A study protocol for MindMoves: A lifestyle physical activity and cognitive training intervention to prevent cognitive impairment in older women with cardiovascular disease

Abstract

Introduction:

Cognitive impairment (CI) and cardiovascular disease (CVD) disproportionately affect women compared to men, and CVD increases risk of CI. Physical activity and cognitive training can improve cognition in older adults and may have additive or synergistic effects. However, no combined intervention has targeted women with CVD or utilized a sustainable lifestyle approach. The purpose of the trial is to evaluate efficacy of MindMoves, a 24-week multimodal physical activity and cognitive training intervention, on cognition and serum biomarkers in older women with CVD. Three serum biomarkers (brain-derived neurotrophic factor [BDNF], vascular endothelial growth factor [VEGF], and insulin-like growth factor 1 [IGF-1]) were selected as a priori hypothesized indicators of the effects of physical activity and/or cognitive training on cognition.

Methods:

The study design is a randomized controlled trial with a 2x2 factorial design, to determine independent and combined efficacies of Mind (tablet-based cognitive training) and Move (lifestyle physical activity with goal-setting and group meetings) on change in cognition (primary outcome) and serum biomarkers (secondary outcomes). We will recruit 254 women aged ≥65 years with CVD and without CI from cardiology clinics. Women will be randomized to one of four conditions: (1)Mind, (2) Move, (3) MindMoves, or (4) usual care. Data will be obtained from participants at baseline, 24, 48, and 72 weeks.

Discussion:

This study will test efficacy of a lifestyle-focused intervention to prevent or delay cognitive impairment in older women with CVD and may identify relevant serum biomarkers that could be used as early indicators of intervention response.

1. Introduction

Women experience disproportionately high rates of cognitive impairment, especially with increasing age [1-5] compared to men [6,7]. A leading risk factor for cognitive impairment is cardiovascular disease (CVD; e.g., coronary artery disease, hypertension) [6-8], which increases the risk for cognitive impairment by 29-66% [9-12] and affects 44 million women in the US alone [13]. Cognitive impairment due to CVD [14-16] may be prevented or delayed with interventions that target modifiable lifestyle behaviors associated with CVD. For instance, both physical activity interventions [17-20] and cognitive training [21-23] (an intervention that increases cognitive activity with mentally-challenging tasks) improve cognition in healthy older adults [24-26]. Physical activity interventions and cognitive training may be even more effective in a combined multimodal intervention due to potential synergistic effects [27-30].

Physical activity interventions and cognitive training also have been shown to improve levels of certain serum biomarkers that are related to cognition and may be early indicators of intervention response. Brain-derived neurotrophic factor (BDNF) improves neuronal survival and cognition [24], and is responsive to both physical activity interventions and cognitive training [31]. Vascular endothelial growth factor (VEGF) is involved in angiogenesis [32,33] and in past studies was associated with increased aerobic physical activity and improved cognition [29]. Higher levels of insulin-like growth factor 1 (IGF-1) have been shown to slow neurodegeneration [34,35], improve cognition [29], and be stimulated by aerobic physical activity [29].

In addition, certain factors may alter or moderate effects of physical activity interventions and cognitive training on cognition and serum biomarker levels. First, over 20% of older women with CVD are estimated to have high levels of depressive symptoms [36-38] that may suppress serum biomarkers associated with cognition [39]. Second, women with the APOE-ε4 allele, an important genetic risk factor for Alzheimer’s disease dementia [40-42] may not garner the same benefits from interventions [43,44]. Additionally, the BDNF Val66Met polymorphism suppresses secretion of BDNF [45].

Although existing physical activity interventions [19,46] and cognitive training [47] both have evidence of improving cognition in healthy older adults, there are significant limitations to prior studies. First, no studies were found in which older women with CVD were evaluated despite their high risk for cognitive impairment [6] and low rates of physical activity [48]. Second, prior studies did not consider the distinct needs or preferences of women, even though studies [49] and federal guidelines [50] indicate women respond better to physical activity interventions specifically designed for them. Most approaches use highly structured exercise that often fail to generate long-term behavior change [51] and have restricted scalability [52]. Third, although serum biomarkers can indicate cognitive changes [53,54] and may quickly identify intervention non-responders [55], to our knowledge, no study of a combined intervention has examined these three serum biomarkers together [56-61].

We have previously established feasibility and acceptability of MindMoves, a 24-week multimodal intervention consisting of a physical activity intervention and cognitive training tailored to the needs and preferences of older women with CVD [62,63]. The current study describes the protocol for a randomized controlled trial that will evaluate the efficacy of MindMoves on cognition and serum biomarkers (BDNF, VEGF, IGF-1) at 24, 48 and 72 weeks in older women with CVD.

2. Methods

The study protocol and consent procedures have been approved by the Rush University Medical Center. The trial protocol (NCT04556305) is registered and published on ClinicalTrials.gov, and the results will be published at that site upon completion of the trial. Given the current COVID-19 pandemic, the original study protocol had to be modified for participant and staff safety. We will describe the original study protocol, noting adaptations (e.g., virtual meetings) that will be implemented due to restrictions necessitated by the pandemic. In the event that the pandemic comes under control and restrictions are lifted, we will expand in-person activities to the degree that safety, patient interest, and related study factors allow.

2.1. Specific Aims

Using a 2x2 factorial design, we will recruit 254 older women with CVD (e.g., coronary artery disease, hypertension, arrhythmias, valve disease) from outpatient cardiology clinics and randomize them to one of the following conditions: (1) Mind, (2) Move, (3) MindMoves, or (4) usual care (control). This approach will allow us to efficiently evaluate main and interaction effects of Mind and Move on cognition and serum biomarkers at 24, 48, and 72 weeks post-baseline [64].

Aim 1 (primary):

Determine the independent and combined efficacies of Mind and Move on cognition assessed by neurocognitive tests among women ≥ 65 years of age with CVD.

Aim 2 (secondary):

Determine the independent and combined efficacies of Mind and Move on serum biomarkers (BDNF, VEGF, IGF-1) among women ≥ 65 years of age with CVD.

Aim 3 (exploratory):

Evaluate depressive symptoms and genetic factors as potential moderators of the association between changes in target behaviors (physical activity and cognitive activity) and health outcomes (cognition and relevant serum biomarkers).

We hypothesize that Mind and Move individually will yield cognitive benefits and improved biomarker levels, but that the combined MindMoves will have a more substantial impact than the sum of the main effects of the two separate interventions. We expect that our findings will clearly demonstrate the efficacy of a lifestyle-focused multimodal intervention to prevent or delay cognitive impairment in older women with CVD and identify relevant biomarkers that would be indicators of intervention response.

