Creatine and Resistance Training in Older Adults With Mild Cognitive Impairment

Examining the Effects of Creatine Supplementation and Resistance Training on Cognition and Brain Health in Older Adults With Mild Cognitive Impairment: a 26 Week Randomized Controlled Trial

The goal of this 26-week trial is to learn if creatine supplementation and resistance training (i.e., weightlifting; exercise that increases muscle mass), alone and together, impact cognition, brain health, and physical function in older adults with mild cognitive impairment. Previous studies have shown that resistance training improves cognition and brain health in older adults. Creatine is naturally occurring in the human body and is known to decline with age. Studies have shown that creatine increases muscle mass and bone density in older adults when supplemented. Some research has suggested that creatine may also improve cognition and brain health. However, little is known about how creatine supplementation affects the aging brain and body alone and when combined with resistance training, especially in those with known cognitive impairment.

In this study, participants will be randomly assigned to one of four groups: 1) creatine and resistance training, 2) placebo and resistance training, 3) creatine and active control (balance and tone classes), or 4) placebo and active control. Participants in the creatine groups will take creatine every day during the study. Participants in the placebo groups will take a look-alike substance that contains no drug every day during the study. Participants in the resistance training groups will attend three 60-minute classes per week that target each major muscle group and will increase in difficulty during the study. Participants in the active control group will attend three 60-minute classes per week that will consist of balance, stretching, and range of motion exercises. This group accounts for variables such as physical training received by traveling to the training centres, social interaction, and changes in lifestyle secondary to study participation.

Researchers will collect information before and after the 26 weeks to see if creatine supplementation and/or resistance training have any effects on cognition, brain health, and/or physical function. The investigators suspect that both creatine supplementation and resistance training will improve cognition, brain health, and physical function alone. However, it is thought that the combination of creatine supplementation and resistance training will improve cognition, brain health, and physical function more.

Research objectives:

To evaluate the effects of 26 weeks of creatine supplementation on its own and in combination with progressive resistance training in community-dwelling older adults with mild cognitive impairment on:

1. visuospatial working memory (primary objective);
2. executive function (working memory, inhibitory control, and mental flexibility), functional mobility, muscle and grip strength, bone density, and blood-based biomarkers for brain health and cognitive decline (secondary objectives); and
3. resting state functional activity, hippocampal volume and structural integrity, and key metabolite concentrations in the brain (exploratory objective).

Hypotheses:

It is hypothesized that 26 weeks of creatine supplementation and resistance training in community-dwelling older adults with mild cognitive impairment will: 1) increase visuospatial working memory performance; 2) improve executive function, functional mobility, strength performance, bone density, and blood-based biomarkers for brain health and cognitive decline; and 3) increase resting state functional activity, volume and structural integrity in the hippocampus, and concentrations of key metabolites in the brain.

The investigators hypothesize that both creatine supplementation and resistance training will improve our outcome measures independently. Moreover, the investigators hypothesize that their combined application will yield superior improvements compared to their individual effects.

Methods:

Screening: Participants interested in the study will reach out to us via phone or e-mail. Interested participants will be sent the study Letter of Information via e-mail to get more detailed information. At the time of study enrolment, interested participants will be screened over the phone to assess for eligibility prior to scheduling their baseline session. At this time, participants will have an opportunity to ask questions. Eligibility will be confirmed by the following:

1. Telephone version of the Montreal Cognitive Assessment (T-Moca) that assesses cognitive impairment status. Participants must obtain <19/22.
2. Instrumental Activities of Daily Living (IADL) questionnaire, which is a clinical assessment used to measure an individual's ability to perform tasks necessary for living independently in the community. Participants must obtain >6/8.
3. Geriatric Depression Scale (GDS). Participants must obtain <5 on the GDS. Those who are eligible and still interested in participating will be scheduled to come into the lab for baseline assessments.

Baseline assessments: When participants arrive in the lab, the researcher will go over the consent form with them, answer any additional questions they have about the study, and obtain informed written consent. At this time, participants may also consent to participate in the optional MRI portion of this study. Participants will then complete baseline assessments. Total time to complete baseline assessments in the lab (excluding MRI) will be ~2.5-3 hours. For those participating in the MRI component, this will be scheduled for another separate visit (1 hour).

