Exercise in Adults With Mild Memory Problems

Mild Cognitive Impairment Clinical Trial

— EXERT  

Official title:

Therapeutic Effects of Exercise in Adults With Amnestic Mild Cognitive Impairment (MCI)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02814526
• Other study ID #: ADC-041-EX
• Secondary ID: U19AG010483-22
• Status: Completed
• Phase: N/A
• Start date: September 13, 2016
• Est. completion date: December 19, 2021

Study information

• Verified date: February 2023
• Source: Alzheimer's Disease Cooperative Study (ADCS)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 296
• Est. completion date: December 19, 2021
• Est. primary completion date: November 17, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 65 Years to 89 Years

Eligibility

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

Related Conditions & MeSH terms

• Cognitive Decline
• Cognitive Dysfunction
• Memory Impairment
• Mild Cognitive Impairment

Intervention

Behavioral:
• 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 .
• 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.

Locations

Country	Name	City	State
United States	Emory University	Atlanta	Georgia
United States	Great Lakes Clinical Trials (Andersonville)	Chicago	Illinois
United States	Duke University	Durham	North Carolina
United States	University of North Texas Health Science Center	Fort Worth	Texas
United States	University of California, Irvine	Irvine	California
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	Cleveland Clinic Lou Ruvo Center for Brain Health	Las Vegas	Nevada
United States	University of Kentucky	Lexington	Kentucky
United States	University of Wisconsin	Madison	Wisconsin
United States	Yale University School of Medicine	New Haven	Connecticut
United States	Mount Sinai School of Medicine	New York	New York
United States	New York University Medical Center	New York	New York
United States	VAPAHCS / Stanford University School of Medicine	Palo Alto	California
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (3)

Lead Sponsor	Collaborator
Alzheimer's Disease Cooperative Study (ADCS)	National Institute on Aging (NIA), Wake Forest University Health Sciences

Country where clinical trial is conducted

United States, 

References & Publications (7)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. Erratum In: JAMA. 2009 Jan 21;301(3):276. — View Citation