2.2. Study Model

The model with key study variables (Figure 1) guiding our study is based on decades of research indicating the benefits of physical and cognitive activity to prevent cognitive impairment in older adults [17,19,22,23,65,66]. Move is our lifestyle physical activity intervention specifically designed for women, in whom increased and maintained target physical behaviors have been observed [62,67,68]. Mind is evidence-based cognitive training that has increased target cognitive behaviors in trials with healthy older adults [23,69,70] and in patients with heart failure from our ongoing study [60,71]. The health outcomes are cognition and serum biomarkers. We will explore potential moderators (depressive symptoms, APOE-ε4, BDNF genotype) of the relations between target behaviors and health outcomes.

Figure 1.

Study Variables

2.3. Study Design

A 2x2 factorial design will be used to test the separate and combined effects of two interventions, Move and Mind. This design enables us to efficiently and cost-effectively examine separate and combined effects of two intervention components whereby two or more independent variables are manipulated [72]. Advantages include higher statistical power, even with relatively few participants per cell, and ability to study interaction effects of a multi-component intervention that are greater than the sum of each intervention’s main effect [72]. Moreover, it is important from a public health perspective to determine if a multimodal intervention has additive or synergistic benefits or if one component is driving the effects.

In the 2x2 factorial design, participants are randomized to one of four combinations of the two interventions being tested: (1) Move, (2) Mind, (3) MindMoves, and (4) usual care (control) (Figure 2). Move [67,73-79] is a lifestyle physical activity program originally designed for community-dwelling women tested for feasibility in older women with CVD, and redesigned to meet their needs and preferences [62]. Move includes a personal physical activity goal with self-monitoring using a Fitbit and five group meetings over 24 weeks based on social cognitive theory. Mind is the 36-hour BrainHQ, a cognitive training program by PositScience™ [26,30,80-82] delivered on a tablet over 24 weeks. The combined MindMoves program was tested for feasibility in older women with CVD [62]. The usual care control group was selected to provide a comparison with older women not receiving any study intervention and allows full testing of the interaction effect.

Figure 2.

Study Design

In the proposed study, participants will be recruited from one of two clinic sites (see Setting) and data collection appointments will be conducted at baseline and post-intervention at 24, 48, and 72 weeks. Participants can continue (for the duration of the study) to self-monitor steps using their Fitbit in Move and will have access to the BrainHQ program in Mind following the end of the 24-week intervention. This extension will allow us to determine if the long-term effects of continued use of these commercially available products are associated with changes in cognition, maintenance of physical activity, and continued use of cognitive training.

A total of 24 cohorts of 10-11 participants each will be recruited sequentially. Because two cells in the factorial design include the group-based Move intervention (Figure 2), we will use cluster randomization to assign cohorts to cells. A permuted block randomization will be used to determine the order of cell assignment within each site. Three permuted blocks of the four intervention conditions within the two clinic recruitment sites (see Setting) will be created to balance order and historical effects. In addition to balancing order effects, the randomization order will be limited to ensure that the two sites will be assigned different conditions for each cohort. This was necessary to ensure relative balance in staffing needs over time. After recruitment of a cohort and baseline assessments are complete, the randomly assigned condition for that cohort will be revealed, and its intervention will begin.

2.4. Participants

2.4.1. Setting

The Rush Heart Center for Women (Center) was the first heart program in Chicago devoted exclusively to women with or at risk for cardiovascular disease. The Center consists of two separate outpatient cardiology clinic sites located six miles apart (Rush University Medical Center [RUMC] and Rush Oak Park Hospital [ROPH]). Baseline, 24-, 48-, and 72-week data collection appointments will be held at the two clinic sites. Patients seen at the Center have an average age of 65 years (SD = 12) and reflect the average racial and ethnic diversity of surrounding communities (41% African American, 27% Hispanic, 27% White, 5% other) [83]. In 2019, the Center saw an average of 375 women ≥ 65 years per month who were potentially eligible for the proposed study. Due to the pandemic, we have adapted all intervention conditions to be completed in participants’ individual homes. Participants will complete Mind at a convenient time and location on a tablet. To minimize gatherings of groups, Move group meetings will be conducted virtually using a videoconference application on a tablet.

2.4.2. Sample

Participants (N = 254) are women ≥ 65 years with CVD, who are recruited from the Center. All participants require approval from their cardiology provider. Inclusion criteria are: (1) self-identified as women; (2) ≥ 65 years old; (3) read/speak English; (4) patient in the Center (RUMC or ROPH); (5) history of CVD (e.g., coronary artery disease, hypertension) and receiving guideline-directed medical therapy when appropriate [13]; (6) no self-reported regular moderate-vigorous physical activity (self-reported ≥30 minutes ≥ 3 days per week in the past month); (7) no cognitive training program in the past month; (8) no disabilities preventing regular physical activity (Physical Activity Readiness Questionnaire, which includes cardiac and lung disease symptoms) [84]; (9) written approval from cardiology provider (Physical Activity Readiness Medical Examination) [85]; (10) no self-reported significant hearing loss that interferes with normal conversation; and (11) access to a Bluetooth-capable phone or tablet. The sample specifically targets women due to substantive findings, including our own, that they have a more favorable response to behavioral interventions specifically designed for women as opposed to interventions broadly designed for both men and women [49]. Exclusion criteria are: (1) symptoms of unstable cardiac or pulmonary disease in the past month (Physical Activity Readiness Questionnaire) [86]; (2) blood pressure (systolic ≥ 160 or diastolic ≥ 100 mm Hg) [86]; (3) cognitive status score < 19 on the blind version (for phone administration) of the Montreal Cognitive Assessment (MoCA) [87,88] consistent with significant cognitive impairment [89]; (4) diagnosis of a neurological disease found in the electronic health record (e.g., Alzheimer’s disease dementia, Parkinson’s disease, vascular dementia); (5) transient ischemic attack or small-vessel stroke in the past three months [90]; (6) taking anti-psychotic medication [91]. (7) diabetes with an A1C ≥ 9.0 within the past six months [92]; or (8) end-stage renal disease on dialysis (Stage 5) [93,94].

2.4.3. Sample Size

Power was estimated using design effect methods to account for clustering of cases within randomized cohorts [95,96]. Due to the group meeting component of Move, participants will be randomized into cohorts of 10-11 participants. Assuming 24 cohorts of 10-11 participants each (6 cohorts per cell in the 2x2 factorial design; Figure 2), a 15% attrition rate (a conservative estimate based on our previous results [62,67]), and a correlation of 0.7 between assessments of cognition (as measured by a battery of neurocognitive tests), we estimate 80% power to detect an interaction effect (d = 0.30) for significance (p < 0.05) with N = 254 initial participants (216 after accounting for attrition). This is a reasonable minimal effect size for the interaction effect described in Aim 1 [97,98]. Although existing systematic reviews [19,23,99,100] suggest an estimated effect size of d = 0.50, we estimate d = 0.40 given our previous work as a more conservative estimate for the main effects of the Move and Mind interventions [67]. Assuming an effect size of d = 0.40, our study design has > 90% power to detect an effect of Mind or Move on cognition. Thus, 254 women with CVD will be recruited (63–64 patients across six cohorts/groups in each cell).

