Regular Exercise for Aging Brain Health

(BIM Trial)

Overseen By Marc J Poulin, PhD, DPhil

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of Calgary

Must not be taking: Beta-blockers, Antidepressants, Blood thinners, Corticosteroids

Disqualifiers: Heart disease, Stroke, Smoking, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

286 Participants Needed

Trial Summary

What is the purpose of this trial?

While it is well established that physical inactivity is a modifiable risk factor for vascular disease and cognitive decline, the mechanism by which exercise exerts its protective effect on the cerebral circulation and cognition is unknown. This knowledge gap was recognized recently in the Centers for Disease Control \& Prevention and the Alzheimer's Association document "National Public Health Road Map to Maintaining Cognitive Health". Our rationale for these studies is that the identification of physical exercise as a lifestyle factor able to improve cerebrovascular reserve and cognition would establish a strong scientific framework justifying design of a randomized clinical trial that could evaluate the role of physical activity in cerebrovascular health and function. This research is based on data we obtained from a cross-sectional study that showed significant relations between physical fitness, vascular regulation and cognition. Cerebrovascular reserve and cognition were better maintained in women who were physically active but reduced in women who were sedentary. Our central hypothesis is that regular aerobic exercise mitigates age-related decreases in cerebrovascular reserve, which in turn imparts benefits in cognition. Further, we believe that these effects will persist after the structured aerobic exercise program is terminated. Our 18 month study began with a 6-month baseline period, followed by a 6-month exercise intervention, and a 6-month follow-up period. In addition, there are 5-year and 10-year follow-up periods. Volunteers (men and women aged ≥ 55 years) from the community were recruited using a variety of recruitment methods including media and distribution lists. After the baseline (pre-training) measurements, participants underwent a six-month aerobic training program, following guidelines previously used by us and according to the new exercise guidelines for older adults established by American College of Sports Medicine and the American Heart Association. The study involves comprehensive assessments of physical fitness, cerebrovascular responses to carbon dioxide at rest and during sub-maximal exercise, and an extensive battery of cognitive function tests.

Will I have to stop taking my current medications?

Yes, you will need to stop taking certain medications to participate in this trial. The trial excludes participants who are currently taking medications like beta-blockers, anti-depressants, digitalis/digoxin, blood thinners, evista, corticosteroids, adrenaline/epinephrine, and anti-arrhythmics.

What data supports the effectiveness of the treatment Aerobic Exercise for aging brain health?

Research suggests that aerobic exercise can improve cardiorespiratory fitness in older adults, including those with Alzheimer's disease, and may positively impact physical fitness, cognitive function, and daily living activities. Although aerobic exercise did not significantly change hippocampal volume in healthy older individuals, it did improve cardiorespiratory fitness, which is beneficial for overall health. ^{1 2 3 4 5}

Is regular aerobic exercise safe for older adults and those with certain health conditions?

Research indicates that aerobic exercise is generally safe for older adults, including those with Alzheimer's disease and post-stroke conditions, although individual responses can vary. It's important to monitor for any adverse cardiovascular events, especially in people with existing health issues. ^{2 4 6 7 8}

How does aerobic exercise as a treatment for aging brain health differ from other treatments?

Aerobic exercise is unique because it is a low-cost, non-drug treatment that can improve brain health by increasing blood flow and enhancing cognitive functions like memory and processing speed in older adults. Unlike other treatments, it also boosts cardiovascular fitness and can be effective even in the short term. ^{9 10 11 12 13}

Research Team

Marc J Poulin, PhD, DPhil

Principal Investigator

University of Calgary

Eligibility Criteria

This trial is for men and women aged 55 or older who are generally inactive, with a BMI under 35, can walk independently, and have not had major surgery or trauma in the past 6 months. Women must be postmenopausal for at least a year. People with recent heart issues, stroke, chronic headaches, blood clots, smokers within the last year or those on certain medications like beta-blockers cannot participate.

Inclusion Criteria

Body mass index (BMI) < 35 kg/m^2

I have been postmenopausal for at least 12 months.

I can walk by myself outside or on stairs.

Exclusion Criteria

I have asthma or sleep apnea.

I have a history of irregular heartbeats.

I experience chest pain when I exert myself physically.

Timeline

Baseline

Participants undergo baseline measurements before starting the exercise program

6 months

Exercise Intervention

Participants engage in a supervised aerobic exercise program, including warm-up, aerobic exercise, and cool-down

6 months

3 sessions per week (in-person)

Follow-up

Participants are monitored for safety and effectiveness after the exercise intervention

6 months

Long-term Follow-up

Participants are monitored for long-term effects on cerebrovascular reserve and cognition

5 years and 10 years

Treatment Details

Interventions

• Aerobic exercise

Trial Overview The study tests if regular aerobic exercise improves brain blood flow (cerebrovascular reserve) and mental functions in older adults. It includes an initial assessment period followed by six months of guided aerobic training based on established guidelines and cognitive testing before concluding with follow-up assessments over several years.