Randomization: Once participants complete baseline assessment, they will be randomly assigned to one of the four conditions. Group allocation will be determined using the Clinical Trial Randomization tool, developed by the National Cancer Institute. The sequence will be held remotely by the PI and will not be revealed until after baseline assessments.

Descriptors and covariates:

1. Anthropometry (height, weight) will be measured at baseline. Weight will be collected at midpoint to adjust dietary supplementation according to body weight, if needed.
2. Demographic information (e.g., age, sex, gender, ethnicity, education, socioeconomic status) will be collected at baseline.
3. Global cognitive function (T-MoCA; Mini-Mental Status Examination, MMSE). T-MoCA is used as a screening tool for mild cognitive impairment. This test assesses cognitive ability in the domains of attention and concentration, executive functions, memory, language, visuo-constructional skills, conceptual thinking, calculations, and orientation. The maximum score is 22 on the telephone version. The MMSE is used as a screening tool for cognitive impairment. This 11-item test assesses global cognitive function in the domains of orientation, registration, attention and calculation, recall, and language with a maximum score of 30. The MoCa will be administered during screening and at endpoint. The MMSE will be administered at baseline and endpoint.
4. Physical activity levels (Physical Activities Scale for the Elderly, PASE). Used to measure the level of self-reported physical activity, and consists of 12 questions about leisure, household, and work-related daily activity. The PASE will be administered at baseline and endpoint, as well as monthly at the last exercise session of every month to assess physical activity habits outside of the intervention.
5. Mood (GDS).The GDS is a 15-item questionnaire used to test for the presence of depression. It will be administered at screening and endpoint. If depression is suspected, the PI will ensure that the participant is provided with a copy of the questionnaire and will advise the participant to make an appointment with their family physician to discuss the results. It will be administered during screening and at endpoint.
6. Number of co-morbidities (Functional Comorbidity Index, FCI). The FCI is an 18-item list of diagnoses used to determine co-morbidities. It will be administered at baseline and at endpoint.
7. Health-related quality of life (Short Form Health Survey, SF-12). A self-report measure examining eight domains: vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, and mental health. Scores range from 0-100, with higher scores indicating greater health status and quality of life. It will be administered at baseline and endpoint.
8. Loneliness (UCLA Loneliness Scale). A 20-item self-report measure on loneliness and interpersonal problems. It will be administered at baseline and endpoint.
9. Independence (IADL questionnaire). An 8-item self-report measure about everyday tasks. It will be administered during screening and at endpoint.
10. Behaviour (Capability, Opportunity, Motivation Behaviour Physical Activity Questionnaire, COM-B PAQ; Motivation to Change Lifestyle and Health Behaviours for Dementia Risk Reduction, MCLHB-DRR). The COM-B PAQ has 6-items measured on a 10-point Likert scale and assesses behaviour in the domains of capability, opportunity, and motivation. The MCLHB-DRR is a 27-item questionnaire measured on a 5-point Likert scale. Items are used to assess behaviour in the domains of perceived susceptibility, benefits, barriers, cues to action, general health motivation and self-efficacy. These questionnaires will be administered at baseline.
11. Dietary intake (Three Day Weighed Food Record). Used to assess nutrient and energy intake. Participants will record their dietary consumption over three days (two weekday and one weekend day). They will be instructed on how to do the food record at the end of the baseline session and will be asked to return it by their first exercise session. A dietetic student will assist in analysing this data.
12. Real-time physical activity levels (ActiGraph ambulatory monitoring wearables). Participants will be given the accelerometer to wear on their non-dominant wrist at baseline for one week prior to the intervention and endpoint for week after the intervention. Our lab has 10 devices, so up to 10 participants can have access to a device simultaneously. This will allow objective quantification of energy expenditure, metabolic equivalent of task rates, steps, physical activity intensity, sedentary bouts, and sleep latency. To support validation of Actigraph-derived sleep measures, participants will also complete a brief written sleep diary during each wear period to capture self-reported sleep timing and related sleep characteristics. They are Bluetooth enabled for real-time data uploads and include a wear-time sensor to assess compliance.