2.4.4. Recruitment

We will build on successful recruitment strategies used in our prior studies [62,67,74]. Recruitment will proceed simultaneously at both center clinic sites. Information sessions will be conducted at the center clinic recruitment sites (or via videoconference) for cardiology providers (i.e., cardiologists, nurse practitioners) prior to the launch of the study. When a provider identifies a patient, who meets basic study criteria (i.e., age, gender, safety to participate in physical activity), the provider will introduce the study and provide the patient with a study information flyer. The provider will be instructed to explain to the patient the purpose of the study, state that participation does not change the care received at the clinic, explain that data will not be included in the electronic health record (EHR), and describe that they can receive more specific details regarding the study by completing the interest form. Participants can either fill out and sign an interest form that is attached to the flyer with name and preferred phone number, or they can provide verbal consent to the clinic staff or provider for the research team to contact them. Study information flyers with interest forms will also be posted in the waiting area and in the exam rooms of the Center clinic recruitment sites. During the first phone contact, the study staff will assess for preliminary eligibility (i.e., current physical activity and cognitive training participation, self-reported hearing loss, Bluetooth capable device, taking anti-psychotic medications) of prospective patients for the study and set up a secondary, in-person screening appointment (help over the phone during the pandemic). During the secondary screening appointment, participants will complete the informed consent process, be screened for cognitive impairment with the MoCA, and complete the Physical Activity Readiness Questionnaire.

Due to the current pandemic, we anticipate that patients may be less likely to schedule and come to the Center for their regular cardiology visits, particularly if patients are not experiencing symptoms. In order to meet our recruitment goals, we will utilize an alternative strategy for which we received IRB approval. We will leverage EHR data to capture patients that may not be pursuing in-person cardiology appointments and may not be utilizing telehealth throughout the current COVID-19 pandemic. Patients will be identified who meet the following criteria: 65 years or older, women, no diagnosis of dementia or mild cognitive impairment, and seen (i.e., in person or virtually) by a Rush cardiology provider within the three months prior to the date of EHR data extraction. Data extraction from the EHR will result in a spreadsheet that includes participant first and last name, associated screening ID, phone number, and mailing address. The search will occur prior to each data extraction. Following Dillman’s methods for research and internet mailings, the study cardiologist (ASV) will send the identified patients a letter to introduce the study, present a summary of the interventions and procedures, provide the phone number and email for the research team, and inform that the patient can expect phone and email contacts from the research team [101]. The letters will also state that patients can call or email the research team for additional information or if the patient does not wish to be contacted. After 10 days following the initial mailing, the research team will begin calling and emailing patients, excluding those who opted out of participation. Interested patients will be screened for preliminary eligibility for the study over the phone and depending on eligibility, a secondary screening appointment will be scheduled.

2.4.5. Retention

We will build on successful retention strategies from our preliminary studies [74,76]. We will ensure that the majority of study protocols can be completed virtually, with a few necessary in-person components (i.e., blood draws). Data collection visits will be held at a convenient location (e.g., clinic or home setting, at participant’s preference) and may take place over several days if the participant prefers. We will use multiple modes of contact with participants, including home and cell phones, text messaging, e-mail, and a personal contact provided by the participant. Participants will receive two reminder phone calls, text messages, or e-mails one week and one day before data collection appointments and group meetings. Participants who miss a group meeting session will be contacted by the interventionist and will be encouraged to attend a standardized 15-minute make-up session before or after the next session. Participants will be given $40 after completing each of the data collection appointments (total $160). At the end of the study, participants will keep their Fitbit (those in Move and MindMoves conditions) or receive one (those in Mind and usual care control conditions).

2.5. Measures

Measures for this study are categorized as physical activity, cognitive activity, outcomes (cognition and serum biomarkers), potential moderators (e.g., depressive symptoms, genetic factors), and sample descriptive variables or potential covariates (e.g., sociodemographics, health variables). Table 1 displays information on measures, including number of items, scales, and reliability/validity. Questionnaire measures, including demographics, health history, depressive symptoms, self-reported physical activity, and cognitive activity, as well as the neurocognitive measures may be completed virtually including over the phone. Participants will be asked to complete data collection at all time points (baseline, 24 weeks, 48 weeks, and 72 weeks) in the same administration delivery (i.e., in-person or phone).

Table 1.

Variables Indicators, Measures, and Reliability Validity

Variable	Measures, Number of items, Scales, Scoring, Reliability/Validity
Physical Activity
Device	ActiGraph GT3XE-Plus Triaxial Accelerometer. Valid assessment of physical activity in adult persons during walking, running, and daily activity [102,103]. Worn on hip for seven consecutive days. Intensities based on the Miller (2010) older adult intensity thresholds: sedentary: < 100, light: 100–1,565, moderate: 1,566–6,139, vigorous: ≥6,140 counts [104].
Aerobic fitness	2-minute step test: Participants step in place at a pre-designated height for two minutes.[105] Can be done in a small space using minimal equipment [106]. Correlation with treadmill r = 0.74 [107].
Self-report	Community Healthy Activities Model Program for Seniors (CHAMPS): 30-item measure of leisure and household physical activity in past 2 weeks [108,109] Test-retest reliability r = 0.62; Validity with VO2 max [109].
Cognitive Activity
Self-report	Self-report frequency (five-point scale rating) of weekly participation in seven information processing activities with minimal physical or social demands (e.g., reading, crossword puzzles, writing letters). Validated in studies of 6,162 older adults [110,111], Updated to include electronic puzzles and games (nine items total).
Outcomes
Cognition	Episodic Memory: East Boston Memory Test: immediate and delayed recall of a brief story with 12 key elements 148. Semantic Memory: Category Fluency Test: participants generate examples for two semantic categories (animals, fruits/vegetables) in separate 60-second trials [112]. Working Memory: Digit Span Forwards and Backwards Tests: examiner says a string of numbers that increase in length forwards and backwards [113]. Digit Ordering Test: recall of digit series [114]. Executive Function: Oral Trails A and B: sequential task switching with no physical demands [115].
Serum biomarkers	BDNF, VEGF-A, IGF-1 (MIFFIPFEX® MAP Human Angiogenesis/Growth Factor Panel and Human Pituitary Panel 2 [116]) Pre-treatment serum specimens archived at −80°C in aliquots with no more than two freeze-thaw cycles [117,118]. All Luminex assays are blinded to clinical data and performed using a 384-well modified method [119].
Potential Moderators
Depressive symptoms	Center for Epidemiologic Studies-Depression Scale 20 items scored 0-3; assesses symptoms of depression [120].
Genetic factors	APOE-ε4: Candidate gene analysis with DNA extraction from whole-blood samples with Autogen DNA isolation kits (Qiagen, Venlo, Netherlands) with a TaqMan SNP genotyping assay (Applied Biosystems, Foster City, CA, USA) [121,122]. BDNF Val66Met SNP: Candidate gene analysis of the SNP in BDNF (on Chromosome 11) [123,1241.
Sample Descriptive Variables and Potential Covariates
Demographics	Date of birth, race and ethnicity, marital status, education, occupation, income level, caregiver status
Health history	General health: PROMIS Global-10 [125]. CVD history (EHR), Medications (EHR), Sex-related factors: pregnancy, gynecologic surgery [49], menopausal symptoms [126].
Biological risk factors	BP: mean of three measures using an Omron HEM-907XL automatic BP machine following the AHA Recommendations for BP Measurement [127]. Body mass index: weight (kg)/m2 [86]
Technology ownership, use	Ownership and use of physical activity monitors (e.g., Fitbits), cognitive training programs, computers, and tablets. Assessed as a potential covariate.

