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. Author manuscript; available in PMC: 2021 Mar 1.
Published in final edited form as: J Am Geriatr Soc. 2019 Nov 22;68(3):559–568. doi: 10.1111/jgs.16252

LONGER TERM EFFECTS OF DIET AND EXERCISE ON NEUROCOGNITION: 1-YEAR FOLLOW-UP OF THE ENLIGHTEN TRIAL

James A Blumenthal 1, Patrick J Smith 1, Stephanie Mabe 1, Alan Hinderliter 2, Kathleen Welsh-Bohmer 1, Jeffrey N Browndyke 1, P Murali Doraiswamy 1, Pao-Hwa Lin 3, William E Kraus 3, James R Burke 4, Andrew Sherwood 1
PMCID: PMC7056586  NIHMSID: NIHMS1066402  PMID: 31755550

Abstract

Objectives:

To evaluate the longer-term changes in executive functioning among participants with cardiovascular disease (CVD) risk factors and cognitive impairments with no dementia (CIND) randomized to a diet and exercise intervention.

Design:

Two (Exercise)-by-two (Dietary Approaches to Stop Hypertension [DASH] eating plan) factorial randomized clinical trial

Setting:

Academic tertiary care medical center

Participants:

Volunteer sample of 160 older sedentary adults with CIND and at least one additional CVD risk factor enrolled in the ENLIGHTEN trial between December 2011 and March 2016.

Interventions:

Six months of aerobic exercise (AE); DASH diet counseling; combined AE + DASH; or Health Education (HE) controls.

Measurements:

Neurocognitive battery recommended by the Neuropsychological Working Group for Vascular Cognitive Disorders, including measures of Executive Function, Memory, and Language/Verbal Fluency. Secondary outcomes included the Clinical Dementia Rating-Sum of Boxes (CDR-SB), Six Minute Walk Distance (6MWD), and CVD risk including blood pressure, body weight, and CVD medication burden.

Results:

Despite discontinuation of lifestyle changes, participants in the Exercise groups retained better Executive function 1 year post-intervention (P = .041) compared to non-Exercise groups, with a similar, albeit weaker, pattern in the DASH groups (P = .054), without variation over time (Ps >.867). Participants in the Exercise groups also achieved greater sustained improvements in 6MWD compared to non-Exercise participants (P<.001). Participants in the DASH groups exhibited lower CVD risk relative to non-DASH participants (P = .032), while no differences in CVD risk were observed for participants in the Exercise groups compared to non-Exercise groups (P = .711). In post-hoc analyses, the AE+DASH group had better performance on Executive functioning (P < .001) and CDR-SB (P = .011) compared to HE controls.

Conclusion:

For participants with CIND and CVD risk factors, exercise for 6 months promoted better executive functioning compared to non-exercisers through 1-year post-intervention, although its clinical significance is uncertain.

Trial registry:

Keywords: Exercise, DASH diet, Cognitive impairment, no dementia (CIND), Cardiovascular risk, Executive functioning

INTRODUCTION

Cognitive impairment without dementia (CIND) is a condition that describes individuals whose cognitive difficulties are not sufficiently severe to meet the diagnostic criteria for dementia, but are judged to be sufficient to distinguish them from healthy individuals.1 CIND is a broad syndrome that affects a wider range of memory and non-memory domains and assigns no specific medical etiology to the observed cognitive deficits, but identifies individuals at risk for Alzheimer’s disease and all-cause dementias.2,3 Strategies to improve cognitive function, or slow the rate of decline among individuals with CIND, are critically important for primary and secondary prevention.

It is widely believed that risk factors for cardiovascular disease (CVD) also are risk factors for dementia and late-life cognitive decline.4 Because there is considerable overlap in risk factors for CVD and dementia,5 we hypothesized that healthy lifestyle behaviors, including regular exercise and the Dietary Approaches to Stop Hypertension (DASH) diet6 would reduce CVD risk and slow the neurocognitive decline in sedentary older adults with CIND. The Exercise and NutritionaL Interventions for neurocoGnitive HealTh EnhaNcement (ENLIGHTEN) randomized clinical trial examined the independent and combined effects of aerobic exercise and the DASH diet on neurocognitive functioning in older adults with CIND. Results of the 6-month intervention showed that exercise was associated with better executive function compared to non-exercisers, and that combining exercise with the DASH diet produced better executive functioning compared to education controls.7 The present report describes the results of a one-year follow-up of the ENLIGHTEN trial.

METHODS

Trial Overview

ENLIGHTEN was a randomized clinical trial of older adults with subjective memory complaints, objective evidence of cognitive impairment, sedentary lifestyles, and at least one additional CVD risk factor (e.g., hypertension, dyslipidemia, diabetes, etc.). The study was approved by the Institutional Review Board at Duke University Medical Center and written informed consent was obtained from all participants. Enrollment began in December 2011 and the last follow-up was completed in January, 2018. Participants completed a comprehensive neurocognitive test battery, along with assessments of dietary habits, functional capacity, and CVD risk factors. Assessors were blinded to intervention group assignment. A 2 (Aerobic exercise) by 2 (DASH diet) factorial design was used, with participants randomly assigned to one of 4 interventions: Aerobic exercise alone (AE), DASH diet alone (DASH), a combination of Aerobic exercise and the DASH diet (AE+DASH), or Health Education (HE).

