Addressing the Chronic Pain–Early Cognitive Decline Comorbidity Among Older Adults: Protocol for the Active Brains Remote Efficacy Trial

Background Chronic pain and early cognitive decline, which are costly to treat and highly prevalent among older adults, commonly co-occur, exacerbate one another over time, and can accelerate the development and progression of Alzheimer disease and related dementias. We developed the first mind-body activity program (Active Brains [AB]) tailored to the needs of older adults with chronic pain and early cognitive decline. Results from our previous study strongly supported the feasibility of conducting AB remotely and provided evidence for improvements in outcomes. Objective We are conducting a single-blinded, National Institutes of Health stage-2, randomized clinical trial to establish the efficacy of AB versus a time-matched and dose-matched education control (Health Enhancement Program [HEP]) in improving self-reported and objective outcomes of physical, cognitive, and emotional functions in 260 participants. The methodology described in this paper was informed by the lessons learned from the first year of the trial. Methods Participants are identified and recruited through multidisciplinary clinician–referred individuals (eg, pain psychologists and geriatricians), the Rally Research platform, social media, and community partnerships. Interested participants complete eligibility screening and electronic informed consent. Baseline assessments include self-report, performance-based measures (eg, 6-min walk test) and objective measures (eg, Repeatable Battery for the Assessment of Neuropsychological Status). Participants are mailed a wrist-worn ActiGraph device (ActiGraph LLC) to passively monitor objective function (eg, steps) during the week between the baseline assessment and the beginning of the programs, which they continue to wear throughout the programs. After baseline assessments, participants are randomized to either AB or HEP and complete 8 weekly, remote, group sessions with a Massachusetts General Hospital psychologist. The AB group receives a Fitbit (Fitbit Inc) to help reinforce increased activity. Assessments are repeated after the intervention and at the 6-month follow-up. Coprimary outcomes include multimodal physical function (self-report, performance based, and objective). Secondary outcomes are cognitive function (self-report and objective), emotional function, and pain. Results We began recruitment in July 2022 and recruited 37 participants across 4 cohorts. Of them, all (n=37, 100%) have completed the baseline assessment, 26 (70%) have completed the posttest assessment, and 9 (24%) are actively enrolled in the intervention (total dropout: n=2, 5%). In the three cohorts (26/37, 70%) that have completed the AB or HEP, 26 (100%) participants completed all 8 group sessions (including minimal makeups), and watch adherence (1937/2072, 93.48%, average across ActiGraph and Fitbit devices) has been excellent. The fourth cohort is ongoing (9/37, 24%), and we plan to complete enrollment by March 2026. Conclusions We aim to establish the efficacy of the AB program over a time-matched and dose-matched control in a live video-based trial and test the mechanisms through theoretically driven mediators and moderators. Findings will inform the development of a future multisite effectiveness-implementation trial. Trial Registration ClinicalTrials.gov NCT05373745; https://classic.clinicaltrials.gov/ct2/show/NCT05373745 International Registered Report Identifier (IRRID) DERR1-10.2196/47319

the present investigation is to test the efficacy of a novel, theory informed multimodal mind body activity program to improve physical, emotional and cognitive functioning in older adults with chronic musculoskeletal pain and early cognitive decline.Through this study, we seek to solve the unmet need of lack of evidence-based treatments to address chronic pain in older adults with early cognitive decline through a feasible, acceptable and credible program, and ideally delay progression toward ADRD.

CRITIQUE 1
Significance: 5 Investigator(s): 3 Innovation: 3 Approach: 4 Environment: 1 Overall Impact: In light of evidence from epidemiologic studies suggesting that chronic pain (CP) may be linked with early cognitive decline (ECD) and the development of Alzheimer's Disease and Related Dementias (ADRD), the investigators propose a mind-body and activity program that is walking-based and teaches individuals how to manage pain and build cognitive reserves as a solution to address the CP-ECD comorbidity among older adults.The environment for the study is excellent, housing the Integrated Brain Health Clinical and Research Program and the Multicultural Alzheimer's Prevention Program.The study team is also very good but could benefit from the addition of an exercise physiologist to refine the exercise program.Innovation is good as this is the first multimodal program to address the CP-ECD comorbidity in older adults.A few methodological issues are noted including 1) primary outcomes that are not pain or cognition related, particularly when the study premise is built entirely on this co-morbidity 2) an exercise program (potential max of 10% increase in steps from baseline) that is not consistent with the literature on exercise and cognition 3) inclusion and exclusion criteria in need of refinement and 4) lack of longer-term follow-up when there is a focus on ADRD prevention.Enthusiasm is also diminished by the lack of assessment of other established risk factors for ADRD or neuroinflammation -a likely commonality in CP and ECD that may portend the transition to ADRD.Overall, the project is likely to have moderate impact in the field of ADRD.

Strengths
• ADRD and chronic pain are prevalent in the elderly and associated with significant economic and societal burden.
• Chronic pain can have significant effects on neurocognitive function.Because the neural systems involved in memory and cognition are closely linked to those involved in pain processing, these systems may affect one another reciprocally disrupting cognitive processing and contributing to a downward spiral of continuing pain, adverse neurostructural changes, and deteriorating cognitive function.Altering this downward trajectory may importantly slow the transition to ADRD.

