Characterizing the Effect of Altered CSF and Blood Flow Dynamics on Alzheimer’s Disease Proteinopathy, Brain Health, and Cognition

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ABSTRACT Although the brain lacks a traditional lymphatic system for clearing waste products, it has been hypothesized that the brain possesses alternative pathways such as the glymphatic system and intramural periarterial drainage. Recent experimental evidence in Alzheimer's disease (AD) models suggests clearance of amyloid beta from the brain occurs along these pathways. These pathways are driven by cardiac pulsations and vasomotion which induce cerebrospinal fluid (CSF) flow dynamics and brain tissue motion. Cerebrovascular disease (CVD), has a strong link with both mild cognitive impairment and AD dementia, and there is potential that CVD modulates waste clearance. However, the interactions between blood flow and CSF flow dynamics in humans are understudied and their relationship to underlying pathophysiology of AD has only recently begun receiving attention. To provide insights into CVD-AD relationships, non-invasive Magnetic Resonance Imaging (MRI) is being utilized in longitudinal studies of AD risk-enriched populations. MRI methods commonly employed today such as fluid attenuation (e.g. white matter hyperintensities) and susceptibility imaging (e.g. microhemorrhages) only indirectly evaluate CVD and cannot inform on the dynamic vascular motion and hemodynamic phenomena that have been indicated in animal models to affect AD pathology. The present study applies previously develop MRI techniques to AD that are sensitive to blood and CSF flow dynamics. Recently, we have successfully use non-invasive 4D-Flow MRI to characterize cerebrovascular health in the context of AD. Using 4D-Flow MRI significant cerebrovascular changes were found in clinically diagnosed AD subjects when compared to cognitively normal. These changes included increased intracranial vessel stiffness and reduced vasomotion; however, hypothesis testing of CVD-AD interactions from these studies was limited by the lack of CSF flow and AD biomarker data. In this project, we propose using 4D-Flow MRI for the quantification of blood and CSF flow dynamics in addition to the integration of AD biomarker data. The vascular biomarkers will be studied in preclinical and impaired AD subjects and correlated with longitudinal amyloid and tau (from CSF assays and PET) measures. Such data will drive hypothesis testing on the modifying effect of vascular alterations on the symptom expression of cognitive impairment, AD biomarker accumulation, and brain health. Participants targeted for this study have extensive existing AD biomarker data and are being followed longitudinally through studies within the Wisconsin Alzheimer's Disease Research Center. Upon completion of this study, we will have a better understanding of the impact of intracranial vessel stiffness and CSF pulsatility on Aβ42/ Aβ40 ratios (an indicator of amyloid brain clearance) and the interacting effect of intracranial vessel stiffness and amyloid on AD pathology accumulation, brain health and cognition. Additionally, we would have collected preliminary data and rationale to submit a larger extramural application (e.g. NIA/NIH R01) to support studies focused on understanding the role of cerebrovascular health on AD pathology and AD related dementia.