Shelby L. Bachman

Background: Wearable sensors that monitor physical behaviors are increasingly adopted in clinical research. Older adult research participants have expressed interest in tracking and receiving feedback on their physical behaviors. Simultaneously, researchers and clinical trial sponsors are interested in returning results to participants, but the question of how to return individual study results derived from research-grade wearable sensors remains unanswered. In this study, we (1) assessed the feasibility of returning individual physical behavior results to older adult research participants and (2) obtained participant feedback on the returned results. Methods: Older adult participants (N = 20; ages 67–96) underwent 14 days of remote monitoring with 2 wearable sensors. We then used a semiautomated process to generate a 1-page report summarizing each participant’s physical behaviors across the 14 days. This report was delivered to each participant via email, and they were asked to evaluate the report. Results: Participants found the reports easy to understand, health-relevant, interesting, and visually pleasing. They had valuable suggestions to improve data interpretability and raised concerns such as comparisons with measures derived from their consumer-grade sensors. Conclusions: We have demonstrated the feasibility of returning individual physical behavior results from research-grade devices to older research participants, and our results indicate that this practice is well-received. Further research to develop more efficient and scalable systems to return results to participants, and to understand the preferences of participants in larger, more representative samples, is warranted.

Background: As the number of cancer survivors increases, maintaining health-related quality of life in cancer survivorship is a priority. This necessitates accurate and reliable methods to assess how cancer survivors are feeling and functioning. Real-world digital measures derived from wearable sensors offer potential for monitoring well-being and physical function in cancer survivorship, but questions surrounding the clinical utility of these measures remain to be answered. Objective: In this secondary analysis, we used 2 existing data sets to examine how measures of real-world physical behavior, captured with a wearable accelerometer, were related to aerobic fitness and self-reported well-being and physical function in a sample of individuals who had completed cancer treatment. Methods: Overall, 86 disease-free cancer survivors aged 21-85 years completed self-report assessments of well-being and physical function, as well as a submaximal exercise test that was used to estimate their aerobic fitness, quantified as predicted submaximal oxygen uptake (VO2). A thigh-worn accelerometer was used to monitor participants’ real-world physical behavior for 7 days. Accelerometry data were used to calculate average values of the following measures of physical behavior: sedentary time, step counts, time in light and moderate to vigorous physical activity, time and weighted median cadence in stepping bouts over 1 minute, and peak 30-second cadence. Results: Spearman correlation analyses indicated that 6 (86%) of the 7 accelerometry-derived measures of real-world physical behavior were not significantly correlated with Functional Assessment of Cancer Therapy-General total well-being or linked Patient-Reported Outcomes Measurement Information System-Physical Function scores (Ps≥.08). In contrast, all but one of the physical behavior measures were significantly correlated with submaximal VO2 (Ps≤.03). Comparing these associations using likelihood ratio tests, we found that step counts, time in stepping bouts over 1 minute, and time in moderate to vigorous activity were more strongly associated with submaximal VO2 than with self-reported well-being or physical function (Ps≤.03). In contrast, cadence in stepping bouts over 1 minute and peak 30-second cadence were not more associated with submaximal VO2 than with the self-reported measures (Ps≥.08). Conclusions: In a sample of disease-free cancer survivors, we found that several measures of real-world physical behavior were more associated with aerobic fitness than with self-reported well-being and physical function. These results highlight the possibility that in individuals who have completed cancer treatment, measures of real-world physical behavior may provide additional information compared with self-reported and performance measures. To advance the appropriate use of digital measures in oncology clinical research, further research evaluating the clinical utility of real-world physical behavior over time in large, representative samples of cancer survivors is warranted. Trial Registration: ClinicalTrials.gov NCT03781154; https://clinicaltrials.gov/ct2/show/NCT03781154

Digital health technologies (DHTs) have the potential to modernize drug development and clinical trial operations by remotely, passively, and continuously collecting ecologically valid evidence that is meaningful to patients’ lived experiences. Such evidence holds potential for all drug development stakeholders, including regulatory agencies, as it will help create a stronger evidentiary link between approval of new therapeutics and the ultimate aim of improving patient lives. However, only a very small number of novel digital measures have matured from exploratory usage into regulatory qualification or efficacy endpoints. This shows that despite the clear potential, actually gaining regulatory agreement that a new measure is both fit-for-purpose and delivers value remains a serious challenge. One of the key stumbling blocks for developers has been the requirement to demonstrate that a digital measure is meaningful to patients. This viewpoint aims to examine the co-evolution of regulatory guidance in the United States (U.S.) and best practice for integration of DHTs into the development of clinical outcome assessments. Contextualizing guidance on meaningfulness within the larger shift towards a patient-centric drug development approach, this paper reviews the U.S. Food and Drug Administration (FDA) guidance and existing literature surrounding the development of meaningful digital measures and patient engagement, including the recent examples of rejections by the FDA that further emphasize patient-centricity in digital measures. Finally, this paper highlights remaining hurdles and provides insights into the established frameworks for development and adoption of digital measures in clinical research.