Adherence: All participants will be asked to record their supplement consumption on a monthly calendar, which will be returned to the lab at end of each intervention month. This monthly calendar will also track exercise attendance and falls during the month. Participants will also receive their supplement container at the beginning of each month and will be asked to return the container with all the sachets to track adherence. Exercise class attendance will be recorded each session by instructors. Participants will be encouraged to adhere to both the supplement protocol and exercise classes. The investigators will implement the following strategies to promote participant engagement:

• Semi-monthly newsletters that will feature personal accomplishments of participants (with permission) and study updates, for example.
• Investigators will follow up with participants who have missed supplement doses or exercise sessions to discuss barriers and strategies to overcome them on an individual basis.

If participants miss classes due to illness/travel, they will be scheduled to make up missing classes as soon as possible. If participants miss classes without notifying investigators in advance, investigators will call to remind them about their classes and encourage increased compliance.

Final assessment: Assessments completed at baseline will also be completed at endpoint (26 weeks). The sub-set of participants at baseline who underwent MRI will also undergo the MRI protocol at endpoint.

Data analysis: Behavioural data (cognitive assessments, mobility, and physical measures) will be analyzed in SPSS. Primary and secondary outcome measures will be examined using linear mixed models (LMMs), with time (baseline, endpoint), creatine supplementation, and RT entered as fixed effects, including all two-way interactions and the creatine × RT × time interaction. The three-way interaction is the primary term of interest, testing whether the combined effect of creatine and RT differs from baseline to endpoint. A random intercept for participant will account for the correlation between each participant's baseline and endpoint values. Models will adjust for relevant covariates, including age, sex, and education. Structural MRI data will be processed and analysed using FreeSurfer and FSL software packages

Analyses will be conducted according to the intention-to-treat principle, whereby all randomized participants will be included in the final analysis regardless of adherence to the intervention. Where outcome data are missing at random, multiple imputation methods will be used if the assumptions for imputation are met. Sensitivity analyses will be conducted to compare results from imputed and complete-case datasets. Reasons for missing data will be reported, and descriptive analyses will be performed to compare participants with complete and incomplete data.

Additional exploratory analyses will be conducted to examine potential moderators of intervention effects, including sex, age, education level, baseline physical activity levels, and baseline cognitive levels. Exploratory associations between changes in neuroimaging outcomes, cognitive performance, and physical function measures will also be explored.

Significance of research: This research is the first to address a critical gap in the literature by examining the effects of creatine and resistance training alone and in conjunction on various measures of physical function, cognitive function, and brain health in older adults with mild cognitive impairment. In the context of an aging population and given the overall safety and accessibility of creatine and resistance training, the findings from our study may inform biomarker-driven, non-pharmacological strategies and interventions to offset or defer further cognitive decline in older adults with mild cognitive impairment.

We will include participants who: 1) are aged >60; 2) are living independently in the community; 3) have normal or corrected-to-normal vision and hearing; 4) read, write, and speak English fluently; 5) are right-handed (if participating in the MRI component); 6) have subjective feelings of memory decline in the past five years; 7) have telephone Montreal Cognitive Assessment (T-MoCA) scores <19/22; 8) have high independence, as indicated by Instrumental Activities of Daily Living (IADL) scale >6/8; 9) have a Geriatric Depression Scale (GDS) score <6/15; 10) are able to exercise at a moderate pace using resistance training for 60 minutes 3x/week; and 11) receive clearance from a physician to participate in an exercise program at baseline.

We will exclude participants who: 1) cannot partake or commit to exercise training 3x/week for 26 weeks or have engaged in resistance training >1x/week over the past three months; 2) cannot partake or commit to consuming a daily supplement for 26 weeks or have consumed nutritional supplements containing creatine monohydrate over the past three months; 3) have a known allergy to creatine monohydrate or dextrose; 4) have been diagnosed with a neurological disorder (e.g., Alzheimer's disease, Parkinson's disease); 5) have pre-existing kidney disease, heart disease, or liver abnormalities; 6) have one or more uncontrolled chronic or psychiatric conditions (e.g., hypertension, diabetes, depression, anxiety); 7) are taking medication that may impact kidney function (e.g., non-steroidal anti-inflammatory drugs, such as ibuprofen and naproxen); or 8) are ineligible or uncomfortable with blood sampling.