Abstract
Alzheimer's disease (AD) is characterized by neurofibrillary tangles and by the accumulation of beta-amyloid (Abeta) peptides in senile plaques and in the walls of cortical and leptomeningeal arteries as cerebral amyloid angiopathy (CAA). There also is a significant increase of interstitial fluid (ISF) in cerebral white matter (WM), the pathological basis of which is largely unknown. We hypothesized that the accumulation of ISF in dilated periarterial spaces of the WM in AD correlates with the severity of CAA, with the total Abeta load in the cortex and with Apo E genotype. A total of 24 AD brains and 17 nondemented age-matched control brains were examined. CAA was seen in vessels isolated from brain by using EDTA-SDS lysis stained by Thioflavin-S. Total Abeta in gray matter and WM was quantified by immunoassay, ApoE genotyping by PCR, and dilatation of perivascular spaces in the WM was assessed by quantitative histology. The study showed that the frequency and severity of dilatation of perivascular spaces in the WM in AD were significantly greater than in controls (P< 0.001) and correlated with Abeta load in the cortex, with the severity of CAA, and with ApoE epsilon4 genotype. The results of this study suggest that dilation of perivascular spaces and failure of drainage of ISF from the WM in AD may be associated with the deposition of Abeta in the perivascular fluid drainage pathways of cortical and leptomeningeal arteries. This failure of fluid drainage has implications for therapeutic strategies to treat Alzheimer's disease.
Highlights
Alzheimer’s disease (AD) is characterized clinically by dementia and pathologically by the accumulation of ubiquitinated tau and other proteins within neurons and by deposition of β-amyloid (Aβ) in the extracellular compartments of gray matter (GM) and in blood vessel walls as cerebral amyloid angiopathy (CAA) [1,2,3]
Tracer studies in experimental animals have shown that in CAA, Aβ accumulates within the perivascular channels around capillaries and arteries that have been identified as interstitial fluid (ISF) drainage pathways [4,5,6,7,8,9,10,11]
There is the distinct possibility that deposition of Aβ in periarterial ISF drainage pathways may interfere with the drainage of ISF from cerebral WM as dilation of periarterial spaces is a feature of white matter in AD
Summary
Alzheimer’s disease (AD) is characterized clinically by dementia and pathologically by the accumulation of ubiquitinated tau and other proteins within neurons and by deposition of β-amyloid (Aβ) in the extracellular compartments of gray matter (GM) and in blood vessel walls as cerebral amyloid angiopathy (CAA) [1,2,3]. Biochemical determinations have shown that it is the levels of soluble Aβ in Alzheimer brains, rather than the insoluble Aβ plaque load, that correlate with severity of cognitive decline [12,13]. These findings support the hypothesis that the failure to eliminate Aβ along ISF drainage pathways is a major factor in Aβ accumulation in the cortex and in the AD pathogenesis. In addition to the pathological changes in cerebral gray matter (GM) in AD, there is significant pathology in the underlying cerebral white matter (WM) This is characterized by a relative increase in ISF detectable through imaging and by histological techniques [14]. There is the distinct possibility that deposition of Aβ in periarterial ISF drainage pathways may interfere with the drainage of ISF from cerebral WM as dilation of periarterial spaces (état criblé) is a feature of white matter in AD
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