Exercise in Adults With Mild Memory Problems

NCT ID: NCT02814526

Last Updated: 2023-02-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 296 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-09-13
• Study Completion Date: 2021-12-19

Brief Summary

This study evaluates the effects of physical exercise on cognition, functional status, brain atrophy and blood flow, and cerebrospinal fluid biomarkers of Alzheimer's disease in adults with a mild memory impairment.

Half of participants will participate in a stretching-balance-range of motion exercise program, while the other half will participate in a moderate/high aerobic training program.

Detailed Description

Overall Study Design:

The EXERT trial was a multicenter phase 3 randomized, single-blind study that examined the effects of aerobic exercise on cognition, functional status, whole and regional cerebral blood flow, and cerebrospinal fluid biomarkers of Alzheimer's disease in approximately 300 adults with amnestic MCI. EXERT included an 18-month behavioral intervention trial, with a 12-month supervised exercise intervention phase with its primary endpoints, followed by a 6-month unsupervised exercised phase.

Subject Populations and Group Assignments:

The study population included male and female subjects aged 65 to 89 diagnosed with test scores and clinical ratings consistent with amnestic Mild Cognitive Impairment (MCI).

Assignment to study groups:

involved randomization to either treatment or active control, and study staff performing assessments were blinded to intervention assignment to maintain the single-blind structure of the trial.

Participants were to complete EXERT interventions at participating YMCAs located near the selected clinic sites across the U.S. The YMCA provided 18-month memberships at no cost to participants. In the first 12 months, a study-certified YMCA Trainer supervised all participants for the first 8 exercise sessions completed (weeks 1 and 2), and for 2 of 4 weekly sessions thereafter through Month 12. At Month 12, participants transitioned to independent exercise and were instructed to continue their assigned exercise programs for the final 6 months of the study without supervision. To encourage adherence and optimize cost efficiency, Trainers provided supervision to small groups of participants (2-4 individuals) randomized to the same intervention whenever possible. Compliance was evaluated using multiple mechanisms including heart rate monitoring, participant ratings of perceived exertion, entries in participants' Physical Activity Logs, Trainer assessment of effort, and weekly data review by the YMCA-Project Manager (Y-PM) and the Intervention Oversight Team (includes the Project Directors, Wake Forest team of exercise trial specialists, and Y-USA). These mechanisms provided multiple and regular opportunities to discuss participant progress, identify and resolve barriers, and encourage high levels of adherence to study protocols. The Intervention Oversight Team had the necessary expertise to successfully accomplish this objective in EXERT.

Conditions

Mild Cognitive Impairment; Cognitive Decline; Memory Impairment

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Aerobic

Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA .

Group Type: EXPERIMENTAL

Aerobic exercise

Intervention Type: BEHAVIORAL

Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA .

Stretching/balance/range of motion

The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA.

Group Type: ACTIVE_COMPARATOR

Stretching/balance/range of motion exercise

Intervention Type: BEHAVIORAL

The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA.

Interventions

Aerobic exercise

Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA .

Intervention Type: BEHAVIORAL

Stretching/balance/range of motion exercise

The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA.

Intervention Type: BEHAVIORAL

Eligibility Criteria

Inclusion Criteria

1. Age between 65 and 89 years old, inclusive

2. MMSE: ≥24 for participants with 13 or more years of education; ≥22 for participants with 12 or fewer years of education

3. Global CDR score of 0.5 with a memory score of at least 0.5

4. Profile of test scores and clinical ratings is consistent with amnestic mild cognitive impairment

5. Speaks English fluently

6. Visual and auditory acuity adequate for cognitive testing

7. Completed at least 6 years of formal education or work history sufficient to exclude mental retardation

8. Has an informant who knows the participant well, has regular contact, and is available to accompany the participant to clinic visits or complete study partner assessments remotely.

9. Sedentary or underactive, determined by responses to the staff-administered EXERT Telephone Assessment of Physical Activity (TAPA) survey

10. Willing to be randomized to either intervention group and to complete the assigned activities as specified for 18 months

11. Willing and able to reliably travel to the identified YMCA, 4 times per week for 18 months

12. Ability to safely participate in either intervention and complete the 400 m Walk Test within 15 min without sitting or use of any assistance

13. Plans to reside in the area for at least 18 months

14. For planned travel, total time away must be no more than 2 months over the course of the study, and no more than 1 month at any one time; participants must be willing to continue the assigned exercise program if travelling out of the area for more than 1 week

15. In overall good general health with no disease or planned surgery that could interfere with study participation

16. Modified Hachinski ≤4

17. Stable use of cholinesterase inhibitors, memantine, vitamin E, estrogens, aspirin (81 300 mg daily), beta-blockers, or cholesterol-lowering agents for 12 weeks prior to screening (important for biomarker analyses)

