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

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 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 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.

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.

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.

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.

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.

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.

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.

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)

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%

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)

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.

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.

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.

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

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

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

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

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

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

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

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

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.

Total non-fat, non-bone tissue mass as measured by a whole-body dual-energy X-ray absorptiometry (DEXA) scan.

The proportion of total fat mass relative to total body mass, calculated via whole-body DEXA scan. Unit of Measure: Percentage (%)

Total body bone mineral density is determined by the attenuation of two X-ray beams of different energy levels. Unit of Measure: (g/cm^2) (Grams per square centimeter)

Total body fat tissue mass as measured by a whole-body DEXA scan. Unit of Measure: Kilograms (kg)

An indicator of kidney function calculated using serum creatinine levels, age, and sex (typically via the CKD-EPI equation). Unit of Measure: mL/min/1.73m^2; Interpretation: Lower scores indicate decreased renal function.

The average speed of walking over a fixed distance. Measured using a GAITRite, pressure-sensitive mat, to determine the total distance traveled divided by the ambulation time (m/s). Higher is better. In older adults, a velocity > 1.0 (m/s) is typically considered "healthy." A velocity < 0.8 (m/s) is a clinically significant marker for increased risk of cognitive decline and falls.

A measure of the consistency or "rhythm" of the gait cycle from one step to the next, measured using a GAITRite. Calculated as the standard deviation of stride time divided by the mean stride time ((SD/Mean) x 100). Lower value is better. Healthy adults typically have a variability < 3%. Values > 5% are strongly associated with executive dysfunction and instability in the frontal lobe's motor control circuits.

The amount of time during a stride during which both feet are in contact with the ground simultaneously. Measured using a GAITRite, pressure-sensitive mat, to determine the cumulative time of double-support phases divided by total gait cycle time.Percentage of Gait Cycle (%GC). Lower is better (within normal limits). A healthy gait typically spends about 20% - 25% of the cycle in double support. Higher values (e.g., > 30%) indicate a "cautious gait" pattern, often used by those with cognitive impairment to compensate for poor balance.