Working Memory and Physical Exercise Training in Patients With Mild Cognitive Impairment

Study Overview
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Brief Summary
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The prevalence of dementia will double in the next three decades in the U.S.; effective treatment or prevention for dementia is urgently needed. The current exploratory project aims to evaluate and understand how the brain and cognition may improve after a 12-week intervention that combines brain training and aerobic exercise training to improve brain function, both in those with mild cognitive impairment (some with possible prodromal Alzheimer's disease) and with healthy aging. Findings from this pilot project will guide and refine the development of a future larger clinical trial that aligns with the goals of the National Alzheimer's Plan of Action (NAPA), especially regarding Prevent and Effectively Treat Alzheimer's Disease (AD) by 2025.

Official Title
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Adaptive Working Memory and Physical Exercise Training to Improve Brain and Mitochondrial Function in MCI

Conditions
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Mild Cognitive Impairment

Intervention / Treatment
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* Behavioral: Progressive aerobic exercise
* Behavioral: Adaptive cognitive training
* Behavioral: Combined


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult men and women of all races and ethnicities who are 50-80 years of age will be eligible. Only sedentary adults will be eligible (engaging in structured activity for exercise (<3x/week). Ability to use, and accessibility to, an iPad or computer. Fluent in English. The diagnosis of MCI will first be confirmed at the screening evaluation using the clinical dementia rating (CDR) scale and the Montreal Cognitive Assessment (MoCA). We will also evaluate their ADL using instrumental activities of daily living (IADL) to ensure they have preserved independence in functional abilities despite the cognitive deficits. The primary caregivers will be interviewed (either in person or by phone) for the participants' IADL to corroborate the independent functional status. Exclusion Criteria: Does not have access to a computer or internet to perform the Cogmed® training AND is unwilling to come to the lab for the training. Unable to undergo an MRI investigation based on claustrophobia or metal foreign bodies. Symptomatic heart disease, Coronary artery disease, congestive heart failure, uncontrolled hypertension, significant cardiovascular disorders (on EKG and graded exercise test) that would prevent the participant from the exercise training; neurologic, musculoskeletal, or other condition that limits the subject's ability to complete study physical assessments. Estimated verbal Intelligence Quotient (IQ) below 70 (based on the Wechsler Test of Adult Reading) which would invalidate the informed consent process for the study. Self-reported moderate to severe substance use disorder(s) (e.g., self-reported intake >3 oz liquor, or three 4 oz glasses of wine, or three 12 oz cans of beer per day or illicit drug use). Severe chronic or acute medical or other (non-MCI) neuropsychiatric conditions that might confound the cognitive or brain imaging measures (e.g., liver function tests >2.5 normal range or evidence for renal failure). Body mass index >40 kg/m2.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aerobic Exercise<br>Progressive aerobic exercise 3x/week for 12 weeks. | Behavioral: Progressive aerobic exercise<br>* Progressive aerobic exercise<br>|
| Experimental: Cognitive Training<br>Adaptive cognitive training on Cogmed 5x/week for a total of 25 sessions in 5-8 weeks. | Behavioral: Adaptive cognitive training<br>* Adaptive cognitive training<br>|
| Experimental: Combined Cognitive and Aerobic Exercise<br>Combined progressive aerobic exercise 3x/week for 12 weeks and adaptive cognitive training on Cogmed 5x/week for a total of 25 sessions in 5-8 weeks simultaneously. | Behavioral: Combined<br>* Combine adaptive cognitive and progressive aerobic exercise training<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Brain structure measures | Changes in brain volume measures from T1-weighted images (volumes in mm3) | At baseline and at 4 weeks after the corresponding training program. | 
| Changes in brain cortical thickness measures | Changes in brain cortical thickness measures from T1-weighted images (thickness measures in mm) | At baseline and at 4 weeks after the corresponding training program. | 
| Changes in Brain microstructure measures | Changes in brain measures of diffused tensor imaging (diffusion coefficient in mm²/s) | At baseline and at 4 weeks after the corresponding training program. | 
| Changes in Brain blood flow from Arterial spin labeling magnetic resonance imaging (ASL-MRI) in milliliters/100 g/minutes | Changes in Brain blood flow from Arterial spin labeling magnetic resonance imaging (ASL-MRI) in milliliters/ 100 g/ minutes | At baseline and at 4 weeks after the corresponding training program. | 
| Changes in Brain Activation on functional MRI | Changes in functional MRI from blood oxygen level dependence (BOLD) contrast on fMRI (in percentage change) | At baseline and at 4 weeks after the corresponding training program. | 
| Changes in cognitive performance, emotions, and motor function based on NIH toolbox | Changes in cognitive performance, emotions, and motor function in raw scores measured by the NIH Toolbox® (reports will be generated as T scores, with higher T scores indicating better outcomes) | At baseline and at 4 weeks after the corresponding training program. | 
| Changes in executive function using the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) | Changes in executive function using the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) (reports will be generated as T scores, with lower T scores indicating better outcomes and T scores higher than 65 indicating significant impairments in the executive function) | At baseline and at 4 weeks after the corresponding training program. | 
| Changes in Blood Bioenergetic Markers | Platelet mitochondrial respiration (OCR) and extracellular acidification rates (ECAR) will be evaluated to assess bioenergetic profiles in platelets isolated from whole blood of fasted participants. OCR will be measured using a Seahorse model XFe96 machine as the high throughput platform. Measurements of OCR/ECAR will be performed with the following modifications. Platelets will be isolated from whole blood with a Beckman Allegra model X-30R centrifuge. Platelets will be counted using a Nexcelom Bioscience Cellometer (Lawrence, MA) using Calcein acetoxymethyl (AM) ester dye to enable the seeding of 10,000,000 platelets per well. | At baseline and at 4 weeks after the corresponding training program. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| VO2peak | VO2peak will be used as the primary measure of aerobic capacity. Subjects will be asked to exercise to voluntary exhaustion during a treadmill test using a modified Bruce protocol. Oxygen (O2) consumption, carbon dioxide (CO2) production, and minute ventilation will be measured breath-by-breath using a metabolic cart and the average of the final two 20 second values of O2 consumption are VO2peak. | At baseline and within one week after the corresponding training program. |