2.5.1. Physical Activity

We will assess physical activity with three different measures at each time point (baseline, 24 weeks, 48 weeks, and 72 weeks). The ActiGraph GT3XE-Plus Triaxial Accelerometer will provide a device measure of physical activity, including minutes per day of light and moderate-vigorous physical activity, corrected for total daily wear time [102,103]. Secondary physical activity measures include the two-minute step test to assess aerobic fitness [105], the Community Healthy Activities Model Program for Seniors (CHAMPS) [108,109] to assess self-reported physical activity in specific physical activity domains (e.g., household, leisure).

2.5.2. Cognitive Activity

We will assess cognitive activity with an adapted version of a validated self-report frequency questionnaire at all four time points, which will provide average score of weekly participation in nine common cognitive activities (e.g., reading, crossword puzzles, writing letters) [128]. The adapted version includes participation in electronic puzzles and games.

2.5.3. Outcomes

Our main outcomes of interest include cognition and relevant serum biomarkers that are known to be related to cognition. Cognition and serum biomarkers will be assessed at all four time points.

Cognitive domains (i.e., episodic memory, semantic memory, working memory, executive function) will be assessed with eight neurocognitive tests, which have been previously validated in epidemiological cohort studies of older adults [129,130]. Due to the pandemic, we will administer the tests over the phone, a methodology that has been previously validated [131]. Episodic memory will be assessed using the East Boston Memory Test, including immediate and delayed recall [132]. Scores include immediate recall and delayed recall. Semantic memory will be assessed using the Category Fluency Test, which results in a summary score of two separate 60-second trials [112]. Working memory will be assessed using the Digit Span Forwards, Digit Span Backwards [113] and Digit Ordering Tests [114]. Scores include number of correct responses for each of the three working memory tests. Executive function will be assessed using the Oral Trails A/B tests. Scores include time to complete each of the two Oral Trails tests [115]. For each cognitive domain, scores from the domain-specific tests will be averaged to create a domain index score. All index scores will be averaged to create an index score of global cognitive function.

The serum biomarkers include BDNF, VEGF-A, and IGF-1. Luminex FlexMAP 3D will be used for serum biomarker data collection. Concentrations will be based on 7-point standard curves using a 5-parametric fit algorithm in xPONENT v4.0.3 [119]. Blood samples for the serum biomarkers will be obtained in the morning (8am-10am) following an 8-hour fast, following recommendations for validated blood collection procedures for these biomarkers [133]. Blood samples will be collected by a trained phlebotomist in the research lab or the participant’s home and will be transported to the lab for processing within 2 hours of collection. Following processing, blood will be stored in a −80 degrees freezer.

2.5.4. Potential Moderators

The potential moderators include depressive symptoms and genetic factors, specifically the APOE-ε4 allele and the BDNF Val66Met single nucleotide polymorphism (SNP). We will assess depressive symptoms at all four time points with the 20-item Center for Epidemiologic Studies-Depression Scale [134,135]. Participants who score ≥16 will be referred to their primary, psychiatric, or another healthcare provider for further evaluation and treatment [120]. For APOE-ε4, candidate gene analysis with DNA extraction at baseline will be used to characterize APOE genotype (APOE-ε4 allele absent or APOE-ε4 present) [121,122]. For the BDNF Val66Met SNP, candidate gene analysis at baseline will be used to characterize BDNF^Met genotypes (Val/Met or Met/Met) [123,124].

2.5.5. Sample Descriptive Variable and Potential Covariates

The descriptive variables that will be considered for potential covariates include demographics, health history, biological risk factors, and technology ownership and use. Demographics, including age, race/ethnicity, marital/partnership status, education, occupational status, self-reported income level, caregiver status, and sexual orientation, will be collected at baseline through self-report questionnaires. Health history will be assessed at all four time points and includes general health and function (PROMIS Global-10 [125]), CVD history and diagnoses (e.g., type of CVD, date of diagnosis; obtained from the EHR), diabetes history and diagnosis (e.g., taking insulin; obtained from the EHR), current medications (i.e., blood pressure medications; obtained from the EHR) and women-specific factors relevant to cognition (self-report questions on age at menopause, pregnancy complications, gynecologic surgery, and menopausal symptoms [126]). Biological risk factors will be assessed at all four time points, including blood pressure [127] and body mass index [86]. Finally, as a potential covariate in analyses, we will assess participants’ current ownership and use of physical activity monitors, cognitive training programs, computers, and tablets at each time point.

2.6. Procedures

All procedures will be approved by the Rush Institutional Review Board. At the secondary screening appointment, the data collector will read the informed consent and HIPAA research authorization. Following informed consent, an in-person data collection appointment will be scheduled, either in the research office laboratory or at the participant’s home. Within 24 hours prior to the in-person data collection appointment, participants will be asked to fill out a COVID-19 symptom or exposure survey. Participants will be given hospital-grade masks upon arrival. At the appointment, participants will have their temperature screened. If no current symptoms or exposure, measurements of weight, height, and BP will be taken, and blood samples will be drawn by the phlebotomist data collector for serum biomarkers and genotyping. The data collector will wear a gown, gloves, and hospital-grade mask for data collection appointments. Participants will be given the ActiGraph accelerometer to wear on the hip during waking hours for seven days, and then return the device to staff in a prepaid, padded envelope with tracking information. Next, the phone data collection appointment will be scheduled. During the phone data collection appointment, questionnaires and neurocognitive tests will be completed.

