DRIVERS OF FLUID AND METABOLITE TRANSPORT IN THE CENTRAL NERVOUS SYSTEM
Open Access
- Author:
- Kedarasetti, Ravi Teja
- Graduate Program:
- Engineering Science and Mechanics
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- January 14, 2021
- Committee Members:
- Francesco Costanzo, Dissertation Advisor/Co-Advisor
Patrick James Drew, Committee Chair/Co-Chair
Bruce Gluckman, Committee Member
Keefe B Manning, Outside Member
Judith Todd Copley, Program Head/Chair
Francesco Costanzo, Committee Chair/Co-Chair
Patrick James Drew, Dissertation Advisor/Co-Advisor - Keywords:
- cerebrospinal fluid
finite element analysis
brain mechanics
two-photon microscopy - Abstract:
- The brain is one of the most metabolically active organs in the mammalian body. For proper brain function, the metabolic waste has to be removed continuously. Accumulation of metabolites in the brain extracellular space (ECS), such as Amyloid-β and Tau, has been linked to Alzheimer’s disease, which currently affects 5–7% of the population in developed countries. While metabolic waste from other major organs in mammals is cleared by lymph vessels, which have valves to prevent backflow, the brain does not contain any lymph vessels. Instead, the brain relies on metabolite clearance through interstitial fluid (ISF) and the movement of cerebrospinal fluid (CSF). This thesis is an investigation on the possible drivers of ISF and CSF movement and the clearance of metabolites from the brain parenchyma. One of the major obstacles to understanding fluid flow in the brain is the sensitivity of the intracranial pressure and fluid flow in the brain to invasive experimental procedures. To partially compensate for this problem, I used mathematical models to predict the fluid flow in the brain in response to the movement of cerebral arteries and tested the predictions of the models with minimally invasive experiments. One of the main conclusions of my models and experiments is that functional hyperemia, or changes to blood volume in the brain in response to local neural activity, can aid the clearance of metabolic waste from the brain. The models also showed that the cerebral blood volume changes observed during rapid eye movement (REM) sleep can appreciably improve fluid movement in and metabolite clearance from the brain. These results suggest that neural activity and REM sleep can hold the key to the prevention and treatment of neurodegenerative diseases like Alzheimer’s.