Participants

One hundred sixty men and women with CIND were enrolled in the trial. Inclusion criteria included adults age ≥ 55 years with subjective memory or other cognitive complaints as reflected by a score of ≥ 0.5 on the Mail-In Cognitive Function Screening Instrument,8 and objective evidence of cognitive impairment with scores between 19–25 on the Montreal Cognitive Assessment (MoCA) or a score of ≤ 12 on Letter fluency or ≤ 15 on Animal fluency.7 Participants also had to be sedentary and either have documented CVD or at least one additional CVD risk factor. The baseline demographic and clinical characteristics of the sample are provided in Table 1.

Table 1.

Select Baseline and Clinical Characteristics of ENLIGHTEN Sample

Variable Exercise No Exercise Total Cohort (n = 160)
DASH (AE+DASH) (n = 40) No-DASH (AE)(n = 41) DASH (DASH) (n = 41) No-DASH (HE) (n = 38)
Age 64.9 (6.2) 65.8 (7.3) 66.0 (7.1) 64.7 (6.6) 65.4 (6.8)
Male Gender 14 (35%) 13 (32%) 15 (37%) 12 (32%) 54 (34%)
Ethnicity
 White 18 (45%) 20 (49%) 25 (61%) 22 (58%) 85 (53%)
 African-American 22 (55%) 20 (49%) 16 (39%) 16 (42%) 74 (46%)
 Other 0 (0%) 1 (2%) 0 (0%) 0 (0%) 1 (1%)
Married
 Married 22 (55%) 22 (54%) 24 (59%) 18 (47%) 86 (54%)
 Divorced / Widowed 16 (40%) 17 (41%) 13 (32%) 17 (45%) 63 (39%)
 Single, Never Married 2 (5%) 2 (5%) 4 (10%) 3 (8%) 11 (7%)
Level of Education
 < High School 0 (0%) 0 (0%) 0 (0%) 1 (3%) 1 (1%)
 High School Graduate 3 (8%) 5 (12%) 4 (10%) 2 (5%) 14 (9%)
 Some College 13 (33%) 14 (34%) 10 (24%) 11 (29%) 48 (30%)
 College Degree/Graduate School 24 (60%) 22 (54%) 27 (66%) 24 (63%) 97 (60%)
Employment Status
 Full-Time 12 (30%) 9 (22%) 9 (22%) 8 (21%) 38 (24%)
 Part-Time 6 (15%) 3 (7%) 6 (15%) 6 (16%) 21 (13%)
 Retired 16 (40%) 24 (59%) 22 (54%) 20 (53%) 82 (51%)
 Not Employed 6 (15%) 5 (12%) 4 (10%) 4 (11%) 19 (12%)
Medications
Blood Pressure Medications, n (%) 27 (68%) 31 (76%) 32 (78%) 32 (84%) 122 (76%)
Cholesterol Medications, n (%) 17 (43%) 16 (39%) 23 (56%) 21 (55%) 77 (48%)
Diabetes Medications, n (%) 6 (15%) 8 (20%) 7 (17%) 6 (16%) 27 (17%)
Cardiovascular Risk Factors
Hypertension 29 (73%) 30 (73%) 32 (78%) 32 (84%) 123 (77%)
Hyperlipidemia 26 (65%) 23 (56%) 25 (61%) 23 (61%) 97 (61%)
Diabetes 9 (23%) 11 (27%) 10 (24%) 7 (18%) 37 (23%)
Obesity 31 (78%) 24 (59%) 24 (59%) 24 (63%) 103 (64%)
Current Smoker 3 (8%) 1 (2%) 0 (0%) 2 (5%) 6 (4%)
Family history of CVD 11 (28%) 13 (32%) 14 (34%) 12 (32%) 50 (31%)
Number CVD Risk Factors 2.9 (1.2) 2.7 (1.1) 2.7 (1.2) 2.6 (1.2) 2.8 (1.1)
ASCVD Risk Profile 14.3 (9.3) 16.1 (10.1) 15.3 (12.0) 14.6 (12.7) 15.4 (11.2)
Framingham Stroke Risk Profile 8.4 (3.6) 9.1 (3.1) 8.7 (4.1) 8.6 (3.5) 8.7 (3.6)
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Note: CVD = cardiovascular; DASH = Dietary Approaches to Stop Hypertension; ACSVD =Atherosclerotic Cardiovascular Disease

Interventions

Participants were randomized to one of four treatment groups:

  1. Aerobic exercise (AE): Participants performed 35 minutes of moderate intensity aerobic exercise (e.g., walking or stationary biking) 3 times per week for 6 months: 3 months under supervision and 3 months of home-based, unsupervised exercise. Participants in the AE alone condition did not receive any counseling in the DASH diet and were encouraged to follow their usual diets for 6 months.

  2. DASH Diet (DASH): Participants in the DASH eating plan condition received instruction in modifying the content of their diet to meet DASH guidelines in a series of weekly sessions for 3-months and then bi-weekly for the remaining 3 months. Participants in the DASH-alone condition were asked not to engage in regular exercise until the completion of the 6-month intervention.

  3. Exercise Combined with the DASH diet (AE + DASH): Participants in the AE + DASH condition received both the Aerobic exercise and DASH interventions as described above for 6 months.

  4. Health Education Control Group (HE): The HE control group received weekly educational phone calls for 3 months and then bi-weekly for 3 months. Phone calls were conducted by a health educator on relevant, CVD health-related topics. Participants were asked to maintain their usual dietary and exercise habits for 6 months until they were re-evaluated.

At the conclusion of the 6-month intervention and outcome assessments, participants were free to engage in whatever activity and dietary habits they desired, with no restrictions. Participants were contacted approximately 1 month prior to their 1-year follow-up visit to schedule their appointment with our research staff.