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. d — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Intervention Effects on Secondary Outcomes in a Subset of Participants Who Completed 12 Months of the Study Prior to the COVID-19 Pandemic.	To examine intervention effects on secondary outcomes listed above in participants who had the opportunity to complete a full 12 months of the study before the pandemic affected trial conduct.	12 months
Other	Exploratory Magnetic Resonance Imaging (MRI) Volumes and Perfusion and Individual AD Biomarkers in CSF and Blood Measures	To test whether 12 months of aerobic exercise, relative to the control, favorably affects MRI whole brain, ventricular and entorhinal volumes; perfusion in whole brain, gray matter and white matter; and individual AD biomarkers in CSF (ab42, ab40, total tau, p-tau, BDNF) and blood (ab42, ab40).	12 Months
Other	Clinical Dementia Rating Scale-Sum of Boxes (CDR) and Alzheimers Disease Assessment Scale-Cognitive 13-item (ADAS-Cog13)	To test whether 12 months of aerobic exercise, relative to the control, reduces clinical ratings of cognitive impairment as measured by the CDR Sum of Boxes, and total score on the ADAS Cog13.	12 Months
Other	Measures of Cognitive Function and Well-being Including (1) ADCS-ADL-MCI); (2) BRIEF-A; (3) GDS; (4) NPI; SF-36; EuroQol: 5-Item Health Questionnaire; (5) CCI: Cognitive Change Index); and (6) Study Partner Self-Assessment	To test whether 12 months of aerobic exercise, relative to the control, improves self-report measures of cognitive function and well-being, including (1) daily living skills (ADCS-Activities of Daily Living-MCI); (2) BRIEF-A: Behavior Rating Inventory of Executive Function-Adult Version); (3) mood (GDS); (4) health-related quality of life (NPI: Neuropsychiatric Inventory; SF-36: 36-Item Short Form Health Survey; EuroQol: 5-Item Health Questionnaire); (5) subjective memory concerns (CCI: Cognitive Change Index); and (6) Study Partner Self-Assessment Questionnaire	12 Months
Other	ADAS-Cog-Exec, Executive Function, and Episodic Memory Composites	To examine enduring cognitive effects (measured by ADAS-Cog-Exec, Executive Function and Episodic Memory Composites) of the intervention following a 6-month extension (through Month 18) when the prescribed exercise is continued without supervision.	18 Months
Other	Subgroup Treatment Responder Analyses	To explore whether sex, age, baseline AD biomarker profile in CSF (ab42/ab40, ab42/tau, ab42/p-tau) and blood (ab42/ab40), and ApoE4 genotype (e4+, e4-) predict treatment response.	12 Months
Primary	ADAS-Cog-Exec Global Composite	The ADAS-Cog-Exec Composite is a weighted sum of standardized (Z-score) change on subtests from the Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog13; Immediate and Delayed Word Recall, Orientation, and Number Cancellation); box scores for the cognitive components of the Clinical Dementia Rating Scale (Memory, Orientation, Judgement & Problem Solving); and additional tests requiring executive function (Trail Making Test A & B, Digit Symbol Substitution, Category Fluency). See https://doi.org/10.1002/trc2.12059 for a detailed description regarding the development and validation of the ADAS-Cog-Exec.; Change for the analysis of this primary outcome was calculated comparing the average of scores from month 6 and month 12 to baseline. The theoretical range for the ADAS-Cog-Exec is -3.00 to +3.00 in EXERT, with higher scores indicating improvement in cognitive function from baseline.	Baseline to mean (Mo 6, Mo 12)
Secondary	ADAS-Cog-Exec Global Composite in Subset Population	The ADAS-Cog-Exec Composite is a weighted sum of standardized (Z-score) change on subtests from the Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog13; Immediate and Delayed Word Recall, Orientation, and Number Cancellation); box scores for the cognitive components of the Clinical Dementia Rating Scale (Memory, Orientation, Judgement & Problem Solving); and additional tests requiring executive function (Trail Making Test A & B, Digit Symbol Substitution, Category Fluency). See https://doi.org/10.1002/trc2.12059 for a detailed description regarding the development and validation of the ADAS-Cog-Exec.; Change for the analysis of this primary outcome was calculated comparing the average of scores from month 6 and month 12 to baseline. The theoretical range for the ADAS-Cog-Exec is -3.00 to +3.00 in EXERT, with higher scores indicating improvement in cognitive function from baseline.	Baseline to mean (Mo 6, Mo 12)
Secondary	Executive Function Composite Score	The Executive Function Composite is the average standardized (Z-score) change on eight measures requiring attention and executive control: Trail Making, Part B; Digit Symbol Substitution; Category Fluency; Letter Fluency; Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog13) Number Cancellation; NIH Toolbox Flanker; NIH Toolbox Dimension Change Card Sort, and Cogstate One Back.; Change for analysis of this secondary outcome was calculated comparing the average of scores from month 6 and month 12 to baseline. The theoretical range for the Executive Function Composite is -3.00 to +3.00, with higher scores indicating improvement in executive function from baseline.	Baseline to mean (Mo 6, Mo 12)
