@article {26006,
	title = {A control mechanism for intra-mural peri-arterial drainage via astrocytes: How neuronal activity could improve waste clearance from the brain.},
	journal = {PLoS ONE},
	volume = {13},
	year = {2018},
	month = {05/2018},
	pages = {e0205276},
	publisher = {PLoS ONE},
	abstract = {The mechanisms behind the clearance of soluble waste from deep within the parenchyma of the brain remain unclear. Experimental evidence reveals that one pathway for clearance of waste, termed intra-mural peri-arterial drainage (IPAD), is the rapid drainage of interstitial fluid along basement membranes (BM) of the smooth muscle cells of cerebral arteries; failure of IPAD is closely associated with the pathology of Alzheimer{\textquoteright}s disease (AD), but its driving mechanism remains unclear. We have previously shown that arterial pulsations generated by the heart beat are not strong enough to drive IPAD. Here we present computational evidence for a mechanism for clearance of waste from the brain that is driven by functional hyperaemia, that is, the dilatation of cerebral arterioles as a consequence of increased nutrient demand from neurons. This mechanism is based on our model for the flow of fluid through the vascular BM. It accounts for clearance rates observed in mouse experiments, and aligns with pathological observations and recommendations to lower the individual risk of AD, such as mental and physical activity. Thus, our neurovascular hypothesis should act as the new working hypothesis for the driving force behind IPAD.},
	doi = {10.1371/journal.pone.0205276},
	author = {Alexandra K. {Diem} and Roxana O. {Carare} and Roy O. {Weller} and Neil W. {Bressloff}}
}
@article {25721,
	title = {Peristalsis with Oscillating Flow Resistance: A Mechanism for Periarterial Clearance of Amyloid Beta from the Brain},
	journal = {Annals of Biomedical Engineering},
	volume = {44},
	year = {2016},
	month = {Jan-05-2016},
	pages = {1553-65},
	publisher = { Springer},
	abstract = {Alzheimer{\textquoteright}s disease is characterized by accumulation of amyloid-β\&nbsp;(Aβ) in the brain and in the walls of cerebral arteries. The focus of this work is on clearance of Aβ\&nbsp;along artery walls, the failure of which may explain the accumulation of Aβ\&nbsp;in Alzheimer{\textquoteright}s disease. Periarterial basement membranes form continuous channels from cerebral capillaries to major arteries on the surface of the brain. Arterial pressure pulses drive peristaltic flow in the basement membranes in the same direction as blood flow. Here we forward the hypothesis that flexible structures within the basement membrane, if oriented such they present greater resistance to forward than retrograde flow, may cause net reverse flow, advecting Aβ\&nbsp;along with it. A solution was obtained for peristaltic flow with low Reynolds number, long wavelength compared to channel height and small channel height compared to vessel radius in a Darcy{\textendash}Brinkman medium representing a square array of cylinders. Results show that retrograde flow is promoted by high cylinder volume fraction and low peristaltic amplitude. A decrease in cylinder concentration and/or an increase in amplitude, both of which may occur during ageing, can reduce retrograde flow or even cause a transition from retrograde to forward flow. Such changes may explain the accumulation of Aβ\&nbsp;in the brain and in artery walls in Alzheimer{\textquoteright}s disease.},
	issn = {0090-6964},
	doi = {10.1007/s10439-015-1457-6},
	url = {http://link.springer.com/10.1007/s10439-015-1457-6http://link.springer.com/content/pdf/10.1007/s10439-015-1457-6http://link.springer.com/content/pdf/10.1007/s10439-015-1457-6.pdfhttp://link.springer.com/article/10.1007/s10439-015-1457-6/fulltext.html},
	author = {Sharp, Keith and Alexandra K. {Diem} and Roy O. {Weller} and Roxana O. {Carare}}
}
@article {25720,
	title = {A Simulation Model of Periarterial Clearance of Amyloid-β from the Brain},
	journal = {Frontiers in Aging Neuroscience},
	volume = {8},
	number = {18},
	year = {2016},
	month = {Dec-02-2016},
	publisher = {Frontiers},
	abstract = {The accumulation of soluble and insoluble amyloid-β (Aβ) in the brain indicates failure of elimination of Aβ from the brain with age and Alzheimer{\textquoteright}s disease (AD). There is a variety of mechanisms for elimination of Aβ from the brain. They include the action of microglia and enzymes together with receptor-mediated absorption of Aβ into the blood and periarterial lymphatic drainage of Aβ. Although the brain possesses no conventional lymphatics, experimental studies have shown that fluid and solutes, such as Aβ, are eliminated from the brain along 100 nm wide basement membranes in the walls of cerebral capillaries and arteries. This lymphatic drainage pathway is reflected in the deposition of Aβ in the walls of human arteries with age and AD as cerebral amyloid angiopathy (CAA). Initially, Aβ diffuses through the extracellular spaces of gray matter in the brain and then enters basement membranes in capillaries and arteries to flow out of the brain. Although diffusion through the extracellular spaces of the brain has been well characterized, the exact mechanism whereby perivascular elimination of Aβ occurs has not been resolved. Here we use a computational model to describe the process of periarterial drainage in the context of diffusion in the brain, demonstrating that periarterial drainage along basement membranes is very rapid compared with diffusion. Our results are a validation of experimental data and are significant in the context of failure of periarterial drainage as a mechanism underlying the pathogenesis of AD as well as complications associated with its immunotherapy.},
	doi = {10.3389/fnagi.2016.00018},
	url = {http://journal.frontiersin.org/Article/10.3389/fnagi.2016.00018/abstract},
	author = {Alexandra K. {Diem} and Tan, Mingyi and Neil W. {Bressloff} and Hawkes, Cheryl and Alan W. J. {Morris} and Roy O. {Weller} and Roxana O. {Carare}}
}