One Year Follow-Up Measures

Neurocognition

Neurocognitive functioning was assessed using a modified test battery recommended by the Neuropsychological Working Group for vascular cognitive disorders that assessed 3 cognitive domains.9 Our primary outcome was Executive function, assessed by the Trail Making Test,10 the Stroop Test, 11 Digit Span Forward and Backwards subtest from the Wechsler Adult Intelligence Scale (WAIS), 12 the Digit Symbol Substitution Test from the WAIS,12 and the Ruff 2 & 7 Test.13 Secondary cognitive domains included Memory, assessed by the Hopkins Verbal Learning Test- Revised (HVLT-R)14 and the Medical College of Georgia Complex Figure Test (CFT)15 and Language/Verbal Fluency, assessed by the Controlled Oral Word Association Test and the Animal Naming Test, which also were included as part of the Executive function domain. Additionally, we used the modified Clinical Dementia Rating-Sum of Boxes (mCDR-SB) to characterize eight domains of cognitive and functional performance.16

Functional Capacity

The Six Minute Walk Test (6MWT)17 is a standardized, self-paced, timed test of the total distance (6MWD) that a participant is able to walk in 6 minutes.

Physical Activity

The CHAMPS18 is a 41-item self-report questionnaire that assesses the amount of time spent in mild, moderate and intense physical activity. The Godin Leisure Time Exercise Questionnaire (LTEQ)19 is a 2-item survey in which participants indicated the number of times per week they engaged in mild, moderate, and strenuous exercise for more than 15 minutes and how many times in a typical 7-day period they engaged in physical activity sufficient to ‘work up a sweat’. We also classified activity levels as ‘Active’ or ‘Inactive’ based on established cutoffs (≥14 units [7–14 kcal/kg/week], and <14 units [<7 kcal/kg/week], respectively).

Dietary Habits

Diet was assessed by the Block Food Frequency Questionnaire (FFQ). To quantify the DASH eating pattern, participants reported their food intake over the past 12 months. We used a modified DASH scoring algorithm to quantify DASH adherence.20 The data were analyzed by Nutrition Quest (Berkely, California).

Cardiovascular Disease Risk

A global measure of CVD risk included systolic blood pressure (SBP), diastolic blood pressure (DBP), body weight, and total CVD medication burden. Participants were asked to bring all medications with them at the time of their follow-up assessments. CVD medications were documented by chart review and confirmed by examination of participant pill bottles to determine Daily Defined Dose (DDD) of CVD medications.21

Quality of Life and Activities of Daily Living.

The Short Form-36 Health Survey (SF-36)22 is a 36-item self-report questionnaire that measures quality of life (QoL) in multiple psychosocial domains. Higher overall scores indicate better health-related quality of life and psychosocial functioning.

The Activities of Daily Living Inventory (ADLI) is a 20-item survey developed by the Alzheimer’s Disease Consortium Study.23 Participants rated their abilities to perform a variety of instrumental activities such as doing the laundry, shopping, preparing meals, and doing housework. Lower scores indicate greater independence.

Data Analysis

Analyses were carried out using SAS 9.4 (Cary, NC). In order to evaluate the persistence of intervention group-related differences in neurocognition at 6 months and 1-year follow-up, we performed a repeated measures, linear mixed modeling (PROC MIXED) ANCOVA in which we controlled for a priori covariates (age, education, gender, race, Framingham Stroke Risk Factor Score, baseline MoCA score, CVD medication burden, chronic anti-inflammatory use, and the baseline level of each outcome). We followed a pre-specified modeling approach in which a compound symmetry covariance structure was employed, although results were unchanged when an unstructured covariance structure was used. We used a similar approach for analyses of changes in 6MWD, dietary adherence, CVD risk, and self-report measures of QoL and physical activity, consistent with the approach used in our primary publication.7 Our primary endpoint was global Executive function, while secondary cognitive endpoints included assessments of Memory and Language/Verbal Fluency. For analyses of intervention-related differences in neurocognition, separate rank-based composites were created using the O’Brien procedure 24 by combining results from all neurocognitive subtests within each cognitive domain, before and after the interventions. This approach allowed for between intervention group comparisons over time, with higher rank-scores indicating relatively better performance. In order to characterize the magnitude of intervention group differences, group differences in the composite measures of neurocognition were reported using Cohen’s d. Post-hoc comparisons were performed to examine the potential additive effect of combining exercise with the DASH diet on neurocognition. In order to account for missing values, analyses of intervention effects followed intention-to-treat with missing data, managed using Markov chain Monte Carlo multiple imputation methods available in SAS (PROC MI) and 100 imputations. Results were unchanged when examined in sensitivity analyses using a constrained mixed modeling approach and an unstructured covariance structure.

RESULTS

Summary of Primary Findings after 6 Months

Primary results of the ENLIGHTEN trial showed that participants randomized to Exercise demonstrated better performance in the Executive function domain compared to the non-exercisers (d = 0.32, P = .046), while the difference between participants in the DASH diet and non-DASH diet was not significant (d = 0.30, P = .059).7 The largest between-intervention group differences were observed for participants randomized to the combined AE and DASH diet group compared to HE controls (d = 0.40; P = 0.012). There were no significant intervention group differences in the Memory or Language/Verbal Fluency domains after 6-months.

One Year Follow-up Results

Among the 160 participants who completed the 6-month intervention, 149 (93% of the original sample) were available one year after completion of the interventions (i.e., 18-months post-randomization). One participant died of pulmonary disease-related complications and 10 participants were lost to follow-up (Figure 1), including two AE+DASH participants, two AE only participants, two DASH only participants, and four HE participants.

