Cognitive Decline in Older Adults, Type 2 Diabetes
Conditions
Keywords
Exercise Training, Semaglutide, Brain Health, Cognitive Function, Older Adults, Physical Activity, Type 2 Diabetes
Brief summary
Type 2 diabetes and low levels of physical activity are associated with an increased risk of cognitive decline in older adults. Improving blood sugar control and engaging in regular exercise may help support brain health and physical function in this population. The MOTIVATE study is a randomized clinical trial designed to examine the effects of supervised exercise and diabetes treatment with semaglutide, alone or in combination, on cognitive function, physical health, and brain-related outcomes in older adults with Type 2 diabetes. Participants will be assigned to one of four study groups involving exercise training, control exercise, semaglutide treatment, or standard diabetes care. Participants will complete supervised exercise sessions three times per week for 32 weeks, with some participants also receiving weekly semaglutide injections for 16 weeks. Assessments will include cognitive testing, physical and functional measures, blood-based metabolic markers, and brain imaging. This study aims to improve understanding of how exercise and diabetes treatments may support brain health in older adults with Type 2 diabetes.
Detailed description
Type 2 diabetes (T2D) and lack of engagement in physical activity are common in Canada, significantly increasing the risk of dementia among older adults. High blood sugar levels in people living with T2D are linked to poorer cognitive performance and faster cognitive decline. Even those at risk for T2D, due to slightly elevated blood sugar levels or being overweight, show signs of cognitive decline and brain abnormalities. Studies show that improving blood sugar control, losing weight, and engaging in physical activity can enhance cognitive function in long-term and spatial memory and decision-making. Semaglutide is primarily used to lower blood sugar levels, while resistance exercise is known to improve brain health and physical fitness. Thus, short-term pharmacotherapy in adjunct to RE may serve as a powerful therapy for older adults with T2D to achieve and sustain clinically relevant improvements in cognitive function and glycemic control, and to facilitate a healthier lifestyle. The present trial is a 32-week, real-world, randomized, open-label waitlist-controlled trial designed to show improvements in cognitive function and compare the effect of injectable semaglutide once-weekly versus standard of care as a short-term (16-weeks) adjunct to resistance exercise (RE) (32 weeks) versus its active control (balance-and-tone training (BAT)) in older adults with T2D. Participants will be randomly put into one of four groups: 1) drug and exercise, 2) no drug and exercise, 3) standard of care and non- intense exercise, or 4) standard of care and non-intense exercise. Exercise will be conducted in classes involving either resistance exercise (weighted movements using exercise machines) or an active control, balance and tone exercise (stretching and core). Cognitive function will be assessed using tasks of memory, learning, flexibility, and processing of information. Brain structure and function will be examined through magnetic resonance imaging (MRI) scans. Blood samples will be analyzed for markers of brain health and inflammation. After randomization, all outcome assessors will remain blinded to the study drug and exercise groups.
Interventions
DRUGsemaglutide
Injectable semaglutide administered once weekly by subcutaneous injection for 16 weeks, as prescribed and monitored by the study physician.
BEHAVIORALModerate-Intensity Resistance Exercise
Supervised moderate-intensity resistance exercise training performed three times per week for 32 weeks.
BEHAVIORALBalance and Tone (BAT) Exercise
Supervised balance-and-tone (BAT) exercise performed three times per week for 32 weeks, serving as an active control exercise condition.