Weaknesses
• While existing studies support a link between chronic pain and ADRD risk, conclusions are limited by substantial study heterogeneity, limited investigation of certain pain conditions, and methodological concerns.
• Noradrenergic system dysfunction and neuroinflammation resulting from microglial proinflammatory activation in brain areas mediating the affective component of pain and cognition have been found to influence both chronic pain and AD.It is not clear that the multimodal program designed for this study, which currently does not measure either of these parameters (or any of the other well known risk factors for ADRD) would have a significant effect upon the development of ADRD.
• Based on the guidelines of exercise in old age recommended by official bodies, exercise modes include aerobic activity, strength training (resistance exercise), flexibility, balance, and coordination.In prior studies, resistance exercise had the highest probability of being the optimal exercise type for slowing cognitive decline in patients with cognitive dysfunction, especially in patients with dementia.Multi-component exercise, however, tended to be most effective in protecting global cognition and executive function in patients with MCI.Thus, it is not clear that simply increasing the step count over 8 weeks would improve cognition over the longterm and decrease the occurrence of ADRD.

Strengths
• PI is the Founding Director of the Integrated Brain Health Clinical and Research Program with a track record in clinical trials and publications on technology enhanced mind-body and lifestyle interventions.

Weaknesses
• The study team would benefit from the addition of an exercise physiologist.
• Postdoctoral fellow and unblinded statistician roles appear to be more consistent with that of "other personnel".

Strengths
• First multimodal program to address chronic pain -early cognitive decline in older adults.
• Integration of technology (actigraphy, video meeting platform, virtual MoCA, Timed Walk app) to conduct a virtual clinical trial that if successful, could significantly increase access to care.
• Linking walking with activities of daily living that are valued (e.g.walking with family) to sustain activity over time.

Weaknesses
• Technology and methods by themselves are not particularly novel.
• An assessment of neuroinflammatory biomarkers (CSF) would add novelty.

Approach:
Strengths BMHO VRANCEANU, A • Multimodal mind-body activity program that is grounded in the fear avoidance model and integrates walking skills, mindfulness, pain-specific cognitive behavioral awareness, and positive psychology skills.
• Rigorous evaluation of intervention fidelity.
• Attempt to enhance access to care using a virtual approach in entirety.
• Evolution of the methodology based on previous trial experience.
• Preliminary data supporting efficacy of the Active-Brains-Digital intervention on improving physical and cognitive function and decreasing pain.

Weaknesses
• Since the premise of the study is that the multimodal mind-body activity program would decrease pain and slow the transition to ADRD (improve cognition) or address the CP-ECD comorbidity, it is not clear why reductions in pain and improvements in cognition are not the primary outcomes.The rationale provided for not assessing pain as the primary outcome is weak -if in fact, the AB-D program will only moderate pain flare-ups and not reduce overall intensity, it appears that the transition to ADRD will not be moderated.
• It is not clear that increasing steps by 600-1000/day (as the primary exercise method) will be sufficient to slow the progression to ADRD.Consideration should also be given to excluding subjects with > 5000 steps/day as part of the broader exclusion criterion of regular exercise for > 30 minutes a day.Such an approach would require a run-in period of evaluation but would minimize confounding from participants who are active but not formally exercising.
• Because it is a treatment confound, any prior exposure to mindfulness practice or CBT should be an exclusion criterion.
• Inclusion criteria for chronic pain should also be defined by a minimum pain score (e.g.> 3).
• Longer-term follow-up (12 months) is desirable since the study premise is focused on slowing the progression to ADRD.Since enrollment will be completed by year 4, a longer-term follow-up focused on pain and cognitive function is feasible.The transition to dementia could also be assessed in a subset of these older patients enrolled in the first 2 years and followed for an additional 3 years.
• The method of assessing subjective cognitive decline (e.g.Subjective Cognitive Decline Questionnaire) or MCI at baseline is undefined.
• Genetic markers of ADRD should be assessed as treatment confounds.
• Practice effects from use of the MoCA within 8 weeks are not addressed.
• With co-primary physical function outcomes, multiple comparisons are not addressed.• Pain Clinic and Memory Unit at MGH serve as referral sources.

Environment
• Multicultural Alzheimer's Prevention Program is a resource for the recruitment of a racially and ethnically diverse population.

Strengths
• Multiple sites for recruitment including Boston area black churches.
• Contingency plan in place for recruitment deficiencies.

