Abstract
White matter hyperintensities (WMH) occur in association with dementia but the aetiology is unclear. Here we test the hypothesis that there is a combination of impaired elimination of interstitial fluid from the white matter together with a degree of hypoxia in WMH. One of the mechanisms for the elimination of amyloid-β (Aβ) from the brain is along the basement membranes in the walls of capillaries and arteries (Intramural Peri-Arterial Drainage – IPAD). We compared the dynamics of IPAD in the grey matter of the hippocampus and in the white matter of the corpus callosum in 10 week old C57/B16 mice by injecting soluble Aβ as a tracer. The dynamics of IPAD in the white matter were significantly slower compared with the grey matter and this was associated with a lower density of capillaries in the white matter. Exposing cultures of smooth muscle cells to hypercapnia as a model of cerebral hypoperfusion resulted in a reduction in fibronectin and an increase in laminin in the extracellular matrix. Similar changes were detected in the white matter in human WMH suggesting that hypercapnia/hypoxia may play a role in WMH. Employing therapies to enhance both IPAD and blood flow in the white matter may reduce WMH in patients with dementia.
Highlights
White Matter Hyperintensities (WMH) on magnetic resonance imaging (MRI) occur in the cerebral hemispheres mainly in elderly patients and are associated with dementia [1]
interstitial fluid (ISF) and solutes are drained from the white matter by Intramural PeriArterial Drainage (IPAD) To determine the pattern of intramural Peri-Arterial Drainage (IPAD) in the white matter, the pattern of drainage of fluorescent Aβ40 injected into the corpus callosum was compared with the drainage of Aβ40 injected into the hippocampus of young adult (10-weekold) C57/Bl6 mice
Of the two major functions of cerebral arteries discussed in this paper in relation to WMH, blood supply to the white matter has received more attention in the literature than elimination of fluid by IPAD
Summary
White Matter Hyperintensities (WMH) on magnetic resonance imaging (MRI) occur in the cerebral hemispheres mainly in elderly patients and are associated with dementia [1]. Detailed anatomical studies of this lymphatic drainage pathway have shown that soluble tracers, including soluble amyloid-β (Aβ), drain from the extracellular spaces of the brain along basement membranes (BM) in the walls of cerebral capillaries and continue out of the brain along BMs that surround smooth muscle cells in the tunica media of arteries [7]. This drainage pathway is termed the Intramural PeriArterial Drainage (IPAD) pathway [8]. The elimination of soluble Aβ is severely impaired in Alzheimer’s disease (AD) with a rise in levels of soluble Aβ in the brain parenchyma suggesting that a loss of homeostasis in the extracellular spaces of the brain accompanies dementia in AD [12]
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