Sponsors
Western University, Canada
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial. 2. Community-dwelling 3. Male or female 4. Age ≥ 65 at the time of signing informed consent 5. Glycated hemoglobin levels of ≥7% (i.e., A1c levels high enough to see intervention-related changes and increase eligibility for recruitment, but can exercise safely) 6. Eligible for the Ontario Drug Benefit (inadequate glycemic control and on max tolerated dose of metformin or metformin contraindicated or inappropriate) 7. Score \>24/30 on the Mini-Mental State Exam (MMSE) 8. Score \>6/8 on the Lawton Instrumental Activities of Daily Living Scale (IADL) 9. Have visual acuity of \>20/40 with or without corrective lenses 10. Speak and understand English fluently 11. Complete the Physical Activity Readiness Questionnaire (PAR-Q+) and obtain physician clearance to start a supervised exercise program 12. Comfortable with a blood draw 13. Not currently engaging in structured resistance exercise more than once per week
Exclusion criteria
1. Have a medical condition for which semaglutide or exercise is contraindicated 2. Use of a GLP-1 receptor agonist in the past 6 months (i.e., offers removal of Semaglutide from the system as it has a half-life of around 1 week; thus, 8-10 weeks are required for a washout. 3\) Have engaged regularly (\>1/week) in aerobic or RE within the past 6 months 4) Have a neurodegenerative disease (i.e., dementia) or psychiatric condition 5) Have had untreated depression in the past 6 months (6) Have experienced a recent vascular incident (i.e., stroke, myocardial infarction in the last 6 months.) (7) Have severe peripheral neuropathy, an active foot wound, or severe musculoskeletal/joint disease (8) Active or untreated retinopathy (9) Taking psychotropic medications (excluding those for the treatment of depression)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Trail Making Test (TMT) Part A and B | Baseline (Week 0), Midpoint (Week 16), Endpoint (Week 32) | Executive function will be assessed using the Trail Making Test (TMT), Parts A and B. The TMT measures visual attention, processing speed (Part A), and executive function/set-shifting ability (Part B). Time to completion (seconds) will be recorded, with faster completion times indicating better performance. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Montreal Cognitive Assessment (MoCA) | Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32) | A 30-point cognitive screening tool designed to detect mild cognitive impairment. Domains assessed include attention, executive function, memory, language, visuoconstructional skills, abstraction, calculation, and orientation. Measurement Scale: Total scores range from 0 to 30. Higher scores indicate better cognitive performance. For this study, a score of ≥26 is considered "normal" cognitive function, while scores below this threshold (typically 18-25) may suggest mild cognitive impairment (MCI). |
| Mini-Mental State Examination (MMSE) | Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32) | An 11-item screening tool assessing global cognitive function across orientation, registration, attention and calculation, recall, and language. Scores range from 0-30, with higher scores indicating better cognitive function. |
| Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog-11) | Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32) | A cognitive test with an 11-task battery assessing memory, language, praxis, attention, and orientation. Widely used in clinical trials to evaluate cognitive dysfunction and disease progression in Alzheimer's disease and related conditions. A score ranges from 0 to 70. Higher scores represent greater cognitive deficit (impairment), with scores of 18 or higher typically indicating cognitive impairment. |
| Digit Span (Forward and Backward) | Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32) | A measure of working memory requiring participants to recall increasingly long sequences of numbers in both forward and reverse order. The final score is usually the total correct sequences (0-14 correct) and the longest sequence length achieved (e.g., if a user correctly repeats a 7-digit string, their span is 7). A minimum sequence length of 3 (forward) or 2 (backward) and a maximum sequence of 9 (forward) or 8 (backward) can be achieved. High scores indicate better performance. |
| Stroop Color-Word Test | (Week 0), Midpoint (Week 16), and Endpoint (Week 32) | Assesses selective attention, processing speed, and cognitive inhibition. Participants are required to identify ink colors while inhibiting automatic word reading. Completion time and/or errors are recorded. Faster completion times and fewer errors indicate better performance. |
| Rey Auditory Verbal Learning Test (RAVLT) | Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32) | A measure of episodic verbal learning and memory. Participants are read a list of words across multiple trials and asked to recall as many words as possible immediately and after a delay. The total number of words recalled immediately and after a delay is recorded. Additionally, a learning rate is calculated across the number of trials. More words recalled and faster learning rates indicate better performance. |
