Modelling cerebral interstitial flows and their failure in Alzheimer's disease

Abstract

The human brain is the organ with the highest metabolic activity; despite this, it lacks a conventional lymphatic system responsible for clearing metabolic products. Cerebral accumulation of soluble metabolites, such as the amyloid-beta (A) protein, has been associated with Alzheimer's disease, the most common form of dementia. The underlying mechanisms for the clearance of the brain are not completely understood through conventional biological sciences alone. With this in mind, this thesis aims to provide a new perspective by developing novel multi-scale physiologically-realistic models that allow quantitative assessment of previously proposed clearance systems of the brain. The first model investigates the global clearance of soluble A from the brain tissue by accounting for a realistic geometry of the human brain and heterogeneous properties of the brain tissue. Within the model, the relative contributions of different transport mechanisms of A out of the brain tissue are assessed. Insights about physically realistic clearance mechanisms and cerebral regional deposition of A in the brain when clearance fails are provided. The second part of this thesis aims to clarify the motive force for the intramural periarterial drainage (IPAD) of soluble A from the brain. Failure of this clearance mechanism could explain the vascular deposition of A as cerebral amyloid angiopathy, which is almost invariably found in Alzheimers dementia. The motive force of the IPAD process has yet not been clarified, hindering in this way any significant therapeutic progress. Here, a novel hypothesis, namely vasomotion-driven IPAD, is proposed and modelled by designing a novel multi-scale mathematical model of cerebral arteries. The periarterial flow rates yielded by the model suggest that vasomotion-driven IPAD is the only mechanism postulated to date capable of explaining the perivascular clearance of solutes observed experimentally.

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Identifiers

ORCID for Giles Richardson: orcid.org/0000-0001-6225-8590

ORCID for Roxana Carare: orcid.org/0000-0001-6458-3776

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