereas the controls did. DISCUSSION: The results of this study imply that processing of sensory position feedback is impaired in people with a DRF history while sensorimotor control during a posture task is unaffected. A possible explanation for these results is that different neural networks are involved during reproduction and posture tasks. CONCLUSIONS: A history of DRF is related to disturbed processing of sensory feedback of the sensorimotor system, especially the Joint Position Sense, which leads to an impairment in detecting a changed environment and adapting to it. Impaired Joint Position Sense and thereby the inability to adapt adequately to a changing environment should be taken into account during the rehabilitation of patients with DRF.

Gait Disturbances are Associated with Increased Cognitive Impairment and Cerebrospinal Fluid Tau Levels in a Memory Clinic Cohort.

BACKGROUND: Gait analysis with accelerometers is a relatively inexpensive and easy to use method to potentially support clinical diagnoses of Alzheimer's disease and other dementias. It is not clear, however, which gait features are most informative and how these measures relate to Alzheimer's disease pathology. OBJECTIVE: In this study, we tested if calculated features of gait 1) differ between cognitively normal subjects (CN), mild cognitive impairment (MCI) patients, and dementia patients, 2) are correlated with cerebrospinal fluid (CSF) biomarkers related to Alzheimer's disease, and 3) predict cognitive decline. METHODS: Gait was measured using tri-axial accelerometers attached to the fifth lumbar vertebra (L5) in 58 CN, 58 MCI, and 26 dementia participants, while performing a walk and dual task. Ten gait features were calculated from the vertical L5 accelerations, following principal component analysis clustered in four domains, namely pace, rhythm, time variability, and length variability. Cognitive decline over time was measured using MMSE, and CSF biomarkers were available in a sub-group. RESULTS: Linear mixed models showed that dementia patients had lower pace scores than MCI patients and CN subjects (p < 0.05). In addition, we found associations between the rhythm domain and CSF-tau, especially in the dual task. Gait was not associated with CSF Aß42 levels and cognitive decline over time as measured with the MMSE. CONCLUSION: These findings suggest that gait - particularly measures related to pace and rhythm - are altered in dementia and have a direct link with measures of neurodegeneration.

A four-dimensional-CT study of in vivo scapholunate rotation axes: possible implications for scapholunate ligament reconstruction.

Additional fixation of the palmar scapholunate interosseous ligament has been advocated to improve the long-term results of dorsal scapholunate interosseous ligament reconstruction. To investigate the validity of this approach, we determined normal scapholunate motion patterns and calculated the location of the scapholunate rotation axis. We hypothesized that the optimal location of the scapholunate interosseous ligament insertion could be determined from the scapholunate rotation axis. Four-dimensional computerized tomography was used to study the wrist motion in 21 healthy participants. During flexion-extension motions, the scaphoid rotates 38° (SD 0.6°) relative to the lunate; the rotation axis intersects the dorsal ridge of the proximal pole of the scaphoid and the dorsal ridge of the lunate. Minimal scapholunate motion is present during radioulnar deviation. Since the scapholunate rotation axis runs through the dorsal proximal pole of the scaphoid, this is probably the optimal location for attaching the scapholunate ligament during reconstructive surgery.