Digital health technologies offer valuable advantages to dementia researchers and clinicians as screening tools, diagnostic aids, and monitoring instruments. To support the use and advancement of these resources, a comprehensive overview of the current technological landscape is essential. A multi-stakeholder working group, convened by the Digital Medicine Society (DiMe), conducted a landscape review to identify digital health technologies for Alzheimer’s disease and related dementia populations. We searched studies indexed in PubMed, Embase, and APA PsycInfo to identify manuscripts published between May 2003 to May 2023 reporting analytical validation, clinical validation, or usability/feasibility results for relevant digital health technologies. Additional technologies were identified through community outreach. We collated peer-reviewed manuscripts, poster presentations, or regulatory documents for 106 different technologies for Alzheimer’s disease and related dementia assessment covering diverse populations such as Lewy Body, vascular dementias, frontotemporal dementias, and all severities of Alzheimer’s disease. Wearable sensors represent 32% of included technologies, non-wearables 61%, and technologies with components of both account for the remaining 7%. Neurocognition is the most prevalent concept of interest, followed by physical activity and sleep. Clinical validation is reported in 69% of evidence, analytical validation in 34%, and usability/feasibility in 20% (not mutually exclusive). These findings provide clinicians and researchers a landscape overview describing the range of technologies for assessing Alzheimer’s disease and related dementias. A living library of technologies is presented for the clinical and research communities which will keep findings up-to-date as the field develops.

Background: The locus coeruleus (LC) innervates the cerebrovasculature and plays a critical role in optimally regulating cerebral blood flow. However, few studies have examined potential relationships between these systems in humans with widely available neuroimaging methods, and none have explored how relationships may change in the presence of growing Alzheimer’s disease (AD) pathology.Method: Participants were 66 community‐dwelling older adults free of dementia (ages 55‐87) recruited at the University of Southern California. Pseudocontinuous arterial spin labeling (pCASL) MRI measured regional perfusion, and T1‐fast spin echo (T1‐FSE) MRI quantified rostral LC contrast, a well‐established measure of LC structural integrity. Subsets of participants underwent neuropsychological testing (n = 36) as well as fasting venipuncture to measure plasma AD biomarker concentrations of Aβ42/40 ratio (n = 56) and ptau181 (n = 35). Multiple linear regression models examined associations among regional perfusion, LC integrity, and cognition (episodic memory, attention, executive function). Moderation analyses included additional terms for plasma AD biomarker concentrations and plasma x LC interaction effects.Result: Higher LC‐MRI contrast was linked to higher frontal (medial and lateral orbitofrontal) perfusion but lower limbic (amygdala and entorhinal) perfusion. Greater LC‐MRI contrast was also associated with better episodic memory recall and recognition but not measures of attention or executive function. Plasma Aβ42/40 ratio and ptau181 moderated LC‐perfusion relationships such that associations significantly weakened in the presence of greater pathology.Conclusion: This is the first human study to directly investigate associations between LC integrity and perfusion in a well‐characterized sample with neuroimaging, cognitive, and AD biomarker data. LC integrity tracked episodic memory performance along with cerebral perfusion, while greater AD pathology in preclinical populations disrupted LC‐perfusion relationships, suggesting that growing amyloid and tau pathology may negatively impact the LC’s ability to optimally regulate cerebral blood flow. Taken together, our findings highlight the importance of tracking the LC over the AD disease course. Concurrent multimodal imaging of the LC and cerebrovascular function may have potential as a novel non‐invasive biomarker, and future studies should track its utility longitudinally and its relationship with disease severity and other disease markers (e.g., grey matter atrophy, amyloid/tau PET).