| Digit Symbol Substitution Test (DSST) | Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32) | Administered using Inquisit software (Millisecond Software) using a computer, this is a timed task assessing processing speed, attention, and visuomotor coordination. Participants use a reference key to match symbols with corresponding numbers within a fixed time period. Total correct responses are recorded. Greater correct responses correspond with better performance. |
| Total Triglycerides (TG) | Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32) | Measurement of the most common type of fat in the body; elevated levels are associated with insulin resistance and metabolic syndrome. Unit of Measure: mmol/L. Fasting levels \< 1.7 (mmol/L) are considered optimal. |
| Total Cholesterol (TC) | Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32) | The sum of the body's cholesterol content (HDL, LDL, and VLDL). Unit of Measure: mmol/L. Higher values are generally considered cardioprotective. |
| Brain-Derived Neurotrophic Factor (BDNF) | Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32) | Concentration of Brain-Derived Neurotrophic Factor in venous serum, reflecting systemic neuroplasticity and trophic support. Measured as ng/mL. |
| Insulin-like Growth Factor-1 (IGF-1) | Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32) | Venous concentration of Insulin-like Growth Factor 1, serving as a marker for neuroprotective growth factor activity. Measured as ng/mL. |
| Serum Interleukin-6 (IL-6) | Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32) | Pro-inflammatory cytokine (Interleukin-6) measured in venous blood to assess systemic and neuro-associated inflammation. Measured as pg/mL or mg/L. |
| C-reactive protein (CRP) | Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32) | C-Reactive Protein measured in venous blood to assess systemic and neuro-associated inflammation. Measured as pg/mL or mg/L. |
| Plasma Neurofilament Light (NfL) | Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32) | Quantified via high-sensitivity digital immunoassay (e.g., Simoa) to detect axonal injury and neurodegeneration in peripheral venous blood. Measured as pg/mL. |
| Plasma p-tau181 | Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32) | Measurement of phosphorylated tau protein at position 181, utilized as a venous biomarker for Alzheimer's-related tau pathology. Measured as pg/mL. |
| Amyloid Beta Ratio (beta42/40) | Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32) | The ratio of amyloid-beta peptides measured in plasma; a lower venous ratio is associated with increased brain amyloid deposition. Measured as a ratio. |
| Body Weight | Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32) | Total body mass measured under standardized conditions. Kilograms (kg). |
| Waist-to-Hip Ratio (WHR) | Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32) | A dimensionless ratio used to assess the distribution of body fat and identify central (android) obesity. Determined using waist Circumference, measured at the narrowest part of the torso (midway between the lowest rib and the iliac crest), and Hip Circumference, measured at the widest portion of the buttocks. Calculated by creating a ratio (Waist Circumference/ Hip Circumference). Lower values are associated with healthier body composition. |
| NIH Toolbox Flanker Task | Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32) | A computerized task assessing attention and inhibitory control. Participants respond to the direction of a central target stimulus while ignoring flanking distractors. The task is administered via the NIH Toolbox platform using a touchscreen or keyboard response on a tablet or computer device. Reaction time and accuracy are automatically recorded. Faster reaction times and greater accuracy correspond with better performance. |
| Timed Up and Go (TUG) Test | Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32) | Used to assess mobility. Participants are seated in a chair and must stand up, walk a distance of 3 meters at their usual pace, turn around, return to their chair, and sit back down. The time to complete each of two separate trials is recorded in seconds. |
| Short Physical Performance Battery (SPPB) | Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32) | Used to assess gait speed, balance, and lower extremity physical function using tasks that mimic daily activities; includes three tasks: (1) Standing Balance Task: participants stand unassisted (side-by-side standing, semi-tandem standing, and tandem standing) for a period of 10 seconds each; (2) Walking Speed Task: participants walk 4 meters at their usual pace; and (3)Chair Stand Test: participants stand up from a chair 5 times consecutively (without the use of their arms if possible). Time to complete tasks 2 and 3 is recorded in seconds. A score between 0 and 12 is assigned based on the above measures. A higher score indicates better daily physical function. |
| Six-Minute Walk Test | Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32) | Used to assess aerobic fitness. Participants walk the furthest distance they can achieve in a total of 6 minutes. The total distance walked in meters is recorded. The greater the distance, the better aerobic fitness. |
