This proposal examines the role of the glymphatic system, a recently discovered novel waste clearance pathway, in patients with Parkinson's Disease (PD), to understand whether improvements in motor and cognitive function observed following exercise can be attributed to this system. The overall rationale for this work is based on decades of research in which we have seen major improvements in the diagnosis and treatment of many central nervous system (CNS) disorders, including many cancers and cerebrovascular diseases, but disappointingly much less progress in terms of progress on long-term prognosis in patients with neurodegenerative disorders such as Parkinson's disease and dementia. Rather, treatment for these patients focuses on symptom management and while such treatments have been fundamental to improving the quality of life of patients suffering from these devastating conditions, they do not address the more fundamental question of disease etiology that is required for finding a cure. Very recently, a novel waste-clearance system in the brain of vertebrate animals, the glymphatic system, has been proposed in which new clearance pathways exist, involving communication between paravascular spaces, interstitial fluid, and, ultimately, meningeal and dural lymphatic vessels, and we have provided evidence that this system may be dysfunctional in patients with Parkinson's disease with cognitive disorders. Such dysfunction could manifest as accumulation of amyloid, a hallmark of PD patients with cognitive complaints. We have worked to develop and optimize methods for visualizing lymphatic dysfunction in the periphery of patients with lymphatic dysfunction of well-characterized etiology (e.g., lymphedema secondary to cancer therapies) and to translate these novel methods to the CNS to begin to evaluate glymphatic clearance disorders as well. Here we will apply many of these previously validated methods to the CNS to understand for the first time how glymphatic clearance may be impaired in PD patients with cognitive disorders. We will first (Aim 1) quantify the association between glymphatic functioning, beta-amyloid burden, and sleep dysfunction in PD using MRI, PET, and neuropsychological examination, after which we will (Aim 2) quantify the glymphatic functioning and beta-amyloid burden response to 12 weeks of a community-based exercise course developed specifically for PD patients, and we will finally (Aim 3) evaluate the degree to which neuroimaging-based response to exercise mediates clinical improvement in neurocognitive functioning and neuropsychiatric symptomatology. The overall significance of this work is that it will, using sensitive methods developed and validated at our site, interrogate the potential role of glymphatic dysfunction on PD symptomatology and treatment. If we can confirm that this system is operative in PD and adjusts in response to these established therapies, this would motivate the investigations of new treatments that specifically stimulate components of the glymphatic system in patients with PD.