Cortical and Leptomeningeal Cerebrovascular Amyloid and White Matter Pathology in Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) is characterized by neurofibrillary tangles and by the accumulation of β-amyloid (Aβ) 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 Aβ 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 Aβ 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 Aβ load in the cortex, with the severity of CAA, and with ApoE ε4 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 Aβ 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.

Topographical distribution of cerebral amyloid angiopathy and its effect on cognitive decline are influenced by Alzheimer disease pathology

“…These findings confirm previous studies, which reported the occipital lobe to be the site preerentially affected with CAA, followed by either frontal, temporal, or parietal lobes [3,17,19,20,40,42,43,49,50,[54][55][56]. In contrast, other authors reported the frontal lobe to be most frequently involved in CAA [27,57].…”

“…CAA seems to be most prominent in occipital, frontal, and temporal lobes, followed by parietal lobe and white matter, whereas basal ganglia and thalamus are usually spared [1,3,4,9,19,42,43,45,46]. Its occurrence in the cerebellum ranges from absent to frequent [16,42].…”

“…Basically, three different mechanisms have been proposed (see [26]): derivation of Aβ from blood and/or cerebrospinal fluid [9,34,35], production of Aβ by smooth muscle cells within vessel walls and/or pericytes [9,[36][37][38][39][40], and derivation of Aβ from the neuropil in the course of its perivascular drainage [2,7,[41][42][43][44][45].…”

Prevalence and pathogenic role of cerebrovascular lesions in Alzheimer disease

“…Although the positive correlation between CERAD/Braak stages and the severity of CapCAA is interesting, the question whether it represents an epiphenomen or an indicator of a pathogenic association between tau pathology and Ag deposition in capillary walls is unclear. The failure of fluid drainage may also be related to white matter pathology in AD [35] and may have implications for therapeutic strategies in the treatment of AD and related morphological findings [36]. Furthermore, the role of pericapillary/perivascular astroglia for Ag deposition in cerebral vessels remains to be elucidated.…”

Topography and associations of perivascular spaces in healthy adults

“…The mechanisms underlying MRI-visible PVS are still unknown, but one potential explanation is that the diminished pulsatility of arterioles or blocking bulk flow impairs perivascular drainage, causing retrograde dilation of PVS. 12,27 Abnormal proteins in the PVS could also trigger perivascular inflammation and neurodegeneration. 12 The association between PVS severity and hypertension in this study suggests that hypertensive arteriopathy (including arteriolosclerosis) is consistent with diminished pulsatility of stiffened small vessels.…”