| Grip Strength Dynamometry | Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32) | Grip strength will be assessed using a calibrated handheld dynamometer to measure maximal voluntary isometric force of the dominant hand, providing an index of overall muscular strength. Measured in kgs. |
| One-repetition maximum (1RM) strength testing | Third Exercise Class, Midpoint (Week 16), and Endpoint (Week 32) | One-repetition maximum is a physical measure of an individual's maximum muscle strength during a single repetition and is used to determine the desired load for resistance training. Exercise includes leg press, latissimus pulldown, leg curl, chest press, bicep curls, tricep extensions, and pulley rows. Measured in kgs. |
| Mean Cortical Thickness | Baseline (Week 0) and Endpoint (Week 32) | The average distance between the white matter surface and the pial (outer) surface across the entire cerebral cortex and by region. Automated vertex-wise calculation of the distance between the gray/white matter boundary and the gray matter/CSF boundary. Millimeters (mm). Greater thickness is typically better. |
| Resting-state functional connectivity | Baseline (Week 0) and Endpoint (Week 32) | Participants will be asked to remain as still as possible with eyes open while a functional scan is acquired to assess intrinsic resting-state brain networks. Measured as Fisher-z transformed correlation coefficients (z). Higher values represent stronger functional synchronization. |
| White Matter Fractional Anisotropy (FA) | Baseline (Week 0) and Endpoint (Week 32) | A diffusion tensor imaging metric that measures the "directionality" of water diffusion within white matter tracts. It reflects the organization and integrity of the myelin and axonal membranes. Calculated from the diffusion tensor at each voxel; typically averaged across major tracts (e.g., Corpus Callosum, Cingulum). Values: Scale from 0 to 1 (unitless). A value of 1 indicates perfectly directional diffusion (healthy, organized white matter), while a decrease in FA indicates axonal degradation, demyelination, or "leaky" white matter. |
| Total Gray Matter & White Matter Volumes | Baseline (Week 0) and Endpoint (Week 32) | The global volume of the brain's neuronal cell bodies (gray matter) and myelinated axons (white matter) using automated whole-brain segmentation. Measured in cubic millimeters (mm\^3). Reduced total gray matter volume indicates global atrophy. White matter volume changes can indicate loss of structural connectivity. |
| Subcortical Gray Matter Volume | Baseline (Week 0) and Endpoint (Week 32) | The total volume of deep brain structures, most notably the hippocampus, thalamus, and amygdala using automated whole-brain segmentation. Measured in cubic millimeters (mm\^3). Reduced volume typically indicates brain atrophy. |
| White Matter Hyperintensity (WMH) Volume | Baseline (Week 0) and Endpoint (Week 32) | A measure of "leukoaraiosis" or white matter lesions, which appear as bright spots on T2-weighted magnetic resonance imaging (MRI) scans. These are primary markers of small vessel disease and vascular brain aging. Automated or semi-automated segmentation (e.g., via FreeSurfer's aseg or specialized toolboxes like BIANCA/LST) on T2- images. Measured as total volume in cubic millimeters (mm\^3) or as a percentage of Total Intracranial Volume (%ICV). Lower is better. Higher WMH volumes are strongly associated with hypertension, diabetes, and increased risk for stroke and vascular dementia. |
| Fasting Blood Glucose (FBG) Measurement | Baseline (Week 0), Midpoint (Week 16), Endpoint (Week 32) | Capillary blood samples will be obtained via finger prick and analyzed using a calibrated glucometer to determine fasting blood glucose (FBG) levels (expressed in mmol/L). Fasting is defined as the absence of caloric intake for a minimum of 8 hours. Glycemic status is categorized according to the following thresholds: Prediabetes Risk: 6.0-6.9 (mmol/L), Diabetes: ≥7.0 (mmol/L) |
| Glycated Hemoglobin (HbA1c) | Baseline (Week 0), Midpoint (Week 16), Endpoint (Week 32) | A measure of average glycemic control over the preceding 2-3 months. Unit of measure: Percentage (%) Thresholds: Normal: \<6.0%, Prediabetes: 6.0%-6.4%, Diabetes: ≥6.5% |
| Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) | Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32) | A calculated index used to quantify insulin resistance and beta-cell function. Calculation: \[(Fasting Insulin (uIU/mL)) x (Fasting Glucose (mmol/L))\] / 22.5 ; Unit of Measure: Numeric index (dimensionless) |
| Low-Density Lipoprotein Cholesterol (LDL-C) | Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32) | Calculated or direct measurement of "bad" cholesterol, a primary target for cardiovascular risk reduction. Unit of Measure: mmol/L. A level of 2.0 (mmol/L) is often the threshold for high-risk intervention. |
| High-Density Lipoprotein Cholesterol (HDL-C) | Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32) | Measurement of "good" cholesterol, which aids in the removal of other forms of cholesterol from the bloodstream. Unit of Measure: mmol/L. Higher values are generally considered cardioprotective. |
Countries
Canada
Contacts
CONTACTOlivia Ghosh-Swaby, PhD
Outcome results
None listed