Weaknesses
• None noted

Protections for Human Subjects:
Acceptable Risks and/or Adequate Protections • Risks related to exercise are appropriately managed.
Data and Safety Monitoring Plan (Applicable for Clinical Trials Only):

Acceptable
• DSMC with members independent of study team

Inclusion Plans:
• Sex/Gender: Distribution justified scientifically Overall Impact: This is a well-written application from a strong scientific team with an excellent environment.Significance and innovation are potentially high: chronic pain and cognitive decline are common in older adults and may together contribute to a disability spiral.The team has previously developed the intervention to be tested based on theory, and has pilot-tested it with the relevant population.
The described intervention has the potential to lead to improved outcomes in a variety of relevant domains.The main weakness in significance and innovation is that the minimal review of previous PA interventions (or lack thereof) in this population or similar populations.Overall, the approach is very strong with numerous elements that represent a scientifically rigorous design.
Investigators are focusing on recruiting a more racially/ethnic diverse sample than they had in their pilot study.I had some minor concerns/ questions about the approach, including some need for clarification on inclusion criteria, content of the control intervention, and the moderator hypotheses.Finally, I would like to see justification of the use of psychologists to lead this program and/or inclusion of other professionals to lead the program.This could contribute to dissemination efforts later.

Strengths
• Chronic pain and cognitive decline are common in older adults; together, they may contribute to a "disability spiral." • The intervention to be tested, Active Minds, uses mind-body skills to promote physical activity.
The target of this intervention is improved physical functioning, cognitive functioning, and emotional functioning.A real strength of this intervention is the possibility that it may lead to improved outcomes in a variety of domains.Further, a walking program may be most accessible to this population (compared to a program that requires gym attendance or equipment).The intervention has been developed based on theory and pilot-tested.

Weaknesses
• There is minimal review of previous physical activity interventions (or lack thereof) in similar populations (i.e., older adults with chronic pain or with cognitive decline).This impedes assessment of significance and innovation.

Strengths
• PI Dr. Vranceanu has expertise in remote delivery of mind-body interventions, interventions to promote physical activity, and research with people with chronic pain.She was PI on an R34 study to develop and pilot-test the proposed intervention.
• The study team includes expertise in gerontology, chronic pain, mind-body interventions, neuropsychology, health disparities, and biostatistics.The team has worked together on previous projects.BMHO VRANCEANU, A • It would be helpful to have more details on HEP to ensure does not overlap with the active intervention.
• It appears that there will be a number of moderator analyses, but there are no specific hypotheses re: "relevant clinical and demographic variables."

Strengths
• There appears to be an adequate-sized pool of potential participants at MGH.
• MGH is an excellent clinical and academic site for this work.

Strengths
• Study timeline is very detailed.

Protections for Human Subjects:
Acceptable Risks and/or Adequate Protections • Risks are minimal.
• Investigators might provide more detail on the potential for loss of confidentiality in a group treatment.
Data and Safety Monitoring Plan (Applicable for Clinical Trials Only):

Acceptable
• Includes a DSMB.

Inclusion Plans:
• Sex/Gender: Distribution justified scientifically • Race/Ethnicity: Distribution justified scientifically • Inclusion/Exclusion Based on Age: Distribution justified scientifically • Investigators plan to increase recruitment of racial/ethnic minorities relative to their pilot trial --to 38% of the sample.
• Investigators plan to include people aged 60 and older, and at least 50% of their sample wil be women.

Vertebrate Animals:
Not Applicable (No Vertebrate Animals) Overall Impact: This application describes an RCT comparing a comprehensive remote group based behavioral intervention to an active control condition to improve physical functioning in older adults with chronic pain and early cognitive decline.The overall impact of this application is judged to be high due to exceptionally strong pilot data that demonstrates feasibility and preliminary efficacy of the intervention, the experienced investigative team and exceptional environment, and the focus on functional everyday engagement.Few weaknesses were identified and the application addressed many of them, including targeted focus on enrolling a diverse sample.While some limitations in traditional cognitive assessment are inherent in a fully remote study design, the objective cognitive assessment is limited to the MoCA, which may not be sensitive to more subtle improvements.The proposal does not sufficiently describe how the MoCA will be used to identify "early cognitive decline" -is there a cut score that will be used?There are also concerns about nonstandard remote administration of the MoCA (i.e., mailing stimuli to participants is not standard practice for telehealth administration of the MoCA).There is also no effort to obtain a clinical diagnosis of MCI or follow-up adjudication of progression to dementia in order to link to the broader literature.

Strengths
• Addressing multiple potentially modifiable risk factors (that contribute substantially to QOL) for cognitive decline and ADRD will have considerable impact, even if it does not alter the cognitive course, in this difficult to manage population

•
The multimodal intervention has the potential to impact multiple outcome domains simultaneously • Targeted strategies for increasing inclusion of racial/ethnic minority participants • Patient population is not restricted to a specific type of pain and early cognitive decline is defined broadly to allow greater generalizability BMHO VRANCEANU, A • Despite cognition being a secondary outcome, the assessment is quite minimal.A more comprehensive remote cognitive assessment would provide more compelling data regarding potential for delaying progression to dementia

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Integrated Brain Health Clinical and Research Program founded by PI for the study, advancement, and clinical practice of evidenced based mind body and lifestyle interventions.

•
Clinical assessment of MCI vs Dementia vs normal at the end of the trial would allow for translation of the intervention outcomes to the broader ADRD literature