Double-task Exercise in Older Adults At Risk of Cognitive Decline (MeMo-Health-Cog-3 Program)

Cerebral small vessel disease is a frequent cause of cognitive disability among older adults (OAs) in Mexico that imposes a significant burden on the health system and OAs' families. We have called the program Mind and Movement for Cognitive Health (MeMo-Salud-Cog-3). Programs to prevent or delay OAs' cognitive decline are scarce. Methods and analysis: A double-blind, randomized clinical trial will be conducted. The study will aim to evaluate two 24-week double-task (aerobic and cognitive) square-stepping exercise programs for OAs at risk of cognitive decline-one program with and another without caregiver participation-and to compare these with an aerobic-balance-stretching exercise program (control group). 255 OAs (85 per group) affiliated with the Mexican Institute of Social Security (IMSS) between 60 and 65 years of age with self-reported cognitive concerns will participate. They will be stratified by education level and randomly allocated to the groups. The intervention will last 24 weeks, and the effect of each program will be evaluated 12, 24, and 52 weeks after the intervention. Participants' demographic and clinical characteristics will be collected at baseline. The outcomes will include: (i) general cognitive function; (ii) specific cognitive functions; (iii) dual-task gait; (iv) blood pressure; (v) carotid intima-media thickness; (vi) carotid arterial compliance; (vii) OAs' health-related quality of life; and (viii) caregiver burden. We will estimate differences in outcomes between each intervention group and the control group at baseline and follow-up evaluations. We will assess differences-in-differences (D-in-D) treatment effects using a D-in-D estimator. If we identify statistically significant differences in participants' baseline characteristics between the groups, we will adjust the D-in-D estimators by these covariates using generalized linear regression models. Ethics and dissemination: The study was approved by the IMSS Ethics and Research Committee (registration number 2018-785-095). All participants will sign a consent form prior to their participation. The study results will be disseminated to IMSS authorities, healthcare providers and the research community.

1. Aim: to evaluate two 24-week double-task (aerobic and cognitive) square-stepping exercise programs for older adults (OAs) at risk of cognitive decline - one program with and another without caregiver participation - and to compare these with an aerobic-balance-stretching exercise program (control group). 255 OAs (85 per group) affiliated with the Mexican Institute of Social Security (IMSS) between 60 and 75 years of age with self-reported cognitive concerns will participate. They will be stratified by education level and randomly allocated to the groups.
2. Study design: A double-blind randomized clinical trial entitled "Mind and Movement: Towards the Cognitive Health of Older Adults" will be conducted. The study will include two intervention groups and one control group: (1) a double-task exercise program with a squared mat led by a coach (a health professional) for 24 weeks (T1-GR); (2) the same exercise program led by a coach (a health professional) for 12 weeks and then led by caregivers of older adults for another 12 weeks (T2-GR); and (3) a control group of an aerobic-balance-stretching exercise program led by a coach for 24 weeks (C-GR).
3. Study hypothesis:

   The investigators hypothesize that T1 and T2 double-task exercise trainings will show more significant improvements in older adults than the control aerobic training with regards to (i) general cognitive function; (ii) specific cognitive functions (executive function, processing speed, verbal learning and memory, and verbal fluency); (iii) usual walking and dual-task gait; (iv) blood pressure; (v) carotid intima-media thickness; (vi) carotid arterial compliance; (vii) older adults' health-related quality of life; and (viii) caregiver burden.
4. Sample Size: It was calculated using the formula suggested by Zong (2009)32 for continuous outcome variable and non-inferiority design (2 \[Z 1-α+Z 1-β/ δ\] \* S2). The investigators considered α \<0.05, a power of 80%, and the assumptions to δ0 (a clinically acceptable margin) and S2(polled standard deviations of both comparison groups): General cognitive function=0.20(0.05), Mental flexibility (EF) part A=0.13(0.03) and B=0.37(0.37), Processing speed=0.06(0.02), Verbal learning=0.63(0.32) and memory=0.16(0.08), Verbal fluency words by category= 0.54 (0.14) and by letter=0.66 (0.17), Walking speed (cm/s)=0.23(0.06), Walking length(cm)=0.86(0.22), Systolic blood pressure(mmHg)=0.27(0.06); Diastolic blood pressure(mmHg)=0.79(0.40), Carotid intima-media thickness(mm)=0.20(0.05).Subjective burden on informal caregivers=0.53, Patient health-related quality of life (SF-36) Mental score=4.0(1.0) and Physical score=4.0(2.0). The maximum required sample size, assuming a possible 20% drop-out rate, is 85 participants per group.
5. Intervention implementation:

   The study will be conducted at IMSS Epidemiology and Health Services Research Unit facilities in Mexico City.