Participants will then be randomized to a condition and complete intervention orientation by the interventionist. Intervention orientation will take place over the phone due to the pandemic with a brief in-person component if needed. Intervention supplies (e.g., Fitbit, iPad, manual) will be delivered to the participant’s home. Because the Move intervention is group-based, all participants will be cluster-randomized by clinic recruitment site. The five group meetings over the 24-week intervention period were originally set to take place at each respective clinic recruitment site, but due to the pandemic, all group meetings will be held virtually. Participants will receive an iPad to use during the intervention period for videoconferencing capabilities along with their other intervention materials. At the 24-, 48-, and 72-week data collection appointments, participants will return to the site to complete appropriate measures in-person and over the phone as previously described.

2.7. Intervention Conditions

MindMoves is a multimodal lifestyle intervention comprised of two evidence-based interventions: Move, a lifestyle physical activity program that targets cognition in older women with CVD, and Mind, cognitive training using the BrainHQ program modified for use on a tablet. Participants in the combined MindMoves intervention group complete both programs simultaneously over the 24-week intervention phase. Due to the pandemic, orientation sessions for the intervention conditions will be held over the phone with minimal in-person contact for participants to receive the appropriate intervention materials. Technical support staff will be available throughout the intervention period.

2.7.1. Move – Lifestyle Physical Activity

The 24-week Move intervention [136] is an adaptation of an evidence-based Women’s Lifestyle Physical Activity program, originally designed for women using stakeholder input, that demonstrated increased and sustained physical activity and aerobic fitness in Caucasian [137] and African American women [67] for up to three years following the 24-week intervention [68]. We encourage participants to incorporate moderate-intensity (≥ 3 Metabolic Equivalents [METs]) lifestyle physical activities into daily routines in every environment, including self-initiated structured exercise and lifestyle activities [138]. In Move, we enhanced the original intervention to address specific needs of older women with CVD [62]. The intervention uniquely targets both coordination and aerobic components of physical activity to benefit cognition [19,29,30], and emphasizes key behavioral components needed for successful adoption and long-term maintenance of lifestyle physical activity. Guided by social cognitive theory, Move’s core elements include an individual orientation and five group meetings.

Individual orientation:

Participants receiving Move will have an individual orientation with the interventionist that will be completed on phone with limited in-person visits. Participants will eventually utilize their personal Bluetooth-capable device (e.g., smart phone) to self-monitor or track goals in the Fitbit application (app). First, participants will complete a brief in-person individual intervention orientation with the interventionist, where the Fitbit is synced with their own device and the app is hidden from participant view on the device. Participants will receive training on Fitbit use, its app, and troubleshooting. The interventionist will use a skills checklist to demonstrate correct use and have participants demonstrate their understanding. Written directions with pictures will be provided. The Fitbit is wrist-worn during all hours except when swimming or bathing [139]. Participants will first wear a Fitbit Charge 4 HR with the monitor display blinded for seven consecutive days to obtain data for determining their initial goal [140,141]. Participants will be instructed to not change their behavior for the blinded seven days and to refrain from removing the blinding tape or viewing the Fitbit app [62,63,67]. Following the seven blinded days, participants will receive another individual intervention orientation over the phone to be oriented on self-monitoring with a Fitbit and be given a personal lifestyle physical activity goal (Move goal). The personal physical activity goal (Move goal) is progressive and tailored and is comprised of: (1) steps and (2) minutes spent in moderate-vigorous physical activity. The Fitbit is used as the motivational tool to prompt participants to move more throughout their day, and to provide feedback on both steps and moderate-vigorous physical activity (Fitbit “Active Zone” minutes) [139,142]. In addition to increasing overall activity time, we emphasize gradually increasing intensity, specifically moderate-vigorous physical activity, using the Fitbit to track daily “Active Zone” minutes (≥ 3 METs [139,142]) and perceived exertion to try to ensure participants obtain aerobic fitness with potential effects to benefit brain health. The overall Move goal is to increase daily steps by 3,000 and reach 22 daily minutes of moderate-vigorous physical activity (or meeting the recommendations of 150 minutes per week [50]) over 24 weeks. In order to ensure that participants are reaching levels of physical activity that elicit cognitive changes, goals (both daily steps and weekly moderate-vigorous minutes) will be progressively increased at each group meeting to reach the overall goals by Group Meeting 4 (Week 15 of 24). Participants will be encouraged to sustain these changes for the duration of the intervention period.

Steps.

Steps are used because they are a simple metric of ambulation in a variety of lifestyle physical activities that are easy to understand. Steps are accumulated beyond walking for exercise to include most lifestyle activities in all environments. Step-based goals help individuals increase and maintain their physical activity levels [67,68], are a predictor of mortality in older women [143], and are recommended by the 2018 U.S. Physical Activity Guidelines [50]. Based on published normative data, daily step counts will be classified with modification as: < 3,000: “sedentary”; 3,000-4,999 steps: “low active”; 5,000-7,499 steps: “somewhat active”; 7,500-9,999 steps: “active”; ≥10,000 steps: “high active” [144]. Each woman will be given an overall goal to increase steps above her baseline by a minimum of 3,000 steps per day by the end of the 24-week intervention, an increase that approximates 30 minutes of moderate-intensity physical activity, as recommended by the American Colleges of Sports Medicine [50,86].

Minutes of moderate-vigorous physical activity.

Minutes of moderate-vigorous physical activity are used due to the known effects of this intensity level on cognition [29,30]. Fitbit uses individual data (e.g., age, sex, heart rate) plus METs based on accelerations to classify “Active Zone” minutes. Although Fitbit has been shown to provide acceptable estimates of moderate-vigorous physical activity when compared to the ActiGraph accelerometer in older adults, there is evidence of overestimations [145,146]. Moreover, those taking heartrate altering medications may not have reliable assessments. Thus, we encourage that participants also track moderate-vigorous physical activity utilizing self-report with the Borg’s Rating of Perceived Exertion for moderate-vigorous physical activity [147]. We use the well-established compendium of physical activities [148] which lists lifestyle activities (e.g., mopping, dog-walking) and structured exercise that provides moderate-vigorous physical activity (i.e., ≥ 3 METs). To enhance self-efficacy, we will gradually increase frequency (number of times), duration (length of time), and intensity [67,149,150], which promotes adherence and reduces the risks of musculo-skeletal injury and adverse cardiac events [86]. Thus, consistent with 2018 Physical Activity Guidelines, we focus first on incorporating movement of any intensity into daily life, and then encourage increasing intensity [50]. This prevents older adults from getting discouraged and promotes long-term adherence and behavior change.

Fitbit data will be sent to the Fitabase® application [151] and will be presented on a virtual dashboard that shows recently synced devices, battery levels, and real-time physical activity data from participants. Interventionists will use Fitabase® to monitor progress toward goals, measure wear time, and provide physical activity goal modifications during group meetings. Following the 24-week intervention, participants may continue to wear their Fitbit as they desire, and Fitabase® will continue to collect usage data until participants have completed their 72-week data collection appointment, thus enabling us to assess maintenance of lifestyle physical activity.

