A Mechanistic Understanding of Glymphatic Transport

An innovative, subject-specific, coupled transport-damage model will be developed and used to simulate the transport, elimination, and deposition of amyloid-β throughout the brain. Despite decades of research and numerous clinical trials, there are no successful disease-modifying therapies for many neurodegenerative diseases including Alzheimer’s Disease (AD); suggesting that there are major gaps in our understanding of underlying disease processes and the progression of key biomarkers. While the deposition of amyloid-β and tau agglomerates in the hippocampus and cortex are key characteristics of AD, whether this accumulation is the cause or effect of neurodegeneration remains unresolved. Physiological factors driving the transport of these biomarkers and their role in the onset and progression of disease are also not clearly understood. Delayed clearance of proteins from the brain leading to excessive deposition is a possible mechanism for triggering the cascade to AD and other neurodegenerative diseases. It has also been shown that exercise clears protein deposits and cellular debris from the brains of mice, allowing hippocampal neurogenesis and cognitive improvement. There is, however, little 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 in preclinical models of AD is currently limited. Well-validated 3D computational models of the glymphatic system may be able to overcome these challenges and enable quantification of the transport and clearance of key AD biomarkers.