Figure 1.

Figure 1.

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Consort chart showing participant flow from randomization to 1-year follow-up.

Intervention Group Differences in Neurocognitive Functioning at 1-Year Follow-up

Participants in the Exercise groups (AE and AE+DASH) maintained higher levels of Executive function after one year relative to non-exercise groups (d = 0.27; P = .041), with a similar, albeit weaker, pattern in the DASH groups (d = 0.20; P = .054) (Figure 2) . Examination of performance on tasks of Executive function from baseline through one-year follow-up revealed that compared to non-exercise groups, participants in the AE groups demonstrated better executive functioning from baseline (AE groups = 41.0 [35.5, 46.5] vs. non-AE groups = 42.3 [36.7, 47.9]) to 6-months (AE groups = 44.4 [41.5, 47.0] vs. non-AE groups = 40.9 [38.1, 43.6]). At one year follow-up, the performance of exercisers relative to non-exercisers was slightly attenuated but remained better compared to non-exercisers (AE groups = 43.3 [40.5, 46.2] vs. non-AE groups = 39.8 [36.9, 42.7]). (see Table 2)

Figure 2.

Figure 2.

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Executive Function performance at Baseline (pre-Intervention), 6-months (post-Intervention), and 1-year follow-up across Exercise factor (AE alone and AE+DASH), non-exercise (DASH alone and HE) and DASH factor (DASH alone and AE+DASH) and non-DASH (AE alone hand HE), controlling for age, education, gender, race, Framingham Stroke Risk Profile, CVD medication burden, chronic anti-inflammatory use, baseline MoCA score, and baseline Executive function scores. Participants in the Exercise conditions (AE and AE+DASH) exhibited better performance on a global Executive function score (P = .041) compared to participants in the non-Exercise conditions (DASH and HE). A non-significant trend was observed for greater improvements in Executive function among participants in the DASH factor groups (DASH and AE+DASH) compared to non-DASH groups (AE and HE) (P = .054). Values for post-intervention (6-months post-randomization) and one-year post-intervention (18-months post randomization) were derived using least squares means from our repeated measures, mixed model analyses with adjustment for all covariates. Baseline values were derived using least squares means from simple linear regression using the same covariates as our primary mixed model.

Table 2.

Pre- and Post-Intervention Measurement of Neurocognition, QoL, and CVD Risk.

