Demonstrating a reduced capacity for removal of fluid from cerebral white matter and hypoxia in areas of white matter hyperintensity associated with age and dementia

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.

Cerebral Vessels: An Overview of Anatomy, Physiology, and Role in the Drainage of Fluids and Solutes

“…There are several, albeit nonspecific, magnetic resonance imaging biomarkers such as dilated PVS, white matter hyperintensity, cerebral microbleeds, and superficial siderosis that characterize SVD, AD, and CAA that are an expression of impaired clearance of proteins and fluids, focal ischemia, and deposition of amyloid-beta within the walls of capillaries and neurodegeneration (82,(86)(87)(88)(89). Neural tissue can become stiffer via several processes such as Wallerian degeneration, axonal atrophy, loss of oligodendroglial cells, microglial activation, neuroinflammation, and microvascular damage, resulting in a range of microstructural changes from increased tissue water content to progressive gliosis and loss of volume.…”

“…As the density of capillaries is lower in the white matter than in the gray matter and capillary basement membranes are the entry portals for IPAD by which ISF and solutes drain from brain tissue, the shortage of capillaries in the white matter may be a factor in a reduced capacity for IPAD in the white matter ( 82 ). Obstruction of CSF drainage from the cerebral ventricles results in dilatation of the ventricular system and the accumulation of fluid in the periventricular white matter in the acute stages of hydrocephalus with the slowly progressive destruction of white matter fibers and gliosis, suggesting that the capacity for IPAD is lower in the white matter compared with the gray matter ( 83 ).…”

Role of White Matter Hyperintensities and Related Risk Factors in Vascular Cognitive Impairment: A Review

“…For example, 1 H-MRS, which measures the neuronal metabolites creatine and N-acetylaspartyl compounds in white matter, is a more reliable determinant of the cognitive consequences of VCI pathology than is white-matter lesion load [48]. Additionally, radioactive iodized tracers have been used to show fluid, soluble metabolites (including soluble Aβ), and tracers flowing along the cerebral artery wall, which, although currently used mainly in animal experiments, may be applied to clarify the pathophysiological process of cognitive impairment associated with WMHs [49].…”

Need for a Paradigm Shift in the Treatment of Ischemic Stroke: The Blood-Brain Barrier

“…Leukoaraiosis has been related to chronic and subclinical cerebral hypoxia-ischemia associated with BBB dysfunction [ 126 , 188 , 189 , 190 , 191 , 192 ]. The clinical importance of this neuroimaging marker is that its prevalence affects 70% of adults over 65 years of age, especially women [ 191 ], and that its presence multiplies the risk of stroke by three, the risk of dementia by two [ 189 ], and the risk of intraventricular haemorrhage by one and thirty-eight hundredths [ 193 ].…”