Exercise is emerging as a promising low-cost intervention to mitigate age-related memory decline and promote successful aging. Aerobic exercise training enhances cardiorespiratory fitness (CRF) and improves integrity of the medial temporal lobe (MTL) memory system. The hippocampus, a brain region located within the MTL, is critically involved in episodic and spatial memory formation, including spatial navigation, and demonstrates subfield-specific plasticity in response to aerobic exercise among both animals and young adult humans. Yet it remains unclear whether hippocampal subfield-specific exercise training and CRF effects also extend to older adults. Another modulator of structural and functional integrity of the MTL is chronic stress. Importantly, chronic stress was shown to predominantly impact brain regions such as the hippocampus and associated cognitive functions, including episodic memory, that are highly vulnerable to the effects of chronic stress and decline with age. Allostatic load (AL), or the integrative biological dysregulation of multiple biological systems resulting from chronic stress, is associated with poorer cognition, and reduced structural brain integrity. Black Americans were shown to have high burden of AL compared to non-Hispanic White Americans, and this was associated with reports of greater perceived discrimination, a salient psychosocial stressor, among the former group. Although race is a sociocultural construct, Black-White disparities exist in cognitive task performance, and risk of Alzheimer’s disease (AD) and dementia, with Black Americans displaying significantly worse cognitive task performance scores, and a greater likelihood to be diagnosed with AD and dementia compared to non-Hispanic White Americans. Thus, greater AL and discriminatory experiences in Black compared to non-Hispanic White older adults may underlie the racial disparity in neurocognitive aging. The goal of this dissertation was to examine the opposing impact of chronic stress and exercise on neurocognitive aging. This was accomplished by 1) investigating aerobic exercise intervention effects on hippocampal subfield volume and fMRI activity during spatial navigation, a complex cognitive function that declines with age and that is, in part, supported by the MTL (Project 1), 2) examining the effect of AL as a cumulative, physiological stress measure on neurocognitive aging (Project 2), and 3) examining the effect of chronic psychosocial stress through the lens of social discrimination on the functional connectivity of the MTL subsystem of the default mode network, a resting state network that has been linked to episodic memory (Project 3). The secondary aim of this dissertation was to look at the effect of AL (Project 2) and social discrimination (Project 3) on racial neurocognitive disparities in cognitively intact older Black and non-Hispanic White adults. In the first project, data from two randomized controlled clinical trials of aerobic exercise intervention targeting healthy, initially sedentary adults aged 55-85 years were used to examine the effect of exercise training and exercise-related CRF on the hippocampal integrity on the subfield level. Both randomized controlled trials randomly assigned participants to either: aerobic exercise group or active control group and underwent baseline and end-of-study fitness testing, cognitive testing, and high resolution structural and functional MRI. The first objective of this project aimed to test whether aerobic exercise training increases CRF level, which, in turn, increases anterior hippocampal subfield volume and/or attenuates volumetric decline among older adults undergoing aerobic exercise training compared to those in the active control group. Partially supporting our prediction, results displayed that following the period of the 12-week exercise intervention, the active control group but not the aerobic exercise group showed a right dentate gyrus (DG) head volumetric decline that was trending toward statistical significance. Additionally, a positive significant association between changes in CRF and left subiculum (SUB) head volume following the exercise intervention among women was found. The second objective sought to examine whether aerobic exercise intervention modulates the activation in the hippocampus in a subfield-specific manner during virtual reality navigation task performance, particularly modulating activation in the SUB subfield. Consistent with our structural results an increase in CRF was associated with a decrease fMRI activity in the left SUB. Whole-brain analysis during virtual reality navigation task performance showed that an increase in CRF was associated with a decrease in fMRI activity in the cuneus and right middle frontal gyrus, both brain regions that repeatedly display activation during virtual navigation. In the second project, existing data from the Framingham Heart Study (FHS) was used. Cognitively intact men and women, who identified as either Black or African American from the first multiracial Omni group 1 cohort (OMNI1), or White non-Hispanic from the second-generation cohort (Gen2), and were native English speakers, were included in the study. AL was calculated using the values for 10 biomarkers available in the FHS database for the two cohorts studied that are biomarkers for immune, metabolic, and cardiovascular system function. The objective of this project sought to test the prediction that AL correlates with cognitive function and brain structures, particularly hippocampal volume. We additionally sought to examine the secondary prediction that AL mediates the relationship between race and cognitive task performance and structural brain integrity, in age- sex- and education matched racial groups of cognitively intact older adults after controlling for quality of education, cardiovascular-related comorbidities and depression in the FHS cohorts. Results demonstrated that there was no significant correlation between AL and cognitive and brain volumetric measures, however there were significant Black-White disparities in cognitive task performance in verbal and visual learning and memory, abstract reasoning and attention span. These Black-White cognitive task performance disparities existed even after controlling for quality of education, and cardiovascular-related comorbidities. Although there was no significant racial disparity in the mean score of AL index, our physiological stress measure, AL partially explained the observed Black-White disparity in cognitive task performance in verbal learning and memory. Importantly the observed AL effect was not driven by the cardio-metabolic component biomarkers that are part of the AL index, known to overlap with cardiovascular risk factors, but rather, the AL index drove this effect as a whole. There were no racial disparities in brain volumetric measures after controlling for cardiovascular-related comorbidities. Furthermore, there were no sex differences in the effect of AL in any of our neurocognitive outcome measures. In the third project, cognitively intact older Black and White adults (aged 55-80 years) were recruited from the greater Boston area. To measure perceived social discrimination, participants were asked to complete the Experiences of Discrimination questionnaires. Additionally, participants underwent fMRI scanning to examine the functional connectivity of resting-state brain networks. This project sought to test the prediction that greater perceived everyday discrimination would be associated with alteration of resting state functional connectivity, particularly in the MTL subsystem. Results showed that greater perceived everyday discrimination predicted stronger resting-state connectivity between the MTL subsystem, and a cluster located in the right control network, suggesting that perceived discrimination, a psychosocial stressor, may cause functional alteration in brain networks supporting memory and cognitive control in older adults. In conclusion, findings of these studies suggest a neuroprotective effect of exercise, where exercise may attenuate aging-related decline in the structure and function of hippocampal subfields, especially among women, and possibly by targeting the SUB. Furthermore, findings of these studies suggest stress related mechanisms underlying neurocognitive integrity, particularly in the MTL memory system.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/48060 |
| Date | 10 February 2024 |
| Creators | Alotaibi, Razan Khalid M. |
| Contributors | Schon, Karin |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
| Rights | Attribution-NonCommercial-NoDerivatives 4.0 International, http://creativecommons.org/licenses/by-nc-nd/4.0/ |
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