Neurocognitive Decline in Metabolic Syndrome: Cerebrovascular Mechanisms and the Therapeutic Potential of Beetroot Juice
Restricted (Penn State Only)
- Author:
- Gosalia, Jigar
- Graduate Program:
- Kinesiology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- June 11, 2024
- Committee Members:
- Jonathan Dingwell, Professor in Charge/Director of Graduate Studies
Andrew Gardner, Outside Unit Member
Jim Pawelczyk, Major Field Member
Nancy Dennis, Outside Field Member
David Proctor, Chair & Dissertation Advisor - Keywords:
- Neurocognitive
Metabolic syndrome
nitrate supplementation - Abstract:
- The metabolic syndrome (MetS) is defined by the simultaneous presence of hypertension, central obesity, hyperglycemia, and blood lipid abnormalities, and is highly prevalent among older adults (~1 in 2 U.S. adults). MetS is related to increased risk of cardiovascular disease and type-II diabetes through dysfunction of the micro- and macro-vasculature, however, less appreciated is the increased risk in neurocognitive decline and disease through these same mechanisms. The vascular contributions to cognitive impairment and disease (VCID) framework postulates that accelerated cognitive decline in MetS may be driven by vascular dysfunction and reduced capacity to match blood flow with the metabolic demands of active neurons – or neurovascular coupling (NVC). Understanding the vascular mechanisms that link MetS and neurocognitive decline is essential for informing preventative strategies. The studies encompassing this dissertation established both systemic and cerebrovascular dysfunction as mediators of cognitive decline in midlife and older adults with MetS. In our first study, we established systemic arterial stiffness as a moderator between MetS and cognitive performance. We then utilized electronic health records to conduct a retrospective cohort study in which we found a moderating role of cerebrovascular health towards neurocognitive decline in MetS at the population level, providing rationale for an assessment of the specific cerebrovascular mechanisms underpinning neurocognitive decline in MetS. In our third study, we found reduced performance and an attenuated NVC response at higher cognitive loads in MetS compared to healthy age matched adults, suggesting MetS exhibits reduced blood flow to active brain regions, which could impact cognitive performance. We also observed that endothelium mediated vasodilation was reduced in MetS, highlighting a targetable mechanism to improve NVC and cerebral blood flow. Our final study was a randomized controlled trial, in which acute and 4-weeks of nitrate-rich beetroot juice supplementation, which is known to improve nitric oxide dependent vasodilation, improved cerebral blood flow regulation. However, this intervention was ineffective in restoring NVC or improving cognitive performance in older (55 - 75 yrs) men and women with MetS. Although improvements in cerebral blood flow regulation are encouraging, the results from this clinical trial suggest that modified or alternative approaches to nitrate supplementation should be investigated to improve NVC and cognitive function in MetS. Exploratory analyses suggest insulin resistance may be an ideal target to improve NVC and subsequent cognitive performance. Our overall findings add support for the VCID framework linking MetS and neurocognitive decline.