Group meetings:

Social cognitive strategies (self-regulation, reciprocal determinism [one’s behavior is determined by the individual], behavioral rehearsal, vicarious experience [feeling what someone else feels]), tested and shown effective in earlier studies [67,68], are applied systematically in group meetings (Table 2) [136]. These targeted meetings provide social support, identify benefits of physical activity on cardiovascular and brain health, address participants’ common personal and environmental barriers to physical activity and questions, anticipate disincentives for physical activity, and demonstrate how to address relapses. Behavioral competencies for women with CVD are also emphasized, including strategies to avoid overheating, signs of low blood sugar, and ways that physical activity positively impacts cardiovascular and brain health. Group meetings consist of five 90-minute visits with 10-11 participants every five weeks and are led by a trained nurse interventionist. Group meetings will be held virtually with videoconferencing as a result of the pandemic but may be held in the clinic in the future. For participants that will be participating in group meetings held via videoconference, they will be provided an iPad tablet and training to use for the virtual group meeting. A tech support staff member will be available prior to the group meeting and throughout the intervention period to assist participants with the videoconference technology.

Table 2.

Move Group Meeting Strategies Based on Social Cognitive Theory

Meeting Theme	Strategies	Competencies
1. Let’s Get Realistic	Self-regulation: how the woman regulates behavior to meet her goals	Identify strategies to put physical activity into life; identify long-term outcome goals
2. Overcoming Personal Barriers	Reciprocal determinism: interactions between the woman and her social networks	Develop strategies for eliciting support of family/friends; time management
3. Overcoming Environmental Barriers	Reciprocal determinism: interaction between the woman and her environment	Identify safe times/locations for physical activity; identify prompts
4. You Can Do It	Behavioral rehearsal: practicing behaviors to anticipate how they will be used in reality	Identify high-risk situations for relapse and strategies for prevention; role-play
5. Learning from Each Other	Vicarious experience: knowledge about a behavior derived from seeing the performance of others	Acknowledge strategies that have been successful for others that may be utilized

In the hour prior to each group meeting, there will be an individual phone call or virtual meeting (based on the participant’s preference) between each participant and the interventionist to review the participant’s physical activity report (Move report). If it is safe to meeting in person in the future, then these individual meetings will occur in-person prior to the group component of the meeting. The Move report will include a summary from the Fitbit data (blinded for the first group meeting), which includes: (1) average daily step counts and “Active Zone” minutes for each of the prior two weeks, and (2) recommended new Move goals [50,86]. At each group meeting, Move goals, including steps and minutes of moderate-vigorous physical activity, are progressed. Step goals are progressed by increasing the number of daily steps by 750 (25% of the overall goal of increasing 3,000 daily steps by group meeting 4). Moderate-vigorous physical activity goals are progressed by increasing by 25% of the difference between baseline and 22 daily minutes, rounded to the next highest whole minute (e.g., if a participant had 5 daily minutes of moderate-vigorous physical activity at baseline, then the first goal would be 10 daily minutes), with the overall goal of reaching 22 daily minutes of moderate-vigorous physical activity by group meeting 4. Participants rate their self-efficacy (confidence) to meet their new recommended goals on a scale of 0–10. If their confidence is < 8, the interventionist recommends a new goal in which they have higher confidence.

Then the participants will join the group component of the meeting. Each group meeting will begin with a 10-minute video of women with CVD demonstrating skills and sharing experiences and approaches related to problem solving and overcoming challenges pertinent to each group meeting [149]. We will encourage increasing lifestyle physical activity by incorporating various activities (e.g., biking, gardening) into daily life based on preference. We will also include the expertise of a cardiology nurse practitioner who provides CVD-targeted health content to safely increase physical activity and its cognitive benefits. Next, each meeting will include a 30-minute group discussion facilitated by the interventionist to role model, provide guidance, and encourage participants to solve problems together. A customized intervention manual will guide the discussion.

2.7.2. Mind – Cognitive Training

Many cognitive training programs are available, but most have not been tested scientifically [152-156]. We selected BrainHQ because it was developed to boost cognitive reserve, has been rigorously tested, was shown to have generalized effects on cognition, and is broadly available [26,30,80-82]. BrainHQ has demonstrated efficacy in improving cognition among healthy older adults [69,81], as well as improving BDNF levels in adults with heart failure [60,71]. BrainHQ is tailored to the individual and is progressive: exercises become increasingly complex based on performance at a rate specific to the individual. The program addresses six key core elements to improve cognition, including auditory stimuli, complexity of stimuli, cognitive demand, working memory, processing speed, and novelty. BrainHQ targets problems that interfere with memory recall and formation, during CVD and age-related cognitive decline. For example, decreased stimulation of sensory and cognitive systems occurs as patients’ life space shrinks [157] and interactions with others decrease due to illness. Patients often participate in fewer cognitively stimulating activities because of retirement and other factors (e.g., chronic health problems), which further decreases sensory and cognitive stimulation, leading to changes in cognition and learning [158]. In addition, sensory input from visual, auditory, tactile, and proprioceptive systems can decline due to deterioration of peripheral sensory organs with age [159].

Mind exercises:

Mind uses six auditory BrainHQ exercises to target memory, sensory function, working memory, and processing speed. Over 20 studies found that these six BrainHQ exercises improve cognition, particularly memory and attention, including a trial of 487 community-dwelling older adults over three months [69], and our study among patients with heart failure [71]. The exercises’ auditory stimuli improves encoding of information, and strengthen auditory processing related to cognition [160], regardless of education and reading level [69]. Previous cognitive training interventions for adults with CVD tested computer-based programs [58,59,71], but none examined a tablet-based intervention, which older adults with CVD may prefer over computer-based interventions due to the portability and intuitive use of tablets [161]. Also, tablet-based cognitive training interventions have been satisfactory and effective in healthy older adults, with high adherence [162].

Orientation.

In Mind, training occurs for three 30-minute sessions per week over 24 weeks (36 hours total) for the required six exercises and does not allow for access to the other BrainHQ exercises. Participants will complete BrainHQ on iPads, which will be provided to them at the intervention orientation. At intervention orientation, participants will be introduced to the iPad, including general use, charging, and troubleshooting. To ensure the participant is comfortable with the tablet and BrainHQ, the interventionist will use a skills checklist to demonstrate correct use and verify the participants’ proficiency. Written instructions with pictures will be provided. Following the 24-week intervention, participants will continue to have access to BrainHQ and the tablet, enabling us to assess activity maintenance and will return the iPad following at the end of the 72-week study.

2.7.3. MindMoves

The 24-week MindMoves combined intervention will be the simultaneous participation of: (1) 60-minute orientation to Move and to Mind; (2) goal-setting and self-monitoring with a Fitbit; (3) five group meetings (90 minutes every five weeks) focusing on benefits and barriers to increasing physical activity and progressive goal setting; and (4) cognitive training sessions on iPad tablets three times per week. Participants receive a Fitbit and tablet to complete the combined intervention.