18. Stable use of antidepressants lacking significant anticholinergic side effects for 4 weeks prior to screening as long as the participant does not meet DSM V criteria for major depression currently or in the last 12 months; GDS scores are to be used to inform clinical decisions but there is no specified cut-off score for inclusion

19. When applicable, willing to complete 4-week washout of psychoactive medications, including disallowed antidepressants, neuroleptics, chronic anxiolytics or sedative hypnotics, and willing to avoid these medications for the duration of the trial

20. Able to complete all baseline assessments

Exclusion Criteria

1. Any significant neurologic disease, other than MCI, including any form of dementia, Parkinsons disease, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma with persistent neurologic sequelae or known structural brain abnormalities

2. Sensory or musculoskeletal impairment sufficient to preclude successful and safe completion of the intervention or assessment protocols; must be able to walk safely and unassisted on a treadmill

3. Contraindications for MRI studies, including claustrophobia, metal (ferromagnetic) implants, or cardiac pacemaker

4. Brain MRI at screening shows evidence of infection, infarction, or other clinically significant focal lesions, including multiple lacunes in prefrontal or critical memory regions; inconclusive findings may be subject to review by the ADCS Imaging Core

5. History of major depression or bipolar disorder (DSM V criteria), psychotic features, agitation or behavioral problems within the last 12 months

6. History of schizophrenia, as per DSM V criteria

7. History of alcohol or substance abuse or dependence within the past 2 years, as per DSM V criteria

8. Currently consumes more than 3 alcoholic drinks per day

9. Clinically significant or unstable medical condition, including uncontrolled hypertension or significant cardiac, pulmonary, hematologic, renal, hepatic, gastrointestinal, endocrine, metabolic or other systemic disease in the opinion of clinic medical personnel that may put the participant at increased risk, influence the results or compromise the participants ability to participate in the study (treated atrial fibrillation for more than 1 year or occasional premature ventricular contractions on ECG are not exclusions)

10. History in the last 6 months of myocardial infarction, coronary artery angioplasty, bypass grafting, or STENT placement

11. History in the last 3 months of transient ischemic attack or small vessel stroke (if more than 3 months, small vessel stroke with no residual effects are permitted)

12. Expected joint replacement surgery within the next 18 months

13. History within the last 5 years of a primary or recurrent malignant disease with the exception of non-melanoma skin cancers, resected cutaneous squamous cell carcinoma in situ, basal cell carcinoma, cervical carcinoma in situ, or in situ prostate cancer with normal prostate-specific antigen posttreatment

14. Hemoglobin A1c >7.0

15. Clinically significant abnormalities in screening laboratory blood tests: low B12 is exclusionary, unless follow-up labs (homocysteine [HCY] and methylmalonic acid [MMA]) indicate that it is not physiologically significant

16. Current or past use of insulin to treat type 2 diabetes (other diabetes medications are acceptable if hemoglobin A1c ≤7)

17. Current use (within 60 days of screening) of psychoactive medications including tricyclic antidepressants, antipsychotics, mood-stabilizing psychotropic agents (e.g. lithium salts), psychostimulants, opiate analgesics, antiparkinsonian medications, anticonvulsant medications (except gabapentin and pregabalin for non-seizure indications), systemic corticosteroids, or medications with significant central anticholinergic activity. Limited use of antipsychotics (quetiapine ≤ 50mg/day or risperidone ≤ 0.5mg/day), and non-chronic use of opiate analgesics on an as needed basis is permitted; such medications must be avoided for 8 hours before clinic assessments

18. Chronic use of anxiolytics or sedative hypnotics except as follows: use of benzodiazepines for treatment on an as-needed basis for insomnia or daily dosing of anxiolytics is permitted; medications must be avoided for 8 hours before clinic assessments

19. Previous or current treatment involving active immunization against amyloid

20. Previous treatment with approved or investigational agents with anti-amyloid properties or passive immunization against amyloid are prohibited 12 months prior to screening and for the duration of the trial; treatment with other investigational agents are prohibited 3 months prior to screening and for the duration of the trial

21. For LP, current use of anticoagulants such as Coumadin, Plavix, or high dose Vitamin E

22. For LP, current blood clotting or bleeding disorder, or significantly abnormal prothrombin time (PT) or partial thromboplastin time (PTT) at screening

23. For LP, presence of physical distortions due to spinal surgery, severe degenerative joint disease or deformity, or obesity that could interfere with CSF collection (as per investigator judgment)

24. Participants whom the PI deems otherwise ineligible

• Minimum Eligible Age: 65 Years
• Maximum Eligible Age: 89 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute on Aging (NIA)

NIH

Sponsor Role: collaborator

Wake Forest University Health Sciences

OTHER

Sponsor Role: collaborator

Alzheimer's Disease Cooperative Study (ADCS)

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Howard Feldman, MDCM FRCP(C)