Exercise Factor (AE, AE+DASH; n = 81) Non-Exercise Factor (DASH, HE; n = 79) DASH Factor (DASH, AE+DASH; n = 81) Non-DASH Factor (AE and HE; n = 79)
Variable Baseline Post-Int 1-Year Post-Int Baseline Post-Int 1-Year Post-Int Baseline Post-Int 1-Year
Post-Int		 Baseline Post-Int 1-Year
Post-Int
Neurocognition
Executive Function* (Primary) 41.0 (35.5, 46.5) 44.3 (41.5, 47.0) 43.3 (40.5, 46.2) 42.3 (36.7, 47.9) 40.9 (38.1, 43.6) 39.8 (36.9, 42.7) 40.1 (34.7, 45.5) 44.2 (41.1, 46.9) 42.9 (40.1, 45.7) 43.2 (37.7, 48.6) 41.0 (38.2, 43.7) 40.2 (37.4, 43.1)
Clinical Dementia Rating Scale-Sum of Boxes* 0.67 (0.6, 0.8) 0.49 (0.4, 0.6) 0.56 (0.5, 0.7) 0.67 (0.6, 0.8) 0.60 (0.5, 0.7) 0.69 (0.6, 0.8) 0.72 (0.63, 0.81) 0.51 (0.4, 0.6) 0.59 (0.5, 0.7) 0.62 (0.5, 0.7) 0.57 (0.5, 0.8) 0.67 (0.6, 0.8)
Memory 80.4 (73.8, 86.9) 78.3 (73.1, 83.5) 78.3 (72.9, 83.7) 79.6 (73.0, 86.3) 82.8 (77.5, 88.0) 82.2 (76.7, 87.7) 81.1 (74.6, 87.6) 79.4 (74.3, 84.6) 82.5 (77.2, 87.9) 78.9 (72.4, 85.4) 81.6 (76.4, 86.9) 77.9 (72.4, 83.3)
Language/ Verbal Fluency 82.4 (74.8, 90.0) 82.2 (76.5, 87.8) 82.2 (76.4, 88.0) 78.6 (70.8, 86.3) 78.8 (73.1, 84.5) 79.1 (73.2, 85.1) 78.5 (71, 86) 83.2 (77.7, 88.7) 82.4 (76.7, 88.1) 82.5 (75, 90) 77.7 (72.1, 83.3) 78.9 (72.0, 84.8)
Quality of Life and Activities of Daily Living
SF-36 General QoL § 66.0 (62,2, 69.9) 72.4 (69.6, 75.3) 71.3 (68.3, 74.3) 66.4 (62.4, 70.4) 69.2 (66.4, 72.1) 65.7 (62.5, 68.8) 64.6 (60.8, 68.4) 72.4 (69.6, 75.3) 67.7 (64.6, 70.8) 67.9 (64.0, 71.8) 69.2 (66.3, 72.5) 69.4 (66.3, 72.5)
Activities of Daily Living (ADL) Score § 2.7 (2.0, 3.4) 1.2 (0.8, 1.6) 1.1 (0.7, 1.5) 3.0 (2.3, 3.7) 1.3 (0.9, 1.7) 1.1 (0.7, 1.6) 2.6 (1.9, 3.3) 1.0 (0.6, 1.4) 0.8 (0.4, 1.3) 3.0 (2.3, 3.8) 1.5 (1.2, 1.9) 1.4 (1.0, 1.8)
Measures of CVD Risk
Six Minute Walk* 463 (455, 471) 519 (482, 514) 498 (480, 517) 461 (452, 469) 469 (453, 484) 466 (450, 482) 460 (452, 468) 493 (470, 503) 487 (470, 503) 464 (456, 472) 496 (480, 511) 477 (461, 494)
CHAMPS Score 7.9 (6.9, 8.9) 13.4 (11.6, 15.2) 11.5 (9.7, 13.3) 9.2 (8.2, 10.2) 10.3 (8.5, 12.1) 11.3 (9.5, 13.2) 9.0 (8.0, 10.0) 11.5 (9.7, 13.2) 11.6 (9.8, 13.4) 8.1 (7.1, 9.2) 12.3 (10.5, 14.1) 11.2 (9.3, 13.1)
DASH Diet Score 3.4 (3.2, 3.6) 3.7 (3.5, 3.9) 3.5 (3.3, 3.8) 3.4 (3.2, 3.6) 3.9 (3.6, 4.1) 3.4 (3.2, 3.7) 3.3 (3.1, 3.5) 4.2 (3.9, 4.4) 3.6 (3.4, 3.8) 3.5 (3.2, 3.7) 3.4 (3.2, 3.6) 3.4 (3.1, 3.6)
CVD Risk Rank* 81.2 (75, 87) 80.6 (76, 85) 82.2 (78, 86) 79.8 (74, 86) 80.1 (76, 84) 79.8 (76, 84) 79.6 (74, 85) 76.7 (73, 81) 79.1 (75, 83) 81.4 (76, 87) 84.1 (80, 88) 83.0 (79, 87)
SBP, mmHg § 131 (128, 134) 130 (127, 132) 130 (127, 133) 130 (127, 133) 129 (126, 132) 128 (125, 131) 128.9 (126, 132) 128 (126, 131) 127 (125, 130) 132 (129, 135) 130 (128, 133) 131 (128, 133)
DBP, mmHg 76 (74, 78) 75 (74, 76) 76 (74, 77) 76 (74, 76) 76 (74, 77) 75 (73, 76) 75.5 (74, 77) 76 (74, 77) 76 (74, 77) 76 (75, 78) 75 (73, 76) 74 (73, 76)
Total CVD Meds DDD 2.0 (1.6, 2.5) 2.4 (2.2, 2.7) 2.3 (2.1, 2.6) 3.0 (2.6, 3.5) 2.5 (2.2, 2.7) 2.3 (2.0, 2.6) 2.3 (1.9, 2.8) 2.3 (2.1, 2.6) 2.3 (2.0, 2.6) 2.7 (2.3, 3.2) 2.6 (2.3, 2.9) 2.3 (2.1, 2.6)
BP DDD § 1.5 (1.1, 1.9) 1.6 (1.4, 1.9) 1.7 (1.4, 1.9) 1.9 (1.5, 2.3) 1.6 (1.4, 1.8) 1.5 (1.3, 1.7) 1.5 (1.1, 1.9) 1.4 (1.2, 1.6) 1.6 (1.3, 1.8) 1.9 (1.5, 2.3) 1.9 ( 1.6, 2.1) 1.6 (1.4, 1.8)
Weight, lbs 198 (191, 205) 195 (194, 197) 194 (192, 195) 198 (191, 205) 195 (193, 196) 196 (194, 198) 199 (192, 206) 196 (194, 198) 194 (193, 196) 196 (189, 203) 194 (192, 196) 195 (193, 197)
BMI, kg/m2 32.3 (31, 33) 32.0 (32, 32) 31.7 (31, 32) 32.5 (31, 34) 31.9 (32, 32) 32.1 (32, 32) 32.7 (31, 34) 31.8 (32, 32) 32.0 (32, 32) 32.1 (31, 33) 32.2 (32, 32) 31.8 (32, 32)
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Note: BMI = body mass index; CVD = cardiovascular; DASH = Dietary Approaches to Stop Hypertension; DBP = diastolic blood pressure; DDD = daily defined dose; SBP = systolic blood pressure; SF-36 = Short Form Health Survey. Neurocognitive outcomes were adjusted for pretreatment levels of the outcome, age, education, gender, race, baseline stroke risk, baseline MoCA score, CVD medication burden, and chronic use of anti-inflammatory medications, with intervention factor (i.e., AE or DASH) as the predictor of interest. QoL / ADL and CVD risk outcomes were adjusted for age, gender, race, baseline MoCA score, history of CVD event, CVD medication burden, and chronic use of anti-inflammatory medications, with treatment factor as the predictor of interest. For analyses of CVD and BP medication burden, we were unable to adjust for baseline medication burden because these variables served as the outcome within these two models and could therefore not be adjusted. Least-squared means were extrapolated from repeated measures, linear mixed models for post-treatment (post-intervention) and one-year post-intervention outcomes using the adjustment variables above. Baseline values were extrapolated from simple linear regression models using the same adjustment variables (without adjustment for pre-intervention levels).

*

Denotes outcomes in which at least one intervention factor was significant at P <.05.

§

Denotes outcomes for which at least one intervention factor was significant at P<.10.

