Immunological and physiological studies have recently provided strong evidence in support of a central nervous system (CNS) lymphatic drainage system in vertebrate animals, which has more recently been implicated in amyloid beta (A?) plaque clearance disorders such as Alzheimer's disease (AD)-related dementias (ADRD). This system comprises (i) dural and meningeal lymphatic vessels that drain CSF and interstitial fluid (ISF) toward cervical lymph nodes and which may (ii) communicate with the recently-proposed glymphatic system, an aquaporin-4 (AQP4)-mediated system that facilitates CSF-ISF efflux from periarterial to perivenous spaces and ultimately to cervical lymphatic vessels and nodes. While multiple independent studies have speculated that the CNS lymphatic system may have relevance to clearance conditions of unknown etiology (including but not limited to A? clearance deficiency and Alzheimer's disease), limited direct information is available on the relevance of this system to CNS clearance disorders in humans. The critical barrier to addressing this problem in patients with these conditions rests with a general lack of imaging methods that can be applied to interrogate multiple aspects of the proposed human CNS lymphatic system in vivo. The parent study focuses on developing magnetic resonance imaging (MRI) methodologies to visualize lymphatic dysfunction in the periphery of patients with known lymphatic dysfunction. Very recently, we have translated these noninvasive MRI methods, optimized in prior work to evaluate peripheral blood and lymphatic circulatory dysfunction, to the CNS. These methods provide a foundation whereby novel, noninvasive metrics can be measured and quantified to understand CNS lymphatic function in healthy tissue and also in the presence of increased A? burden and ADRD. As such, the goal of this work is to apply novel MRI and established PET approaches, optimized for evaluating peripheral circulatory dysfunction and A? deposition, respectively, to evaluate relationships between CNS glymphatic function, A? burden, and cognitive impairment in older adults with and at risk for Alzheimer's disease. Study findings are intended to provide imaging biomarkers of CNS lymphatic dysfunction which can be recorded noninvasively in vivo using clinically-available imaging equipment. If successful, results will provide a new avenue for both understanding AD pathophysiology and evaluating novel glymphatic-based therapeutic avenues in patients with ADRD.
Recent physiological studies have provided evidence in support of a central nervous system (CNS) lymphatic drainage system in animals, which has been implicated in clearance disorders such as Alzheimer's disease and several Alzheimer's disease related dementias (ADRD). We have shown that imaging methods utilized to evaluate lymphatic dysfunction in the extremities can be re-parameterized and applied to the head and neck to distinguish older adults with vs. without cognitive impairment. Here, we propose to apply these methods in the CNS and to evaluate the extent to which lymphatic dysfunction may be altered in a cross-sectional study of patients with ADRD; if these methods can provide observables of lymphatic dysfunction in patients with ADRD, they may be used as fundamental tools to guide and evaluate novel treatments that target components of this newly proposed pathway.