Role: PRINCIPAL_INVESTIGATOR

Alzheimer's Disease Cooperative Study (ADCS)

Locations

University of California, Irvine

Irvine, California, United States

VAPAHCS / Stanford University School of Medicine

Palo Alto, California, United States

Yale University School of Medicine

New Haven, Connecticut, United States

Emory University

Atlanta, Georgia, United States

Great Lakes Clinical Trials (Andersonville)

Chicago, Illinois, United States

University of Kansas Medical Center

Kansas City, Kansas, United States

University of Kentucky

Lexington, Kentucky, United States

Cleveland Clinic Lou Ruvo Center for Brain Health

Las Vegas, Nevada, United States

New York University Medical Center

New York, New York, United States

Mount Sinai School of Medicine

New York, New York, United States

Duke University

Durham, North Carolina, United States

Wake Forest University Health Sciences

Winston-Salem, North Carolina, United States

University of North Texas Health Science Center

Fort Worth, Texas, United States

University of Wisconsin

Madison, Wisconsin, United States

Countries

United States

References

Baker LD, Frank LL, Foster-Schubert K, Green PS, Wilkinson CW, McTiernan A, Plymate SR, Fishel MA, Watson GS, Cholerton BA, Duncan GE, Mehta PD, Craft S. Effects of aerobic exercise on mild cognitive impairment: a controlled trial. Arch Neurol. 2010 Jan;67(1):71-9. doi: 10.1001/archneurol.2009.307.

Reference Type: BACKGROUND

PMID: 20065132 (View on PubMed)

Lautenschlager NT, Cox KL, Flicker L, Foster JK, van Bockxmeer FM, Xiao J, Greenop KR, Almeida OP. Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial. JAMA. 2008 Sep 3;300(9):1027-37. doi: 10.1001/jama.300.9.1027.

Reference Type: BACKGROUND

PMID: 18768414 (View on PubMed)

Colcombe SJ, Erickson KI, Scalf PE, Kim JS, Prakash R, McAuley E, Elavsky S, Marquez DX, Hu L, Kramer AF. Aerobic exercise training increases brain volume in aging humans. J Gerontol A Biol Sci Med Sci. 2006 Nov;61(11):1166-70. doi: 10.1093/gerona/61.11.1166.

Reference Type: BACKGROUND

PMID: 17167157 (View on PubMed)

Voss MW, Prakash RS, Erickson KI, Basak C, Chaddock L, Kim JS, Alves H, Heo S, Szabo AN, White SM, Wojcicki TR, Mailey EL, Gothe N, Olson EA, McAuley E, Kramer AF. Plasticity of brain networks in a randomized intervention trial of exercise training in older adults. Front Aging Neurosci. 2010 Aug 26;2:32. doi: 10.3389/fnagi.2010.00032. eCollection 2010.

Reference Type: BACKGROUND

PMID: 20890449 (View on PubMed)

Colcombe SJ, Erickson KI, Raz N, Webb AG, Cohen NJ, McAuley E, Kramer AF. Aerobic fitness reduces brain tissue loss in aging humans. J Gerontol A Biol Sci Med Sci. 2003 Feb;58(2):176-80. doi: 10.1093/gerona/58.2.m176.

Reference Type: BACKGROUND

PMID: 12586857 (View on PubMed)

Burns JM, Cronk BB, Anderson HS, Donnelly JE, Thomas GP, Harsha A, Brooks WM, Swerdlow RH. Cardiorespiratory fitness and brain atrophy in early Alzheimer disease. Neurology. 2008 Jul 15;71(3):210-6. doi: 10.1212/01.wnl.0000317094.86209.cb.

Reference Type: BACKGROUND

PMID: 18625967 (View on PubMed)

Nichol KE, Poon WW, Parachikova AI, Cribbs DH, Glabe CG, Cotman CW. Exercise alters the immune profile in Tg2576 Alzheimer mice toward a response coincident with improved cognitive performance and decreased amyloid. J Neuroinflammation. 2008 Apr 9;5:13. doi: 10.1186/1742-2094-5-13.

Reference Type: RESULT

PMID: 18400101 (View on PubMed)

Shadyab AH, Aslanyan V, Jacobs DM, Salmon DP, Morrison R, Katula JA, Jin S, Thomas RG, LaCroix AZ, Pa J, Cotman CW, Feldman HH, Baker LD; ADCS EXERT Study Group. Effects of exercise versus usual care on older adults with amnestic mild cognitive impairment: EXERT versus ADNI. Alzheimers Dement. 2025 Apr;21(4):e70118. doi: 10.1002/alz.70118.

Reference Type: DERIVED

PMID: 40271887 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

ADC-041-EX

Identifier Type: -

Identifier Source: org_study_id

U19AG010483-22

Identifier Type: NIH

Identifier Source: secondary_id

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