Dose-Response of Aerobic Exercise on Cognition: A Community-Based, Pilot Randomized Controlled Trial

Epidemiological studies suggest a dose-response relationship exists between physical activity and cognitive outcomes. However, no direct data from randomized trials exists to support these indirect observations. The purpose of this study was to explore the possible relationship of aerobic exercise dose on cognition. Underactive or sedentary participants without cognitive impairment were randomized to one of four groups: no-change control, 75, 150, and 225 minutes per week of moderate-intensity semi-supervised aerobic exercise for 26-weeks in a community setting. Cognitive outcomes were latent residual scores derived from a battery of 16 cognitive tests: Verbal Memory, Visuospatial Processing, Simple Attention, Set Maintenance and Shifting, and Reasoning. Other outcome measures were cardiorespiratory fitness (peak oxygen consumption) and measures of function functional health. In intent-to-treat (ITT) analyses (n = 101), cardiorespiratory fitness increased and perceived disability decreased in a dose-dependent manner across the 4 groups. No other exercise-related effects were observed in ITT analyses. Analyses restricted to individuals who exercised per-protocol (n = 77) demonstrated that Simple Attention improved equivalently across all exercise groups compared to controls and a dose-response relationship was present for Visuospatial Processing. A clear dose-response relationship exists between exercise and cardiorespiratory fitness. Cognitive benefits were apparent at low doses with possible increased benefits in visuospatial function at higher doses but only in those who adhered to the exercise protocol. An individual’s cardiorespiratory fitness response was a better predictor of cognitive gains than exercise dose (i.e., duration) and thus maximizing an individual’s cardiorespiratory fitness may be an important therapeutic target for achieving cognitive benefits

A community-based approach to trials of aerobic exercise in aging and Alzheimer’s disease

The benefits of exercise for aging have received considerable attention in both the popular and academic press. The putative benefits of exercise for maximizing cognitive function and supporting brain health have great potential for combating Alzheimer’s disease (AD). Aerobic exercise offers a low-cost, low-risk intervention that is widely available and may have disease modifying effects. Demonstrating aerobic exercise alters the AD process would have enormous public health implications. The purpose of this paper is to a report the protocol of a current, community-based pilot study of aerobic exercise for AD to guide future investigation. This manuscript provides 1) an overview of possible benefits of exercise in those with dementia, 2) a rationale and recommendations for implementation of a community-based approach, 3) recommendation for implementation of similar study protocols, 4) unique challenges in conducting an exercise trial in AD

Effect of aerobic exercise on amyloid accumulation in preclinical Alzheimer’s: A 1-year randomized controlled trial

Background Our goal was to investigate the role of physical exercise to protect brain health as we age, including the potential to mitigate Alzheimer’s-related pathology. We assessed the effect of 52 weeks of a supervised aerobic exercise program on amyloid accumulation, cognitive performance, and brain volume in cognitively normal older adults with elevated and sub-threshold levels of cerebral amyloid as measured by amyloid PET imaging. Methods and findings This 52-week randomized controlled trial compared the effects of 150 minutes per week of aerobic exercise vs. education control intervention. A total of 117 underactive older adults (mean age 72.9 [7.7]) without evidence of cognitive impairment, with elevated (n = 79) or subthreshold (n = 38) levels of cerebral amyloid were randomized, and 110 participants completed the study. Exercise was conducted with supervision and monitoring by trained exercise specialists. We conducted 18F-AV45 PET imaging of cerebral amyloid and anatomical MRI for whole brain and hippocampal volume at baseline and Week 52 follow-up to index brain health. Neuropsychological tests were conducted at baseline, Week 26, and Week 52 to assess executive function, verbal memory, and visuospatial cognitive domains. Cardiorespiratory fitness testing was performed at baseline and Week 52 to assess response to exercise. The aerobic exercise group significantly improved cardiorespiratory fitness (11% vs. 1% in the control group) but there were no differences in change measures of amyloid, brain volume, or cognitive performance compared to control. Conclusions Aerobic exercise was not associated with reduced amyloid accumulation in cognitively normal older adults with cerebral amyloid. In spite of strong systemic cardiorespiratory effects of the intervention, the observed lack of cognitive or brain structure benefits suggests brain benefits of exercise reported in other studies are likely to be related to non-amyloid effects

Visuospatial processing but not attention increases with increasing aerobic exercise dose.

<p>Percent change in VO₂ peak (blue bars) increases in a dose-response fashion across the PP exercise groups. The best fitting model of Visuospatial Processing (red bars) follows a similar dose-response pattern. The best fitting model of Simple Attention (green bars) shows that any exercise results in improvement.</p

Study enrollment flow.

<p>Baseline measures of enrolled participants are provided in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0131647#pone.0131647.t001" target="_blank">Table 1</a>. Of the intent-to-treat (ITT) cohort (n = 101), 8 individuals withdrew due to time or travel concerns, 8 withdrew due to medical issues, 1 was dissatisfied with his group allocation, and 1 was lost to follow-up. Another 6 individuals were non-adherent to the exercise prescription. Those who did not adhere had slightly more education (17.8yrs [3.2] vs 16.1yrs [2.4]) otherwise there were no significant differences. The remaining 77 individuals were included in per-protocol (PP) analyses: control (n = 23), 75min/wk (n = 18), 150min/wk (n = 21), and 225min/wk (n = 15).</p

Cardiorespiratory fitness change mediates exercise duration effects on visuospatial performance.

<p>In the basic model without cardiorespiratory fitness change (%change in VO2 peak over 26 weeks) as a mediator, total number of minutes exercised (Exercise Duration) was associated with change in Visuospatial Processing. When change in cardiorespiratory fitness was added to the model as a potential mediator, it fully mediated the relationship of Exercise Duration and Visuospatial Processing improvement. Betas (Standard Error) are reported as the product of simultaneous regression with bootstrap replacement.</p

Demographic and descriptive baseline data.

<p>All values are group mean (standard deviation). LLFDI and SF-36 n = 100 due to computer malfunction. Baseline scores on component cognitive tests can be found in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0131647#pone.0131647.s005" target="_blank">S2 Table</a>.</p><p>Demographic and descriptive baseline data.</p

Mean fitness and physical function change from baseline in both the intent-to-treat and per protocol cohorts.

<p>The Group * Time interaction tests for group differences in response to exercise. The Best Fitting Model was assessed using an orthogonal contrast to test the shape of the dose-response. Both the interaction and the contrast had to reach a level of significance to be adopted as the best fitting model. In the ITT cohort, eleven individuals did not return for follow-up physical function testing and an additional six refused follow-up cardiopulmonary exercise test. Nine individuals did not return for follow-up cognitive testing. All values mean (standard deviation) unless otherwise noted.</p><p>Mean fitness and physical function change from baseline in both the intent-to-treat and per protocol cohorts.</p