Participant Groups

Group I: Aerobic exercise Experimental Treatment 1 Intervention

Participants took part in a supervised 6-month long aerobic (walk/jog) training program held 3 days/week. Each session included a 5-min warm-up, 20-40 min of aerobic exercise (walking, jogging), 5-min cool-down, and stretching. Exercise prescriptions follow current principles and guidelines established by ACSM/AHA, including sufficient warm-up, cooldown, and ongoing provision of safety precautions/exercise tips. As participants progress, the duration of aerobic exercise increased from 20 (month 1) to 30 (months 2-3) and 40 min (months 4-6), with proportional increases to warm-up and cool-down periods. Exercise intensity is based on individual maximal oxygen uptake (VO2 max), measured at baseline. Intensity builds from 30-45% (months 1-3) to mitigate the risk of injury and will progress to 60-70% (months 4-6) heart rate reserve (HRR).

Aerobic exercise is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Aerobic Exercise for:

• Rehabilitation after stroke
• Improvement of physical function
• Enhancement of cognitive function
• Reduction of depression

Approved in European Union as Aerobic Exercise for:

• Cardiovascular rehabilitation
• Improvement of physical function
• Enhancement of cognitive function

Approved in Canada as Aerobic Exercise for:

• Rehabilitation after stroke
• Improvement of physical function
• Enhancement of cognitive function

Who Is Running the Clinical Trial?

University of Calgary

Lead Sponsor

Trials

827

Recruited

902,000+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

Findings from Research

In a study of 20 elderly patients with mild Alzheimer's disease, those who engaged in aerobic exercise on a treadmill for 30 minutes twice a week showed significant improvements in cognitive function compared to a control group that declined over the same period.

The exercise group also demonstrated enhanced functional capacity, suggesting that regular aerobic activity could be a beneficial addition to treatment plans for Alzheimer's patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treadmill training as an augmentation treatment for Alzheimer's disease: a pilot randomized controlled study. Arcoverde, C., Deslandes, A., Moraes, H., et al.[2022]

A 2-month aerobic training program showed that older men with moderate Alzheimer's disease (AD) can improve their cardiorespiratory fitness, while those with severe AD may not benefit as much, indicating variability in response to exercise.

The study suggests that a longer duration of aerobic training, such as 6 months, may be more effective for improving fitness in older adults with AD, highlighting the need for tailored exercise programs based on individual fitness levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aerobic training for older men with Alzheimer's disease: individual examples of progression. Yu, F., Leon, AS., Bliss, D., et al.[2021]

A meta-analysis of eight studies involving 554 cognitively healthy older adults found that aerobic exercise training (AET) lasting 3 to 12 months did not significantly increase hippocampal volume, suggesting that AET may not impact this brain region in healthy aging individuals.

However, AET did lead to a moderate improvement in cardiorespiratory fitness (CRF), indicating that while it may not affect hippocampal size, it can enhance overall physical fitness in older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aerobic exercise training effects on hippocampal volume in healthy older individuals: a meta-analysis of randomized controlled trials. Balbim, GM., Boa Sorte Silva, NC., Ten Brinke, L., et al.[2023]

A 12-week high-intensity aerobic exercise program significantly improved physical and neuromotor performance in 22 inactive healthy older adults, including increases in knee strength, walking distance, and reaction time.

Participants in the exercise group showed notable improvements, such as a 12% increase in knee extensor strength and a 20% improvement in whole-body reaction time, while the control group showed no significant changes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Functional and neuromotor performance in older adults: effect of 12 wks of aerobic exercise. Kalapotharakos, VI., Michalopoulos, M., Strimpakos, N., et al.[2019]

Aerobic exercise training may improve physical fitness, performance, daily living activities, cognition, and psychological symptoms in older adults with Alzheimer's disease, based on a review of 12 studies.

The Functional Impact of aerobic exercise Training in Alzheimer's disease (FIT-AD) model was developed to guide future research and practice, emphasizing the interconnected benefits of aerobic exercise for individuals with Alzheimer's.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Guiding research and practice: a conceptual model for aerobic exercise training in Alzheimer's disease. Fang Yu, .[2021]

A scoping review of 13 studies involving 452 participants found that submaximal aerobic exercise testing protocols for individuals post-stroke can be safely implemented without serious adverse events, addressing concerns about cardiovascular risks.

The most common comorbidities among participants included hypertension (41%), diabetes (31%), and dyslipidemia (27%), indicating that these factors should be considered when designing exercise protocols for stroke rehabilitation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events During Submaximal Aerobic Exercise Testing in People With Subacute Stroke: A Scoping Review. Legasto-Mulvale, JM., Inness, EL., Thompson, AN., et al.[2023]

Aerobic exercise, especially when started 5 days post-stroke, can significantly improve recovery by reducing lesion size, inflammation, and enhancing neuroplasticity, as shown in animal studies.

