Interaction between microvascular function and CSF clearance in Lewy body dementia

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PROJECT SUMMARY/ABSTRACT Extant literature suggests that impaired microvascular function, and CSF clearance from the brain that has been linked with the cerebral lymphatic system, are intricately involved in the pathogenesis of ADRDs. Accumulating evidence has indicated the interaction between the microvascular and lymphatic systems in the brain. The flow of lymphatic fluid is believed to be driven primarily by the pulsatility of small blood vessels. Therefore, a change in blood flow may lead to impaired lymphatic clearance, which may both contribute to the pathogenesis of dementia. Nevertheless, details regarding such interaction is unclear, largely due to the lack of in vivo data of the two systems that can be captured in the same subjects. Besides, most existing MRI methods for imaging these mi- crovessels have not been systemically validated using multi-modality approaches such as histology. Finally, the relationship between such dysfunction and cognitive impairment, and their relationship to pathological hallmarks of dementia such as beta-amyloid and tau are still not well understood, particularly in humans. This proposal is designed to address these knowledge gaps. The PI's laboratory has been focusing on the development of non-invasive MRI approaches for assessing microvascular and lymphatic function in the human brain. Our pre- liminary studies using these techniques have shown strong evidence that significant microvascular and lym- phatic changes can be detected in patients with ADRD. The central goal of this proposal is to investigate the impact from dysfunction of small blood and lymphatic vessels in ADRDs using a newly developed MRI method that can measure perfusion parameters related to small blood and lymphatic vessels simultaneously. To date, most imaging methods can only measure blood or lymphatic vessels separately. The proposed new method (Aim 1) builds upon our previous work of individual MRI techniques to measure blood and lymphatic vessels respectively. An approach that can measure the two systems in one single scan will offer the advantage of sig- nificantly shorter scan time, and less confounding effects and signal contamination from physiological variations between scans. For MRI methods based on contrast agents, a combined method will reduce the number of doses of contrast media needed for each participant. Human studies will be paralleled by studies in animal models so that MRI methods can be validated using histology (Aim 2). Importantly, in Aim 3, using the pro- posed methods, we will study the small blood and lymphatic vessel changes associated with cognitive deficits due to Lewy Body Dementia (LBD), a type of ADRD and the second most common progressive dementia in the US. We will examine the cross-sectional relationship between the MRI measures, amyloid and tau pathology, and cognitive function in 80 individuals (LBD patients and matched controls). Interaction between blood and lymphatic vessels will be studied in the same subjects. Taken together, the proposed studies are expected to advance our understanding of changes in microvascular function and CSF clearance in LBD and their impact on cognitive impairment, which may facilitate the development of biomarkers and potential treatment targets.