Secondary	Episodic Memory Composite Score	The Episodic Memory Composite is the average standardized (Z-score) change on five measures of memory: Immediate and Delayed Word Recall from the Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog13); Cogstate Face-Name Associative Memory; Cogstate Behavioral Pattern Separation of Objects; and Cogstate One Card Learning.; Change for analysis of this secondary outcome was calculated comparing the average of scores from month 6 and month 12 to baseline. The theoretical range for the Episodic Memory Composite is -3.00 to +3.00, with higher scores indicating improvement in episodic memory from baseline.	Baseline to mean (Mo 6, Mo 12)
Secondary	Volumetric Magnetic Resonance Imaging (MRI) of Hippocampus	Assessment of volumetric change in the hippocampus region of the brain, measured by structural Magnetic Resonance Imaging (MRI), comparing MRI scans taken at baseline and month 12. Scans are compared and analyzed to give a percent deformation between timepoints.	12 Months
Secondary	Volumetric Magnetic Resonance Imaging (MRI) of Prefrontal Composite Region	Assessment of volumetric change in prefrontal composite regions of the brain, measured by structural Magnetic Resonance Imaging (MRI), comparing MRI scans taken at baseline and month 12. The prefrontal composite includes: superior frontal, caudal-middle frontal, rostral-middle frontal, pars opercularis, and pars triangularis regions. Scans are compared and analyzed to give a percent deformation between timepoints.	12 Months
Secondary	Volumetric Magnetic Resonance Imaging (MRI) of AD Signature Composite Region	Assessment of volumetric change in Alzheimer's Disease (AD) signature regions of the brain, measured by structural Magnetic Resonance Imaging (MRI), comparing MRI scans taken at baseline and month 12. The AD signature composite includes: parahippocampus, fusiform, inferior temporal, middle temporal, and inferior-parietal regions. Scans are compared and analyzed to give a percent deformation between timepoints.	12 Months
Secondary	Arterial Spin Labeling (ASL) Magnetic Resonance Imaging (MRI) of Hippocampus	Assessment of change in blood flow activity in the hippocampus region of the brain, measured using Arterial Spin Labeling (ASL) magnetic resonance imaging (MRI) scans. Scans taken at baseline and month 12 are compared and analyzed to assess change in blood flow between the timepoints. The unit of cerebral blood flow from ASL is ml/100g/min, which means the amount of blood flow into 100g of tissue during one minute.	Baseline to 12 Months
Secondary	Arterial Spin Labeling (ASL) Magnetic Resonance Imaging (MRI) of Prefrontal Composite Region	Assessment of change in blood flow activity in the prefrontal composite regions of the brain, measured using Arterial Spin Labeling (ASL) magnetic resonance imaging (MRI) scans. The prefrontal composite includes: superior frontal, caudal-middle frontal, rostral-middle frontal, pars opercularis, and pars triangularis regions. Scans taken at baseline and month 12 are compared and analyzed to assess change in blood flow. The unit of cerebral blood flow from ASL is ml/100g/min, which means the amount of blood flow into 100g of tissue during one minute.	Baseline to 12 Months
Secondary	Arterial Spin Labeling (ASL) Magnetic Resonance Imaging (MRI) of AD Signature Composite Region	Assessment of change in blood flow activity in the Alzheimer's Disease (AD) signature regions of the brain, measured using Arterial Spin Labeling (ASL) magnetic resonance imaging (MRI) scans. The AD signature composite includes: parahippocampus, fusiform, inferior temporal, middle temporal, and inferior-parietal regions. Scans taken at baseline and month 12 are compared and analyzed to assess change in blood flow. The unit of cerebral blood flow from ASL is ml/100g/min, which means the amount of blood flow into 100g of tissue during one minute.	Baseline to 12 Months
Secondary	Ratio of AD Biomarkers in Blood	Change in ratio of plasma amyloid beta peptides in blood plasma from baseline to12 months. A lower ab42/ab40 ratio in plasma is associated with a higher risk of dementia.	12 Months
Secondary	AD Biomarkers in CSF (ab42/ab40)	Change in ratio of amyloid beta peptides in cerebrospinal fluid (CSF) from baseline to 12 months. A lower ab42/ab40 ratio is associated with a higher risk of dementia.	12 Months
Secondary	AD Biomarkers in CSF (ab42/Tau)	Change in ratio of key peptides in cerebrospinal fluid (CSF) from baseline to 12 months. A lower ab42/tau ratio is associated with a higher risk of dementia.	12 Months
Secondary	AD Biomarkers in CSF (ab42/P-tau)	Change in ratio of key peptides in cerebrospinal fluid (CSF) from baseline to 12 months. A lower ab42/p-tau ratio is associated with a higher risk of dementia.	12 Months