Examination of performance on tasks of Executive function in the DASH factor groups revealed a similar pattern, with better performance in the DASH factor groups compared to the non-DASH factor groups from baseline (DASH groups = 40.1 [34.7, 45.5] vs. non-DASH groups = 43.2 [37.7, 48.6]) to 6-months (DASH groups = 44.2 [41.1, 46.9] vs. non-DASH groups = 41.0 [38.2, 43.7]), which diminished slightly at one-year follow-up (DASH groups = 42.9 [40.1, 45.7] vs. non-DASH groups = 40.2 [37.4, 43.1]) (Table 2). The test for the interaction between Exercise and DASH factors was not significant (P = .809).

To further illustrate the potential clinical significance of these changes, we estimated changes in predicted age based on participants’ performance on the Executive function subtests for which published estimates were available (i.e., TMT-A, TMT-B, and Stroop Color-Word). At 6-months, AE+DASH participants exhibited improvements of 8.8 years, the AE- or DASH-alone groups exhibited improvements of 6.5 years, and the HE group showed a 0.5 year worsening of performance. At one-year follow-up, performance in the AE+DASH group continued to be 7.9 years better compared to baseline, AE and DASH alone groups were 5 years better, and HE was 0.7 years worse.

A similar pattern was noted on the mCDR-sum of boxes (Table 2), with the Exercise factor groups showing lower CDR scores at post-intervention follow-up relative to non-exercise factor groups (d = .22; P = .027) (Figure 3). Greater improvements were observed in Exercise factor participants from baseline (AE groups = 0.67 [0.58, 0.77] vs. non-AE groups = 0.67 [0.58, 0.77]) to 6-months (AE groups = 0.49 [0.40, 0.58] vs. non-AE groups = 0.60 [0.51, 0.69]) compared to non-exercisers, which diminished slightly at one-year follow-up (AE groups = 0.56 [0.47, 0.65] vs. non-AE groups = 0.69 [0.60, 0.79]). The pattern also was similar, albeit non-significant, for the DASH participants relative to non-DASH participants (d = 0.16, P = .134), with the changes from baseline (DASH groups = 0.72 [0.63, 0.81] vs. non-DASH groups = 0.62 [0.53, 0.72]) to 6-month (DASH groups = 0.51 [0.42, 0.60] vs. non-DASH groups =0.57 [0.49, 0.76]) representing the largest improvement, but diminished at the one-year follow-up (DASH groups = 0.59 [0.49, 0.67] vs. non-DASH groups = 0.67 [0.58, 0.77]). Post-hoc analysis also revealed that the combined AE+DASH group had better performance compared to HE controls both on the composite measure of Executive functioning (P <.001) and on mCDR-SB scores (P=.011).

Figure 3.

Figure 3.

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Modified Clinical Dementia Rating Scale (Sum of Boxes) at Baseline (pre-Intervention), 6-months (post-Intervention), and 1-year follow-up across Exercise factor (AE alone and AE+DASH), non-exercise (DASH and HE), DASH factor (DASH alone and AE+DASH) and non-DASH (AE and HE) groups, controlling for age, education, gender, race, Framingham Stroke Risk Profile, CVD medication burden, chronic anti-inflammatory use, baseline MoCA score, and baseline mCDR-SB scores. Participants in the Exercise conditions (AE alone and AE+DASH) exhibited better performance on the mCDR-SB scores (P = .027) compared to participants in the non-Exercise conditions (DASH alone and HE). A non-significant trend was observed for greater improvements in CDR-SB scores among participants in the DASH factor groups (DASH and AE+DASH) compared to non-DASH groups (AE and HE) (P = .054). Values for post-intervention and one-year post-intervention (18 months post-randomization) were derived using least squares means from our repeated measures, mixed model analyses with adjustment for all covariates. Baseline values were derived using least squares means from simple linear regression using the same covariates as our primary mixed model.

There were no intervention group differences in either Memory or Language/Verbal Fluency performance (Exercise factor: Ps = 0.292, 0.310; DASH factor: Ps = 0.310, 0.180 for Memory and Language/Verbal Fluency respectively).

Intervention Group-Related Lifestyle Changes at One Year Follow-up

Physical Activity, Exercise, and Functional Capacity.

Among the exercise participants, physical activity levels at follow-up remained higher compared to baseline but decreased relative to post-intervention levels. Examination of CHAMPS scores at one year revealed that 54% of participants remained active, including 50% in AE+DASH, 54% of DASH, 66% of AE, and 44% of HE controls. Examination of longitudinal changes in physical activity revealed a marginally significant Time by Exercise factor interaction (P = .053). Examination of individual time-point changes in CHAMPS scores revealed that the Exercise factor groups increased more compared to non-exercise groups at 6-months (Exercise factor = 13.4 [11.6, 15.2] vs. non-Exercise factor = 10.3 [8.5, 12.1]), but declined when re-assessed at one-year follow-up (Exercise factor = 11.5 [9.7, 13.3] vs. non-Exercise factor = 11.3 [9.5, 13.2]) such that there were no intervention group differences in reported physical activity when compared at one-year follow-up for either Exercise (P = .764) or DASH factor participants (P = .799) (Table 2). In response to the item on the Godin LTEQ at one-year, only 8 participants (21%) in the AE+DASH group reported that they engaged in regular physical activity ‘enough to work up a sweat’ at least 3 times per week, compared to 5 participants (15%) in AE only, 5 participants in the DASH only (15%) and 3 participants (10%) in HE.

With respect to changes in functional capacity as assessed by 6MWD, we found a time main effect (P = .007) and a Time by Exercise factor interaction (P = .011). While 6MWD remained relatively unchanged from 6-months to one-year follow-up in the non-Exercise factor groups (467 [452, 482] vs. 466 [449, 483]), 6MWD levels improved substantially in the AE groups following the 6-month exercise intervention, and then decreased slightly (520 [505, 534] vs. 496 [480, 513]) at one-year follow-up, but remained greater than the non-AE groups (P = .009). (see Table 2) .

