Dementia Risk and Dynamic Response to Exercise: A non-randomized clinical trial

Abstract

Background: Physical exercise may support brain health and cognition over the course of typical aging. The goal of this nonrandomized clinical trial was to examine the effect of an acute bout of aerobic exercise on brain blood flow and blood neurotrophic factors associated with exercise response and brain function in older adults with and without possession of the APOE4 allele, a genetic risk factor for developing Alzheimer's. We hypothesized that older adult APOE4 carriers would have lower cerebral blood flow regulation and would demonstrate blunted neurotrophic response to exercise compared to noncarriers. Methods: Sixty-two older adults (73±5 years old, 41 female) consented to this prospectively enrolling clinical trial, utilizing a single arm, single visit, experimental design, with post-hoc assessment of difference in outcomes based on APOE4 carriership. All participants completed a single 15-minute bout of moderate-intensity aerobic exercise. The primary outcome measure was change in cortical gray matter cerebral blood flow in cortical gray matter measured by magnetic resonance imaging (MRI) arterial spin labeling (ASL), defined as the total perfusion (area under the curve, AUC) following exercise. Secondary outcomes were changes in blood neurotrophin concentrations of insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), and brain derived neurotrophic factor (BDNF). Results: Genotyping failed in one individual (n=23 APOE4 carriersand n=38 e4 non-carriers) and two participants could not complete primary outcome testing. Cerebral blood flow AUC increased immediately following exercise, regardless of APOE4 carrier status. In an exploratory regional analyses, we found that cerebral blood flow increased in hippocampal brain regions, while showing no change in cerebellar brain regions across both groups. Among high interindividual variability, there were no significant changes in any of the 3 neurotrophic factors for either group immediately following exercise. Conclusions: Our findings show that both APOE4 carriers and non-carriers show similar effects of exercise-induced increases in cerebral blood flow and neurotrophic response to acute aerobic exercise. Our results provide further evidence that acute exercise-induced increases in cerebral blood flow may be regional specific, and that exercise-induced neurotrophin release may show a differential effect in the aging cardiovascular system. Results from this study build upon previous research in younger adults by providing an initial characterization of the acute brain blood flow and neurotrophin responses to a bout of exercise in older adults with and without this known risk allele for cardiovascular disease and Alzheimer’s disease. Trials registration: Dementia Risk and Dynamic Response to Exercise (DYNAMIC); Identifier: NCT04009629 Funding: This study was funded by grants from the national institutes of health R21 AG061548, P30 AG072973 and P30 AG035982, and the Leo and Anne Albert Charitable Trust. The Hoglund Biomedical Imaging Center is supported by a generous gift from Forrest and Sally Hoglund and funding from the National Institutes of Health including S10 RR29577, and UL1 TR002366.

Hippocampal blood flow rapidly and preferentially increases after a bout of moderate-intensity exercise in older adults with poor cerebrovascular health

“…To date, a clinically-meaningful CBF threshold indicative of poor cerebrovascular health has not been established, as CBF has been assessed using different methods (e.g. single-photon emission computed tomography (SPECT), transcranial Doppler ultrasound (TCD), ASL-MRI)) (Alwatban et al, 2020, 2021; Kaufman et al, 2021; Vidoni et al, 2022; Ward et al, 2018; Weijs et al, 2022; Wolters et al, 2017). As a first step, the present study used the cohort median value for regional perfusion level to classify older individuals with “low” and “high” baseline perfusion; however, future studies are needed to empirically test the clinical significance of this baseline perfusion threshold as a metric of cerebrovascular health in larger cohorts of older adults and utilizing a standardized CBF assessment approach.…”

“…The study design is detailed in Figure 1 . A detailed trial protocol has been described in White et al (2021) and primary endpoint analyses have been described previously (Vidoni et al, 2022).…”