Recent immunological and physiological studies have provided evidence in support of a central nervous system (CNS) lymphatic drainage system in vertebrate animals, which has more recently been implicated in brain amyloid beta (A?) plaque clearance disorders such as Alzheimer's disease (AD)-related dementias (ADRD). This system is believed to comprise (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 in humans (including but not limited to sleep disorders, CSF clearance disorders, multiple sclerosis, Parkinson's disease, and ADRD), limited direct information is available on the relevance of this system to these disorders in humans. The critical barrier to addressing this problem 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. As such, even basic knowledge about how this system changes with age, sex, and behavioral state remain debated, and these limitations preclude identification of pathological features in patients. Very recently, we have translated non-invasive magnetic resonance imaging (MRI) methods optimized in prior work for evaluating peripheral blood and lymphatic circulatory dysfunction to the CNS. We have quantified measures of intracranial glymphatic function in 61 older adults with Parkinson's disease (PD), with and without associated cognitive dysfunction, and have provided evidence that PD patients with amnestic mild cognitive impairment (aMCI) have significantly reduced markers of intracranial glymphatic function compared to age-matched patients without aMCI, and also that markers of glymphatic flow velocity inversely correlate with brain A? burden quantified from gold-standard PET imaging. These findings provide a foundation in which novel, non-invasive markers can be applied to understand lymphatic function in healthy tissue and also in the presence of increased brain A? burden. As such, the goal of this work is to apply novel MRI and established PET approaches to evaluate (i) how the CNS lymphatic system varies with age and sex for healthy aging, and subsequently the clinical relevance of CNS lymphatic function on (ii) brain A? burden and (ii) behavioral state in PD patients with cognitive impairment, a recognized ADRD. Study findings will provide fundamental insights into the behavior of the CNS lymphatic system in humans with and without ADRD. More broadly, the methods developed and refined will provide a support structure for the growing number of studies seeking to interrogate CNS lymphatic function, but where current imaging tools lack sufficient sensitivity.

Public Health Relevance

Recent immunological and physiological studies have provided evidence in support of a central nervous system (CNS) lymphatic drainage system in vertebrate animals, and preliminary evidence has suggested that a similar system exists in humans. If operative, this system may have central relevance to many vascular and fluid clearance disorders such as stroke, multiple sclerosis, Parkinson's disease, and Alzheimer's disease related dementia (ADRD): diseases which represent some of the most pressing healthcare challenges of the 21st century. Evaluating this possibility will require improved, robust imaging methods sensitive to lymphatic drainage dysfunction; as such, the goal of this work is to apply novel magnetic resonance imaging approaches, optimized already for evaluating lymphatic circulation in patients with peripheral lymphatic dysfunction, to quantify relationships between physiological hallmarks of ADRD and CNS lymphatic function in humans.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Clinical Neuroscience and Neurodegeneration Study Section (CNN)
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Mackiewicz, Miroslaw
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Vanderbilt University Medical Center
United States
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