   The T1-GR will consist of 60-minute training sessions delivered three days a week during a 24-week period. Each session will be guided by a health professional with a nursing background previously certified to coach SSE trainings by the Institute of Square-Stepping Exercise in Mie, Japan (Chief Tomohiro Okura and Overseas Director Professor Ryosuke Shigematsu).

   In the case of T2-GR, older adults and their caregivers will participate in the same SSE program led by a coach for 12 weeks; older adults will then be asked to continue SSE at home under the supervision and with the active participation of their caregivers for another 12 weeks. They will be asked to practice SSE for 60 minutes, three times a week, and to reach a ≥65% heart rate increase. In the field of sports, the people who perform the above-mentioned activities are called "pacers," and they supervise physical activity through active accompaniment of older adults.
6. Compliance and adverse events monitoring A monitoring system will be developed to perform long-distance monitoring of compliance with physical activity. It will include three components: i) the system that will collect the information from a chipset connected to the SSE mats (e.g., time of exercise, velocity); ii) the system that will transmit and store the data on the study computer; iii) the system for supervision and follow-up, which will allow connecting with participants through different electronic devices, such as mobile phones and e-mails.

   The monitoring system will be an important strategy to avoid missing data, drop-out rates and low program adherence.

   In addition, the investigators will monitor study adverse events through direct observations of the study participants during the exercise sessions, monitoring system, and 12-, 24-, and 54-week evaluations.

   The investigators will register number, type (e.g., dizziness, pain, fatigue, muscle strains, falls, or injuries), and severity of adverse events during the exercise sessions and outside the hours of the exercise sessions but during the intervention period. The severity of events will be categorized as follows: mild (do not affect activities of daily living); moderate (have moderate effect on activities of daily living); and severe (requires hospitalization, or results in persistent or significant disability or results in some life-threatening, or other medically important condition). RSA and ABD will review all adverse events on a weekly basis. They will report all moderate and severe adverse events to the IMSS Ethics Committee and stop the study if the adverse events data demonstrate any hazard of the intervention.
7. Motivation strategies The monitoring system will be an important strategy to avoid drop-outs and low program adherence. It will be complemented by motivation phone calls to those participants who fail to attend the group sessions or to perform home-based SES activities.

   Moreover, the study will include 10-15 minute group discussions to explore health-related topics, such as the benefits of healthy lifestyles (e.g., physical activity, nutrition) to maintaining cardiovascular and brain health or to exchange experiences on past events. The discussions will precede exercise training sessions.
8. Evaluations The investigators will conduct four evaluations during the study: the baseline evaluation and 12-week, 24-week, and 52-week evaluations. The study outcome variables will be measured at each evaluation, while the covariates will be collected only at the beginning of the study. The investigators will also measure the participants' adherence to the programs, defined as 80% or higher compliance with the assigned exercise training regimen. Finally, the investigators will document the reasons for dropouts and poor adherence. Previously trained health professionals with a medical specialty in geriatrics will perform these evaluations.

   The study covariates will cover Participant demographic and clinical characteristics: age (years from birth); biological sex (male or female); formal educational attainment (years); current employment status (retired, employed, volunteer, unpaid worker, unemployed); marital status (married, widowed, divorced, single, other); and current living situation (living alone, living with a spouse, living with or without children); self-reported comorbidities relevant to this study (e.g., vascular risk factors, orthopedic conditions, etc.); and self-reported baseline physical activity defined as i) ideal (≥150 minutes per week of moderate-intensity activity or ≥75 minutes per week of vigorous-intensity activity, or an equivalent combination); ii) moderate/intermediate (≤149 minutes per week of moderate-intensity activity or ≤74 minutes per week of vigorous or intense activity, or an equivalent combination); and iii) poor (without any moderate or intense physical activity). The apolipoprotein E (APOE) ε4 allele is a genetic risk factor for Alzheimer's.