DASH dietary habits.

Examination of DASH scores revealed a time main effect (P = .005) as well as a Time by DASH factor interaction (P = .001). DASH scores improved at 6 months in the DASH intervention groups (4.2 [3.9, 4.4] vs 3.4 [3.1, 3.6]), but declined upon completion of the interventions, so that by one-year follow-up there were no differences in adherence to the DASH diet for DASH participants compared to non-DASH participants (3.6 [3.3, 3.8] vs. 3.4 [3.2, 3.6], P = .422), or between Exercise participants compared to non-exercise participants (P = .477) (Table 2).

CVD Risk Factors.

Examination of our composite CVD risk marker did not demonstrate significant variation over time (P = .726), and there were no Time by Intervention group interactions. Over the one-year follow-up, individuals in the DASH groups continued to exhibit lower CVD risk compared to non-DASH participants (P = .016), while no intervention group differences were observed for the Exercise participants compared to non-exercise participants (P = .856). Examination of individual CVD risk components revealed that the improvements for DASH participants were largely driven by differences in SBP (P = .064) and BP medication load (P = .078). (Table 2)

Intervention-Related Differences in Activities of Daily Living and Quality of Life at One-Year

While the time main effect for ADLs was not significant (P =.525), examination of ADL scores at one-year revealed that participants in the DASH groups exhibited better ADLs compared to non-DASH participants (P = .027), whereas there were no consistent differences in ADLs in the Exercise groups compared to the non-exercise groups (P = .726) (Table 2).

Examination of quality of life (QoL) quantified by total SF-36 scores revealed a time main effect (P = .043) and a Time by DASH factor interaction (P = .020), such that QoL improved for the DASH groups compared to non-DASH groups at 6-months (DASH factor = 73.3 [70.6, 76.0] vs. non-DASH factor = 69.1 [66.3, 71.8]) but then declined at one-year (DASH factor = 68.4 [65.1, 71.7] vs. non-DASH factor = 69.4 [66.0, 72.7]). In contrast, the Exercise factor groups demonstrated better QoL compared to non-exercisers (P = .017) that did not vary over time (Time by Exercise factor, P = .250), with the Exercise groups consistently reporting better QoL compared to non-AE participants (AE = 72.3 [69.8, 74.9] vs. non-AE = 67.7 [65.1, 70.4]) (Table 2).

DISCUSSION

Results of this 1-year follow-up of the ENLIGHTEN trial showed that participants who were randomly assigned to aerobic exercise for 6 months, and to a lesser extent, those participants who were assigned to the DASH diet for 6 months, continued to demonstrate better executive functioning compared to non-exercisers and non-DASH dieters one year after completing the interventions, despite their relatively modest adherence to the lifestyle modifications that they initiated during the 6-month interventions. These results extend findings from observational studies that reported physically active individuals perform better on neurocognitive tests compared to their less active counterparts,25 as well as findings from a number of interventional studies, 26–31 albeit not all studies,32 showing that aerobic exercise is associated with improved cognitive functioning over short follow-up intervals. Previous exercise studies often excluded patients with cognitive impairments26,33 and few studies provided follow-up after completion of the intervention. In one meta-analysis, it was noted that individuals with diminished cognitive abilities actually may achieve greater improvements compared to more cognitively intact patient samples.34 Indeed, reviews and meta-analyses generally have confirmed the benefits of exercise on neurocognition in adults with cognitive impairments.30,35–37

There also is growing evidence that healthy eating patterns may improve cognitive functioning, independent of exercise. In a review by Lourida et al.38 it was noted that the Mediterranean diet was associated with slower cognitive decline and reduced risk of developing AD, especially among older adults. Observational studies have shown that the Mediterranean diet is associated with reduced risk of MCI39 and interventional studies have confirmed the value of the Mediterranean diet in improving neurocognition in healthy adults.40 The DASH diet is a similar diet, but emphasizes greater consumption of low fat dairy products and carbohydrates, and is lower in fat and cholesterol. Findings from the ENLIGHTEN trial extend results from previous studies that established the value of the DASH diet in reducing CVD risk 41 and improving neurocognition in adults without cognitive impairments.33

There has been increased recognition of the value of multidomain trials in which exercise is one component of the intervention. For example, in a study of 113 MCI patients randomized to a multidomain training program consisting of cognitive training, social stimulation, movie watching, music therapy, and aerobic exercise training, global cognitive status improved for participants in the training group, while scores declined in the control group.42 In addition, training increased parahippocampal cerebral blood flow, but had no effect on gray matter volume. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER)43 randomized cognitively intact older adults to a 2-year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring or to a health advice control group. Results showed that overall cognitive performance improved more in the intervention group. Executive functioning improved by 83% in the intervention group compared to the control group and processing speed was 150% higher. However, because the FINGER trial involved multiple components, the unique contribution of exercise could not be determined, and no follow-up after the completion of the FINGER intervention was reported.

The ENLIGHTEN trial confirmed the beneficial effects of exercise training for executive functioning relative to non-exercisers, and suggested that adding a heart-healthy diet could provide added benefit for improving cognitive performance. Although the DASH factor did not attain statistical significance, participants randomized to the DASH diet conditions exhibited improved CVD risk both at 6-month and 1-year follow-up. Moreover, combining the DASH diet with exercise appeared to provide added value, with the AE+DASH group achieving better executive functioning compared to HE controls after the 6-month intervention and at 1-year follow-up. These findings support the observations of Scarmeas et al.,44 who demonstrated that greater adherence to a Mediterranean-type diet and higher levels of physical activity were independently associated with lower risk of developing AD, indicating that the effects of exercise and diet are additive.

