MechE PhD Prospectus Defense | Samuel Halvorsen

TITLE: CEREBROVASCULAR REMODELING IN AGING AND NEUROPATHOLOGICAL DISEASE PROGRESSION

ABSTRACT: Cerebral arteries are responsible for delivering oxygenated blood to the brain, which is necessary for the brain to function properly. Like other vascular systems, these vessels are prone to remodel in aging and disease, impacting their ability to adequately perfuse the brain. Decreased brain perfusion is commonly reported in neurodegenerative diseases including Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE). However, the complex relationship between arterial biomechanics, aging, and neuropathological progression remain to be fully elucidated. The objective of this study is to provide new understandings on the changes in structural and mechanical properties of cerebral arteries with age and neuropathological disease progression. Using matched and parallel studies of cerebrovasculature and brain tissue, we examined changes to human cerebral arteries from subjects with various degrees of AD and CTE neuropathology. Structural and mechanical remodeling of cerebral arteries was assessed using mechanical testing, histological staining, and multiphoton imaging. Our study revealed age-related changes to the circumferential mechanics of the anterior cerebral artery (ACA), described by an increased low pressure circumferential stiffness leading to decreased compliance in older subjects. Microstructural studies revealed collagen fiber straightening, elastic fiber degradation, and smooth muscle cell atrophy, which are related to the arterial stiffening with aging. Using various neuropathological measures derived from immunohistochemical staining of subjects’ brain tissue, we found a relationship between ACA stiffening and the progressive formation of neurofibrillary tangles (NFTs) associated with both AD and CTE. These results suggest a direct relationship between cerebrovascular remodeling and neuropathological disease progression. Building upon understandings on the relationship between ACA remodeling and neurodegeneration, ongoing research involves studies of the middle cerebral arteries (MCAs), which may experience more changes in CTE due to its proximity to the surface of the head and is often examined in vivo in the context of traumatic brain injury (TBI). Studies have also reported TBI to increase risk of AD onset. Further studies will focus on understanding the separated effects of AD and CTE on cerebral arteries. This will help us better understand the different patterns of NFT and amyloid plaque deposition in different regions of the brain from neuropathological studies. Additionally, the internal elastic lamina and myelin structures in the cerebral artery wall will be investigated due to their physiological relevance in nutrient transfer and cerebrovascular regulation, respectively.

COMMITTEE: ADVISOR/CHAIR Professor Katherine Yanhang Zhang, ME/BME/MSE; Professor Michael Albro, ME/MSE/BME; Professor Béla Suki, BME/MSE; Professor Thor D. Stein, Pathology & Laboratory Medicine