   Caregivers will be asked the following: age, biological sex, formal educational attainment, current employment status, marital status, relation to the patient, and self-reported baseline physical activity, as previously defined; availability of social support networks; and presence of animal companions at home. Social support will be measured using the Household and Family Support Networks subsection (part 5) of the World Health Organization Study on Global AGEing and Adult Health.
9. Data Management and confidentiality Data entry will be conducted by trained staff. Data quality will be assessed before statistical analysis (eg, range checks for data values).

   Only members of the study team will have access to the study information and all information that will be collected from participants will be kept private to ensure confidentiality. The consent forms with participant signatures will be stored in a locked location only accessible by the principal investigator (PI). All electronic data will be stored on the PI laptop and a back-up hard drive which will be password protected. Any handwritten information such as field notes or other related research materials will be stored and secured in a locked cabinet when not in use. Data will be erased and destroyed after 5 years, as per IMSS Ethics and Research Committee guidelines. Only deidentified data will be used for reporting, publication, and dissemination of findings.
10. Statistical Analysis First, the investigators will perform a descriptive analysis of the older adults' and caregivers' characteristics at each evaluation and evaluate the distribution of quantitative variables using the Kilmogorov-Smirnov normality test. Variables that have normal distribution will be analyzed using means and standard deviations, variables with non-normal distribution will be presented using medians and 25th and 75th percentiles, and categorical variables will be analyzed by using frequencies and percentages. Second, for each evaluation the investigators will compare study variables between T1-GR and C-GR and between T2-GR and C-GR. The comparison between these groups will be performed using Student's t-test (for normally distributed continuous variables), Mann Whitney-U test (for continuous variables that are not normally distributed), or Chi-square test (for categorical variables), as appropriate. The difference between baseline and post-intervention evaluations for each group will be measured using the Student's paired t-test or Mann-Whitney U test when the distribution is non-normal. The effect of the intervention on the outcome variables will be assessed by estimating the differences-in-differences (D-in-D) treatment effects using a D-in-D estimator.46 If the investigators identify statistically significant differences in participants' baseline characteristics and adherence to the exercise regimens among the studied groups, the model will adjust the results of the D-in-D treatment effects by these covariates using a generalized linear regression model (GLM), where Yi= ß0+ ß1Xi+ß2X+ ß3X +ßjCov +ei; in this regression equation, ß1 represents the mean difference within each group, β2 the mean change after the intervention, β3 the difference in mean change between the two groups (e.g., T1-GR and C-GR), ßjCov the covariates that were different between the study groups, and ei= the standard error. This model considers the correlation among repeated observations of the same subject and allows a more precise estimate to be obtained. The investigators will conduct a model for each outcome variables. P-values \< 0.05 will be interpreted as statistically significant. The analyses will be performed using the software Stata 14.0 (Stata Corp, College Station, TX, USA).

Eligibility Criteria:
Inclusion criteria.

1. With 60-75 years of age.
2. They have self-reported cognitive concerns (ie, have answered "yes" to the question: "Do you feel like your memory or thinking skills have gotten worse recently?").
3. They demonstrate functional independence in activities of daily living and instrumental activities of daily living.
4. They have one or more vascular risk factors (eg, type 2 diabetes or hypertension).
5. They have symptoms or signs of underlying cognitive dysfunction without a diagnosis of dementia (ie, confirmed by a review of their health records and a Mini Mental State Exam \[MMSE\] score\> 24).
6. They have an informal caregiver who accepts to participate.

Exclusion criteria.

1. With depression (score\> 15 according to the Center for Epidemiological Studies Depression Scale - Revised \[CESD-R\]).
2. With clinically significant neurological or psychiatric disorders (eg, Parkinson's, schizophrenia).
3. With a recent severe cardiovascular event (eg, myocardial infarction, stroke).
4. With a major orthopedic condition (eg, severe osteoarthritis).
5. With blood pressure that is unsafe for exercise (ie,\> 180/100 mmHg or \<100/60 mmHg).
6. With a severe visual or auditory impairment.
7. With an unwillingness to adhere to the intervention schedules.