2.7.4. Usual Care Control

Participants in the usual care group do not receive any Mind- or Move-related intervention. At the Center, providers assess and counsel patients regarding self-management and lifestyle habits at every appointment and offer the following resources (standard clinical practice for patients with CVD [163,164]): (1) referral to a dietician; (2) cardiac rehabilitation for patients with a new qualifying diagnosis [165]; (3) referral to a gym for weight management for obese patients; and (4) educational materials on risk management. Resources are offered per any change in CVD risk status. Patients will be excluded in the intervention group if currently in a physical activity program or cardiac rehabilitation. The usual care condition is necessary because we hypothesize that Move alone and Mind alone will improve cognition and serum biomarkers more than usual care [166]. We do not expect issues with attrition in this condition as prior physical activity studies with usual care groups have comparable drop-out rates across conditions [167,168]. There are no physical activity or cognitive training clinical guidelines specifically for older adults with CVD [163].

2.8. Fidelity

The Behavior Change Consortium’s Model of Treatment Fidelity will guide the fidelity plan [169]. Treatment fidelity checklists will be utilized throughout the study.

2.8.1. Training

To minimize possible intervention contamination, separate training sessions will be held for each group of research team members (data collectors and interventionists) [170]. Over two weeks, data collectors will be trained on how to conduct appointments and administer study measures, including training on neurocognitive tests. Data collectors will be certified for accuracy of test administration. A 1.5-day session for interventionists will include use of the Intervention Manual, including mock sessions of Move and Mind intervention delivery, facilitation of participant intervention orientations, leading the Move group meetings, and best practices for conducting virtual sessions via phone and videoconference. The Breitenstein Adherence and Competence Scales [171] will be used to evaluate interventionists’ competence and adherence to intervention content. A paper test will evaluate knowledge of the intervention content. Half-day re-training sessions will occur yearly to prevent drift. Interventionists will be nurses with experience in leading behavior change groups.

2.8.2. Delivery of Intervention

For Move, the technical performance of the Fitbit will be checked every week on Fitabase®. All group meetings will be audio recorded. For each cohort completing Move, Group Meeting 1 will be reviewed by JW along with a random selection of Group Meetings 2–5 to assess adherence and competence with the Breitenstein Fidelity Checklist [171,172]. We will use tablets for all cognitive training delivery. Tablets are preferred by older adults [173-175], strengthen intervention delivery, and reduce its variation. Stimuli are delivered with precision to all participants, and their responses are measured immediately. For the Mind BrainHQ program, training is tailored, progress is tracked, and feedback is provided.

2.8.3. Receipt of Intervention

At the intervention orientation, a checklist will be used to evaluate behavioral competency regarding (1) use of the Fitbit and group meeting attendance in Move, and (2) use of the tablet and BrainHQ program in Mind. In Move, we will use Fitabase® to track weekly Fitbit wear time, as determined by the device’s capability to register heart rate [151]. The group meeting interventionist will record meeting attendance, and the numbers of meetings attended will be counted to obtain the dose. For Mind, we will use time spent using the program weekly as recorded by BrainHQ [80,176]. For MindMoves, both Mind and Move receipt of intervention fidelity strategies will be used. At the conclusion of the study period, participant satisfaction will be measured with the Client Satisfaction Tool [177], a 12-item instrument that assesses accessibility and program satisfaction.

2.8.4. Enactment

Enactment will be measured over the 24-week intervention period [23,67,71]. For Move, enactment will be measured by checking Fitabase® to determine the number of weeks the participants wore the Fitbit for at least 10 hours a day for a minimum of three days. For Mind, enactment will be measured by checking the BrainHQ program to determine the number of weeks the participants completed the prescribed schedule.

2.9. Data Management

Research Electronic Data Capture (REDCap) will be used to manage participant recruitment, scheduling, and tracking [178]. All surveys will be collected via Computer-assisted Personal Interviews (CAPI) where an interviewer reads the questions and enters the data into REDCap. The CAPIs include variable range checks and skip rules. Fitabase®.com will track data synced from participants’ Fitbits. Fitabase® is a secure research platform that collects and stores data from Fitbit devices. In addition to current user data, a dashboard will show which devices have been recently synced and individual device battery levels [151]. BrainHQ tracks participant level and number of minutes spent in each activity [80]. Data from BrainHQ, Fitabase®, and accelerometers will be exported (using study ID variables) to SAS for merging, management and analyses.

All variables will be checked for errant values. Descriptive statistics will be computed for all items and scale scores. Distributions will be examined for non-normality and outliers and transformed if necessary. We expect outcome measures to be normally distributed. Outcome measures that cannot be transformed to achieve normality will be analyzed by appropriate generalized linear models in SAS. All statistical tests will use α=0.05.

2.10. Data Analysis Plan

All analyses will use an intent-to-treat approach (i.e., participants analyzed according to their assigned cell) independent of their actual dose of each intervention. All analyses will employ multi-level mixed models with repeated observations (baseline, 24, 48, and 72 weeks) nested within participants, and participants nested within cohorts. Three parameters for factorial design will be included in the models: (1) Move main effect, (2) Mind main effect, and (3) Move x Mind interaction effect. Time and interactions of time with the factorial design parameters will be included in the models. Potential covariates in the multi-level mixed models are in Table 1. Although many of these covariates may be associated with cognitive level, they are generally less likely to influence change over time. Covariates will be at Level 2 (person level) or Level 1 (assessment level) as appropriate. To minimize the number of covariates in the final models, we will first test each candidate covariate individually in models with cognitive change over time as the outcome (time x covariate interaction). We will retain only significant covariates in the final models.

Time can be handled flexibly with multilevel mixed models [179], allowing us to model hypothesized patterns of change over time that deviate from linear or quadratic patterns. For example, we may expect that Mind effects will be greatest from baseline to 24 weeks [23,47,60,70,71], followed by a change plateau; thus, a parameterization of time would reflect a relatively large increase from baseline to 24 weeks followed by stabilization after 24 weeks. Adding a term for this discontinuity in cognitive level (coded 0, 1, 1, 1 for baseline, 24, 48, and 72 weeks, respectively) allows us to test this pattern. In contrast, for the Move effects, we may expect a more gradual linear change in cognition from baseline through 48-72 weeks [19,67,68]; therefore, a discontinuity term may not be needed.

Due to the COVID-19 pandemic, we will also consider two additional covariates: the Illinois COVID-19 reopening phase (i.e., Illinois Restore Plan) and the Move group meeting format (i.e., in-person or virtual). The COVID-19 reopening phase will be modeled as a time-varying covariate based on the phase at the time of the assessment. Move group meeting format will be a person-level covariate.