Objective:The locus coeruleus (LC) innervates the cerebrovasculature and plays a crucial role in optimal regulation of cerebral blood flow. However, no human studies to date have examined links between these systems with widely available neuroimaging methods. We quantified associations between LC structural integrity and regional cortical perfusion and probed whether varying levels of plasma Alzheimer’s disease (AD) biomarkers (Aß42/40 ratio and ptau181) moderated these relationships.Participants and Methods:64 dementia-free community-dwelling older adults (ages 55-87) recruited across two studies underwent structural and functional neuroimaging on the same MRI scanner. 3D-pCASL MRI measured regional cerebral blood flow in limbic and frontal cortical regions, while T1-FSE MRI quantified rostral LC-MRI contrast, a well-established proxy measure of LC structural integrity. A subset of participants underwent fasting blood draw to measure plasma AD biomarker concentrations (Aß42/40 ratio and ptau181). Multiple linear regression models examined associations between perfusion and LC integrity, with rostral LC-MRI contrast as predictor, regional CBF as outcome, and age and study as covariates. Moderation analyses included additional terms for plasma AD biomarker concentration and plasma x LC interaction.Results:Greater rostral LC-MRI contrast was linked to lower regional perfusion in limbic regions, such as the amygdala (ß = -0.25, p = 0.049) and entorhinal cortex (ß = -0.20, p = 0.042), but was linked to higher regional perfusion in frontal cortical regions, such as the lateral (ß = 0.28, p = 0.003) and medial (ß = 0.24, p = 0.05) orbitofrontal (OFC) cortices. Plasma amyloid levels moderated the relationship between rostral LC and amygdala CBF (Aß42/40 ratio x rostral LC interaction term ß = -0.31, p = 0.021), such that as plasma Aß42/40 ratio decreased (i.e., greater pathology), the strength of the negative relationship between rostral LC integrity and amygdala perfusion decreased. Plasma ptau181levels moderated the relationship between rostral LC and entorhinal CBF (ptau181 x rostral LC interaction term ß = 0.64, p = 0.001), such that as ptau181 increased (i.e., greater pathology), the strength of the negative relationship between rostral LC integrity and entorhinal perfusion decreased. For frontal cortical regions, ptau181 levels moderated the relationship between rostral LC and lateral OFC perfusion (ptau181 x rostral LC interaction term ß = -0.54, p = .004), as well as between rostral LC and medial OFC perfusion (ptau181 x rostral LC interaction term ß = -0.53, p = .005), such that as ptau181 increased (i.e., greater pathology), the strength of the positive relationship between rostral LC integrity and frontal perfusion decreased.Conclusions:LC integrity is linked to regional cortical perfusion in non-demented older adults, and these relationships are moderated by plasma AD biomarker concentrations. Variable directionality of the associations between the LC and frontal versus limbic perfusion, as well as the differential moderating effects of plasma AD biomarkers, may signify a compensatory mechanism and a shifting pattern of hyperemia in the presence of aggregating AD pathology. Linking LC integrity and cerebrovascular regulation may represent an important understudied pathway of dementia risk and may help to bridge competing theories of dementia progression in preclinical AD studies.

BACKGROUND As the number of cancer survivors increases, maintaining health-related quality of life in cancer survivorship is a priority. This necessitates accurate and reliable methods to assess how cancer survivors are feeling and functioning. Real-world digital measures derived from wearable sensors offer potential for monitoring well-being and physical function in cancer survivorship, but questions surrounding the clinical utility of these measures remain to be answered. OBJECTIVE In this secondary analysis, we used 2 existing data sets to examine how measures of real-world physical behavior, captured with a wearable accelerometer, were related to aerobic fitness and self-reported well-being and physical function in a sample of individuals who had completed cancer treatment. METHODS Overall, 86 disease-free cancer survivors aged 21-85 years completed self-report assessments of well-being and physical function, as well as a submaximal exercise test that was used to estimate their aerobic fitness, quantified as predicted submaximal oxygen uptake (VO2). A thigh-worn accelerometer was used to monitor participants’ real-world physical behavior for 7 days. Accelerometry data were used to calculate average values of the following measures of physical behavior: sedentary time, step counts, time in light and moderate to vigorous physical activity, time and weighted median cadence in stepping bouts over 1 minute, and peak 30-second cadence. RESULTS Spearman correlation analyses indicated that 6 (86%) of the 7 accelerometry-derived measures of real-world physical behavior were not significantly correlated with Functional Assessment of Cancer Therapy-General total well-being or linked Patient-Reported Outcomes Measurement Information System-Physical Function scores (Ps≥.08). In contrast, all but one of the physical behavior measures were significantly correlated with submaximal VO2 (Ps≤.03). Comparing these associations using likelihood ratio tests, we found that step counts, time in stepping bouts over 1 minute, and time in moderate to vigorous activity were more strongly associated with submaximal VO2 than with self-reported well-being or physical function (Ps≤.03). In contrast, cadence in stepping bouts over 1 minute and peak 30-second cadence were not more associated with submaximal VO2 than with the self-reported measures (Ps≥.08). CONCLUSIONS In a sample of disease-free cancer survivors, we found that several measures of real-world physical behavior were more associated with aerobic fitness than with self-reported well-being and physical function. These results highlight the possibility that in individuals who have completed cancer treatment, measures of real-world physical behavior may provide additional information compared with self-reported and performance measures. To advance the appropriate use of digital measures in oncology clinical research, further research evaluating the clinical utility of real-world physical behavior over time in large, representative samples of cancer survivors is warranted. CLINICALTRIAL ClinicalTrials.gov NCT03781154; https://clinicaltrials.gov/ct2/show/NCT03781154