There are a number of potential mechanisms by which these lifestyle interventions my improve neurocognition, including increased neurotropic factors related to neurotransmission, increased hippocampal neurogenesis, increased cerebral blood flow, and enhanced brain plasticity. Our findings that increased functional capacity were related to improved executive functioning are consistent with observations that higher levels of aerobic fitness are associated with lower risk of developing dementia in late life.45,46 Moreover, better aerobic fitness has been shown to be associated with greater brain volume, which is associated with better cognitive performance47,48 and exercise has been shown to potentially improve cerebral blood flow.49 Reduction in CVD risk factors such as hypertension also has been shown to be associated with improved neurocognition.50

Our study had a number of strengths including a diverse sample of men and women, a 93% follow-up rate, objective measures of functional capacity, quantifiable measures of adherence to the DASH diet, and a comprehensive assessment of cognitive function. The study also had several limitations including a single site, relatively small sample of 160 participants, lack of objective indices of exercise participation over the follow-up period, and no measurement of brain structure or function using neuroimaging. One year after the completion of the interventions, individuals who exercised and consumed the DASH diet performed almost 8 years better compared to baseline on a select subset of measures of executive function, compared to a half-year decline in executive function among health education controls. Because only two tests in the cognitive battery (Trail making and Stroop Color Word test) had age-predicted norms available, which may not have been representative of the entire batter; a reliable estimate of clinically meaningful improvements in executive function could not be determined. Moreover, the effect sizes at the 1-year follow-up were quite modest, so that the clinical significance of the lifestyle-related improvements on cognitive functioning remains uncertain. Nevertheless, our data provide promising evidence that better executive function one year after completion of a 6-month exercise intervention can be sustained. Studies with larger samples, more comprehensive measures of neurocognition, and longer follow-up intervals are needed. The extent to which neurocognitive function can be improved with greater adherence to healthy eating plans and physical activity recommendations needs further study.

ACKNOWLEDEMENTS

We want to express our thanks to the members of our Data and Safety Monitoring Board: Diane Catellier PhD (chair), David Sheps MD, and Robert Carney PhD for their guidance and oversight of this study. We also thank Catherine Wu, MA for her assistance in the preparation of this manuscript.

Sponsor’s Role: This study was supported by a grant from the National Heart, Lung, and Blood Institute (HL109219). The study sponsor had no role in the study design, conduct of the trial, data analyses, or preparation of this manuscript.

Footnotes

Author Disclosures: The study was supported by a grant from the National Institutes of Health (HL109219). All co-authors received some salary support for their effort on the project. However, no co-author had any financial disclosure relevant to the study.

James Blumenthal: James Blumenthal has received grant support from the National Institutes of Health.

Patrick Smith: Patrick Smith has received grant support from the National Institutes of Health.

Stephanie Mabe: Stephanie Mabe has received grant support from the National Institutes of Health.

Alan Hinderliter: Alan Hinderliter has received grant support from the National Institutes of Health.

Kathleen Welsh-Bohmer: Kathleen Welsh-Bohmer receives grant funding from Takeda Development Company of the Americas as the neuropsychology lead for the TOMMORROW Clinical Trial program & from VeraSci Corporation of Durham NC for her work in developing improved methods of clinical detection of neurodegenerative disease using digital neurocognitive solutions. She also has received support from the National Institutes of Health.

Jeffrey Browndyke: Jeffrey Browndyke served as a consultant for Claret Medical, Inc. and received grant support from the National Institutes of Health.

P. Murali Doraiswamy: Murali Doraiswamy has received research grants (through Duke University) from Lilly, Neuronetrix, Avanir, Alzheimer’s Drug Discovery Foundation, DOD and NIH. PMD has received speaking or advisory fees from Anthrotronix, Neuroptix, Genomind, MindLink and CEOs Against Alzheimer’s. PMD owns shares in Muses Labs, Anthrotronix, Evidation Health, Turtle Shell Technologies and Advera Health Analytics whose products are not discussed in this manuscript. He also serves on the board of Baycrest, Apollo Hospitals, Goldie Hawn Foundation and Live Love Laugh Foundation. He is a co-inventor (through Duke) on patents relating to dementia biomarkers and therapies.

Pao Hwa-Lin: Pao-Hwa Lin declares one private sector partnership that involves collaboration with BERG LLC, Framingham, MA USA in analyzing specimens from a study termed “Carbohydrate and Prostate Study 1, NCT00932672 and in writing of the manuscript. She declares no other role in any private sector partnerships including research collaborations and development of proprietary testing platforms. She has received support from the National Institutes of Health.

William Kraus: William Kraus has received grant support from the National Institutes of Health.

James R. Burke: James Burke is the principal investigator on clinical trials for treatment or prevention of cognitive impairment for Takeda, Merck, Novartis, and Abbvie. He has been an advisor for clinical trial development for Takeda, Eisai, and Abbvie. In addition, he is an investigator for CARE-IDEAS, a study of the impact of amyloid disclosure on patients and caregivers, and the Agricultural Health study, evaluating the role of pesticides in development of cognitive impairment in farmers. He also is an unpaid investigator on the EXERT study (examining the role of exercise and diet in subjects with MCI) and a study examining the retina as a biomarker of Alzheimer’s disease.

Andrew Sherwood: Andrew Sherwood has received grant support from the National Institutes of Health.

Conflicts of interest: The authors have no conflicts of interest to report.

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