Aim 1 tests the effects of Move and Mind individually (main effects) and combined (interaction effect) on cognition at 24, 48, and 72 weeks post-baseline. The primary outcome is the global cognition index score (a composite of all eight tests), with domain scores based on the neurocognitive tests of episodic memory (immediate and delayed East Boston Memory Test), semantic memory (Category Fluency Test: animals and fruits/vegetables), working memory (Digit Span Forwards, Backwards, and Ordering Tests), and executive function (Oral Trails A and B). Significant Move x Time, Mind x Time, and Move x Mind x Time interaction effects will provide evidence of intervention main and interaction effects, respectively.

Aim 2 tests the effects of Move and Mind individually (main effects) and combined (interaction effect) on the secondary outcomes of each serum biomarker separately (BDNF, VEGF, IGF-1) at 24, 48, and 72 weeks post-baseline. Analyses will use multi-level mixed models as described in Aim 1. Due to known variation in BDNF levels throughout the day, time of day of assessment will be included as a time-varying covariate for analyses of impact on all three serum biomarkers. Although every effort will be made to collect blood in the morning, after fasting, we will examine within-person variation in levels of serum biomarkers as a function of time of data collection. If found to be a significant time-varying covariate, time of day will be included as a covariate in analyses of biomarkers with significant time-of-day effects.

Several secondary analyses related to Aims 1 and 2 are planned. We will test intervention effects on the target behaviors of physical activity (ActiGraph accelerometer, self-report) and cognitive activity (self-report). Although both Move and Mind have proven efficacy [67-69,71], we will verify their impact on target behaviors. Second, we will explore whether there is evidence that the treatment effects of Mind and/or Move were attenuated by behavior changes among those who did not receive one or both intervention (e.g., due to increased use/ownership of physical activity monitors and/or computers). For those in the control group, we expect no change in target behaviors (physical activity for Move, cognitive activity for Mind). From the models in the former secondary analysis described above, we will calculate estimates of the time slope for the appropriate no-treatment groups and confirm that they are not significantly greater than zero. We also will assess change in use or ownership of physical activity monitors and computers.

Aim 3 examines depressive symptoms and genetic factors as potential moderators of intervention efficacy on cognition and effect on serum biomarker levels. A continuous measure of baseline depressive symptomatology (CES-D) and dichotomous indicators of BDNF genotype and APOE-ε4 allele status will be added to the models in Aims 1 and 2. Intervention effect x time x moderator interaction effects will be evaluated for significant moderation of the intervention effects by these three variables. We expect that intervention effects will be attenuated by higher levels of depressive symptoms and by the presence of a BDNF^Met genotype or APOE-ε4 allele. When significant moderation is found, we will test the extent to which moderation occurs between the intervention and the increase of the target behaviors (e.g., physical activity and cognitive activity) as well as between change in target behaviors and health outcomes (e.g., cognition and serum biomarkers). For example, depressive symptoms are hypothesized to reduce the degree to which changes in physical activity and cognitive activity lead to improved cognition. In addition, participants with higher levels of depressive symptoms may participate less in the intervention and therefore exhibit fewer changes in target behaviors. Though power is likely to be lower for Aim 3 than for Aims 1 and 2, these analyses will contribute important deductive data for planning future studies.

2.11. Study Limitations

There are two main study limitations. Despite our previous success and long-time collaboration with site providers [62,67,78], we may not meet our recruitment and retention goals within the planned timeframe, particularly due to changes in willingness to participate in research induced by the pandemic. To address this possible limitation, we can recruit women from two other Center clinic sites, both of which are located in the Chicago metropolitan area. If differential recruitment rates occur between the two clinic sites of greater than 33%, our permuted block approach allows one block of four cohorts to be shifted to the faster site without generating study bias. In addition, participants in the usual care (control) group may increase physical activity or cognitive activity on their own. We will collect self-reported use of physical activity monitors (e.g., Fitbit) and computers (e.g., laptop, tablet/iPad) at each time point to account for this potential effect. However, participants in no-intervention control groups are unlikely to increase physical activity [180] or cognitive activity [22,23,181] based on prior trials. Furthermore, introducing the Fitbit alone has a short-term effect, and activity quickly regresses to baseline levels [182]. Finally, due to the pandemic we have amended some of our study protocols to minimize in-person contact, including administering questionnaires and neurocognitive tests on the phone. To address this limitation, we have selected measures that can be administered over the phone and the neurocognitive tests have been validated for phone use in older adults [131].

3. Discussion

Our study will evaluate behavioral approaches through a combination of a lifestyle physical activity intervention and cognitive training (MindMoves) to prevent or delay cognitive impairment in older women with CVD. This population has not been targeted in previous or current studies testing physical activity interventions or cognitive training, despite their high risk for cognitive decline. In addition, this study directly addresses important gaps in existing interventions [19,46,47,183] and focuses on a critical issue in public health and clinical practice.

Many previous studies relied on structured exercise interventions in supervised settings. Lifestyle physical activity in home and community settings for patients with CVD is safe, convenient, and has the potential to improve health outcomes including cognition [163]. By emphasizing total daily lifestyle physical activity that does not solely rely on structured exercise that is often supervised or specific to a setting, participants are more likely to increase and adhere to the physical activity changes beyond the course of the study. As recently noted by the American Heart Association, practical home-based interventions that can be broadly disseminated in clinical and community settings are needed for patients with high cardiovascular risk [163]. Moreover, there is a critical need for scalable home-based lifestyle interventions given the current COVID-19 pandemic. Older adults with CVD are at higher risk for complications as a result from the SARS-CoV-2 virus [184], and public health officials have generally recommended that such high-risk populations avoid indoor communal settings where individuals have traditionally engaged in physical activity, such as gyms or community centers [185].

By employing a 2x2 factorial design, we can evaluate the individual and synergistic long-term (over 72 weeks) effects of Move and Mind. Testing multimodal interventions has been emphasized by the National Academies of Sciences, Engineering and Medicine [186], as pharmacological approaches to addressing cognitive impairment continue to be challenging [187,188]. We aim to identify relevant serum biomarkers, which is critical for examining mechanisms and determining early individual responses to behavioral interventions that aim to improve cognition. Serum biomarkers may indicate early changes in cognition too subtle to be assessed by neurocognitive tests [60,189]. Serum biomarkers are safe, convenient, have low patient burden, and are more cost-effective compared to other biomarker measures, such as neuroimaging [33,123].

In MindMoves, participants engage in home-based activity that is often preferred by older adults and women, is less complicated, more convenient, less intimidating, and inexpensive. No known studies have used this individualized, home-based, lifestyle approach to improve cognitive health specifically in older women with CVD. This study will contribute to current existing research in cognitive aging by focusing on practical, scalable lifestyle changes in a population at elevated risk for cognitive impairment.