Exercise and Diabetes Interventions to Improve Brain Health in Older Adults With Type 2 Diabetes

Montreal Cognitive Assessment (MoCA)

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).

Time frame: Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32)

Mini-Mental State Examination (MMSE)

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.

Time frame: Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32)

Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog-11)

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.

Time frame: Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32)

Digit Span (Forward and Backward)

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.

Time frame: Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32)

Stroop Color-Word Test

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.

Time frame: (Week 0), Midpoint (Week 16), and Endpoint (Week 32)

Rey Auditory Verbal Learning Test (RAVLT)

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.

Time frame: Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32)

Digit Symbol Substitution Test (DSST)

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.

Time frame: Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32)

NIH Toolbox Flanker Task

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.

Time frame: Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32)

Timed Up and Go (TUG) Test

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.

Time frame: Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32)

Short Physical Performance Battery (SPPB)

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.

Time frame: Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32)

Six-Minute Walk Test

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.

Time frame: Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32)

Grip Strength Dynamometry

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.

Time frame: Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32)

One-repetition maximum (1RM) strength testing

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.

Time frame: Third Exercise Class, Midpoint (Week 16), and Endpoint (Week 32)

Mean Cortical Thickness

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.

Time frame: Baseline (Week 0) and Endpoint (Week 32)

Resting-state functional connectivity

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.

Time frame: Baseline (Week 0) and Endpoint (Week 32)

White Matter Fractional Anisotropy (FA)

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.

Time frame: Baseline (Week 0) and Endpoint (Week 32)

Total Gray Matter & White Matter Volumes

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.

Time frame: Baseline (Week 0) and Endpoint (Week 32)

Subcortical Gray Matter Volume

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.

Time frame: Baseline (Week 0) and Endpoint (Week 32)

White Matter Hyperintensity (WMH) Volume

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.

Time frame: Baseline (Week 0) and Endpoint (Week 32)

Fasting Blood Glucose (FBG) Measurement

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)

Time frame: Baseline (Week 0), Midpoint (Week 16), Endpoint (Week 32)

Glycated Hemoglobin (HbA1c)

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%

Time frame: Baseline (Week 0), Midpoint (Week 16), Endpoint (Week 32)

Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)

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)

Time frame: Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32)

Low-Density Lipoprotein Cholesterol (LDL-C)

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.

Time frame: Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32)

High-Density Lipoprotein Cholesterol (HDL-C)

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.

Time frame: Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32)

Total Triglycerides (TG)

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.

Time frame: Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32)

Total Cholesterol (TC)

The sum of the body's cholesterol content (HDL, LDL, and VLDL). Unit of Measure: mmol/L. Higher values are generally considered cardioprotective.

Time frame: Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32)

Brain-Derived Neurotrophic Factor (BDNF)

Concentration of Brain-Derived Neurotrophic Factor in venous serum, reflecting systemic neuroplasticity and trophic support. Measured as ng/mL.

Time frame: Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32)

Insulin-like Growth Factor-1 (IGF-1)

Venous concentration of Insulin-like Growth Factor 1, serving as a marker for neuroprotective growth factor activity. Measured as ng/mL.

Time frame: Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32)

Serum Interleukin-6 (IL-6)

Pro-inflammatory cytokine (Interleukin-6) measured in venous blood to assess systemic and neuro-associated inflammation. Measured as pg/mL or mg/L.

Time frame: Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32)

C-reactive protein (CRP)

C-Reactive Protein measured in venous blood to assess systemic and neuro-associated inflammation. Measured as pg/mL or mg/L.

Time frame: Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32)

Plasma Neurofilament Light (NfL)

Quantified via high-sensitivity digital immunoassay (e.g., Simoa) to detect axonal injury and neurodegeneration in peripheral venous blood. Measured as pg/mL.

Time frame: Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32)

Plasma p-tau181

Measurement of phosphorylated tau protein at position 181, utilized as a venous biomarker for Alzheimer's-related tau pathology. Measured as pg/mL.

Time frame: Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32)

Amyloid Beta Ratio (beta42/40)

The ratio of amyloid-beta peptides measured in plasma; a lower venous ratio is associated with increased brain amyloid deposition. Measured as a ratio.

Time frame: Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32)

Body Weight

Total body mass measured under standardized conditions. Kilograms (kg).

Time frame: Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32)

Waist-to-Hip Ratio (WHR)

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.

Time frame: Baseline (Week 0), Midpoint (Week 16), and Endpoint (Week 32)