Alzheimer’s disease (AD) is a devastating neurodegenerative disease and the primary cause of dementia worldwide. Despite the magnitude of AD’s impact on patients, caregivers, and society, nearly all AD clinical trials fail. A potential contributor to this high rate of failure is that established clinical outcome assessments fail to capture subtle clinical changes, entail high burden for patients and their caregivers, and ineffectively address the aspects of health deemed important by patients and their caregivers. AD progression is associated with widespread changes in physical behavior that have impacts on the ability to function independently, which is a meaningful aspect of health for patients with AD and important for diagnosis. However, established assessments of functional independence remain underutilized in AD clinical trials and are limited by subjective biases and ceiling effects. Digital measures of real-world physical behavior assessed passively, continuously, and remotely using digital health technologies have the potential to address some of these limitations and to capture aspects of functional independence in patients with AD. In particular, measures of real-world gait, physical activity, and life-space mobility captured with wearable sensors may offer value. Additional research is needed to understand the validity, feasibility, and acceptability of these measures in AD clinical research.

PURPOSE: The burden of cancer cachexia on patients' health-related quality of life, specifically their physical functioning, is well documented, but clinical trials thus far have failed to show meaningful improvement in physical functioning. The purpose of this review is to summarize existing methods of assessing physical function in cancer cachexia, outline a path forward for measuring what is meaningful to patients using digital measures derived from digital health technologies (DHTs), and discuss the current landscape of digital measures from the clinical and regulatory standpoint. DESIGN: For this narrative review, peer-reviewed articles were searched on PubMed, clinical trials records were searched on clinicaltrials.gov, and records of digital measures submitted for regulatory qualification were searched on the US Food and Drug Administration's Drug Development Tool Qualification Program database. RESULTS: There are gaps in assessing aspects of physical function that matter to patients. Existing assessment methods such as patient-reported outcomes and objective performance outcomes have limitations, including their episodic nature and burden to patients. DHTs such as wearable sensors can capture real-world physical behavior continuously, passively, and remotely, and may provide a more comprehensive picture of patients' everyday functioning. Recent regulatory submissions showcase potential clinical implementation of digital measures in various therapeutic areas. CONCLUSION: Digital measures of real-world physical behavior present an opportunity to detect and demonstrate improvements in physical functioning in cancer cachexia, but evidence-based development is critical. For their use in clinical and regulatory decision making, studies demonstrating meaningfulness to patients as well as feasibility and validation are necessary.

Physiological arousal affects attention and memory, sometimes enhancing and other times impairing what we attend to and remember. In the present study, we investigated how changes in physiological arousal-induced through short bursts of isometric handgrip exercise-affected subsequent working memory performance. A sample of 57 younger (ages 18-29) and 56 older (ages 65-85) participants performed blocks of isometric handgrip exercise in which they periodically squeezed a therapy ball, alternating with blocks of an auditory working memory task. We found that, compared with those in a control group, participants who performed isometric handgrip had faster reaction times on the working memory task. Handgrip-speeded responses were observed for both younger and older participants, across working memory loads. Analysis of multimodal physiological responses indicated that physiological arousal increased during handgrip. Our findings suggest that performing short bouts of isometric handgrip exercise can improve processing speed, and they offer testable possibilities for the mechanism underlying handgrip's effects on performance. The potential for acute isometric exercise to temporarily improve processing speed may be of particular relevance for older adults who show declines in processing speed and working memory. (PsycInfo Database Record (c) 2023 APA, all rights reserved).