In stroke patients, regular moderate to high-intensity aerobic exercise (2-5 days per week) can enhance cardiorespiratory fitness and metabolic health, potentially overcoming limitations in rehabilitation effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Four birds with one stone? Reparative, neuroplastic, cardiorespiratory, and metabolic benefits of aerobic exercise poststroke. Ploughman, M., Kelly, LP.[2022]

Life-long aerobic exercise in Masters athletes (average age 74.5) was associated with higher cerebral blood flow (CBF) in critical brain regions compared to sedentary elderly individuals, suggesting a protective effect against age-related decline.

However, the athletes exhibited lower cerebral vascular reactivity (CVR) to CO2, indicating a potential desensitization effect from prolonged aerobic exercise, which may dampen the brain's response to changes in carbon dioxide levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Life-long aerobic exercise preserved baseline cerebral blood flow but reduced vascular reactivity to CO2. Thomas, BP., Yezhuvath, US., Tseng, BY., et al.[2021]

A 3-week high-intensity aerobic exercise program significantly improved verbal memory in individuals with multiple sclerosis compared to a standard exercise program, highlighting its potential cognitive benefits.

Participants in the high-intensity training group also showed improvements in physical fitness (measured by VO2-peak) and a reduction in matrix metalloproteinase-2, suggesting that high-intensity exercise may positively influence both cognitive and physical health in MS patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-intensity interval exercise improves cognitive performance and reduces matrix metalloproteinases-2 serum levels in persons with multiple sclerosis: A randomized controlled trial. Zimmer, P., Bloch, W., Schenk, A., et al.[2022]

In a study of 37 cognitively healthy sedentary adults aged 57-75, a 12-week aerobic exercise program significantly increased resting cerebral blood flow in the anterior cingulate region compared to a control group.

Participants in the exercise group also showed improved memory performance, which was positively associated with increased blood flow in the hippocampus, indicating that even short-term aerobic exercise can enhance brain health and cognitive function in older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Shorter term aerobic exercise improves brain, cognition, and cardiovascular fitness in aging. Chapman, SB., Aslan, S., Spence, JS., et al.[2022]

Moderate exercise has been linked to improved cognitive function and increased brain volume in older adults, suggesting it may help combat cognitive decline associated with aging and dementia-related conditions.

Animal studies indicate that exercise promotes neurogenesis, particularly in the dentate gyrus, highlighting the potential biological mechanisms through which aerobic exercise could protect against dementia, warranting further prospective studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Can aerobic exercise protect against dementia? Graff-Radford, NR.[2021]

A 6-month aerobic exercise program involving 206 healthy middle-aged and older adults led to improvements in cognitive functions and cerebrovascular regulation, indicating that physical activity can enhance brain health.

The study found specific associations between cognitive improvements and changes in cerebrovascular function, suggesting that better blood flow regulation during exercise and hypercapnia may contribute to enhanced executive functions and fluency.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aerobic exercise improves cognition and cerebrovascular regulation in older adults. Guadagni, V., Drogos, LL., Tyndall, AV., et al.[2020]

A short-term (8 weeks) training program involving lower body strength and aerobic training, upper body strength and aerobic training, or gross motor activities led to equivalent improvements in cognitive functions among 47 healthy older adults, suggesting that various exercise types can enhance cognition.

Despite differences in physical fitness improvements, all exercise interventions resulted in similar cognitive benefits, particularly in inhibition, indicating that the specific type of exercise may not be as critical as previously thought for cognitive enhancement in older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multiple roads lead to Rome: combined high-intensity aerobic and strength training vs. gross motor activities leads to equivalent improvement in executive functions in a cohort of healthy older adults. Berryman, N., Bherer, L., Nadeau, S., et al.[2021]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Treadmill training as an augmentation treatment for Alzheimer's disease: a pilot randomized controlled study. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Aerobic training for older men with Alzheimer's disease: individual examples of progression. [2021]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Aerobic exercise training effects on hippocampal volume in healthy older individuals: a meta-analysis of randomized controlled trials. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Functional and neuromotor performance in older adults: effect of 12 wks of aerobic exercise. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Guiding research and practice: a conceptual model for aerobic exercise training in Alzheimer's disease. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Adverse Events During Submaximal Aerobic Exercise Testing in People With Subacute Stroke: A Scoping Review. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Four birds with one stone? Reparative, neuroplastic, cardiorespiratory, and metabolic benefits of aerobic exercise poststroke. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Life-long aerobic exercise preserved baseline cerebral blood flow but reduced vascular reactivity to CO2. [2021]

9. England pubmed.ncbi.nlm.nih.gov

High-intensity interval exercise improves cognitive performance and reduces matrix metalloproteinases-2 serum levels in persons with multiple sclerosis: A randomized controlled trial. [2022]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Shorter term aerobic exercise improves brain, cognition, and cardiovascular fitness in aging. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Can aerobic exercise protect against dementia? [2021]

12. United States pubmed.ncbi.nlm.nih.gov

Aerobic exercise improves cognition and cerebrovascular regulation in older adults. [2020]

13. Netherlands pubmed.ncbi.nlm.nih.gov

Multiple roads lead to Rome: combined high-intensity aerobic and strength training vs. gross motor activities leads to equivalent improvement in executive functions in a cohort of healthy older adults. [2021]