A mechanistic understanding of glymphatic transport and its implications in neurodegenerative disease

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Abstract: An estimated 6.5 million Americans suffer from neurodegenerative diseases such as Alzheimer’s Disease (AD) and Parkinson’s Disease that result in progressive degeneration and death of nerve cells (neurons) impairing movement and/or mental functioning. Delayed clearance of key biomarkers of AD, including amyloid-beta (Aβ) and tau agglomerates, has been suggested as a possible mechanism for triggering neurodegeneration that could lead to AD. To date, however, there is little to no quantitative and mechanistic understanding of the transport and clearance of small molecules, agglomerates, and debris from the brain. Such clearance is thought to occur through a brain-wide perivascular pathway for cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange, known as the glymphatic system. Characterization of glymphatic transport is currently limited, however, well-validated 3D computational models may enable quantification of the transport and clearance of key AD biomarkers throughout the brain. The long-term goal of this proposal is to develop an integrated toolset of image-based computational modeling to describe subject-specific glymphatic transport that is experimentally parameterized and validated. We propose a novel approach, using an immersed isogeometric method, where the transport model is constructed directly from the 3D imaging data, resulting in a flexible, subject-specific model that accounts for anatomical geometry and heterogeneous material properties. Our preliminary studies indicate that transport parameters such as CSF flow velocity play a large role in Aβ deposition. We hypothesize that 1) amyloid-bearing mice exhibit differences in glymphatic function, including CSF flow velocity, which lead to Aβ deposition and that 2) increased exercise in a mouse model of amyloid deposition will improve glymphatic function and reduce amyloid deposition. The main objective therefore is to 1) parameterize subject-specific 3D models of glymphatic transport and study brain-wide deposition of proteins under pathological conditions in amyloid bearing mice, and 2) model the effects of exercise on glymphatic transport and subsequent amyloid deposition. Our advanced image-guided modeling of glymphatic transport tightly integrated with experiments and adjusted with subject-specific attributes, offers a unique opportunity to quantitatively assess the effect of glymphatic dysfunction on waste clearance and study how specific factors such as exercise drive glymphatic function and protein deposition. The proposed research is significant because it will provide an architecturally and physiologically faithful platform, grounded in experiments, for informing future preventive and therapeutic interventions in neurodegenerative disease.