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. 2003 Mar-Apr;9(3-4):112-22.

Cortical and leptomeningeal cerebrovascular amyloid and white matter pathology in Alzheimer's disease

Alex E Roher  1 , Yu-Min Kuo, Chera Esh, Carmen Knebel, Nicole Weiss, Walter Kalback, Dean C Luehrs, Jennifer L Childress, Thomas G Beach, Roy O Weller, Tyler A Kokjohn
Affiliations

Cortical and leptomeningeal cerebrovascular amyloid and white matter pathology in Alzheimer's disease

Alex E Roher et al. Mol Med. 2003 Mar-Apr.

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.

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Figures

Figure 1
Figure 1
Thioflavin-S–stained whole-mounted tufts of cortical vessels after complete brain parenchyma lysis by EDTA-SDS. A: Ring-like amyloid deposits in leptomeningeal arterial walls. The pattern of deposition follows the orientation of the smooth muscle cells. Magnification 25×. B: Tufts of cortical-penetrating arteries heavily loaded with amyloid from an AD patient with Apo E ɛ4/ɛ4 genotype. The perivascular spaces are probably occluded in the saturated amyloid vessels, and in some cases may be totally destroyed by the encroaching amyloid, thus hindering the elimination of interstitial fluid. Magnification 100×. C: Cortical arterioles and capillaries showing an abundant deposition of amyloid cores, in an individual with Apo E ɛ4/ɛ4 genotype, at different stages of development that are intimately linked to the basal laminae of the vessels. The profuse deposits of amyloid at the arteriolar/capillary junction may block the openings of the perivascular spaces that drain the brain’s interstitial fluid. Magnification 200×. D: At a higher magnification, each of the fluorescent blebs represents a fully developed globular deposit of amyloid evenly spread around and constricting the microvessel, probably creating areas of ischemia and alterations in blood-brain barrier. Magnification 400×.
Figure 2
Figure 2
Electron micrographs of a normal cortical artery and of arteries destroyed by amyloid deposition in 3 AD cases homozygous for Apo E ɛ4/ɛ4. A: An electron micrograph of a small normal cortical artery. The endothelial cells are joined by tight junctions (small arrows) that participate in the blood-brain barrier. Both their nuclei and thin cytoplasm have a normal morphology. These cells are in contact with the subjacent basal lamina (opposing large arrows). The smooth muscle cells (white arrows) have a normal-looking fibrillar cytoplasm, and a typical nucleus is seen on the left margin of the photograph. The thin periarterial space (black arrowheads) contains the extracellular matter of the adventitia and is on its outer margin limited by a single layer of pial cells (8). Magnification 5500×. B and C: Small cortical arteries surrounded by heavy amyloid deposition. The endothelial cells are apparently swollen. The tight junctions have an abnormal morphology (black arrows). The dense amyloid deposits are fused with the basal lamina of the vascular cells. The myocytes have vanished or are reduced to a collection of cellular debris (white arrows) that is enclosed by concentric layers and peripheral wisps of amyloid surrounded by a large amount of tissue debris (open stars). The tunica adventitia, perivascular spaces, and the glia limitans have degenerated as the result of heavy amyloid deposition. Magnification 4300× and magnification 3500×, respectively. D: An abnormal cortical artery with abundant fine wisps of amyloid perpendicular to the main axis of the vessel. The amyloid bundles, interspersed by large amounts of cellular debris, pushed out the glia limitans (open arrows). On the left margin of the micrograph, the amyloid has destroyed the glia limitans invading the surrounding cortical tissue (black stars). All myocytes and the tunica adventitia have been replaced by amyloid fibrils and debris. Magnification 2000×. One may assume from the extensive vascular pathology that the delivery of oxygen and nutrients as well as arterial contractility are largely compromised.
Figure 3
Figure 3
Hematoxylin- and eosin-stained superior frontal gyrus and underlying WM sections from an ND individual and an AD case. Magnification: about 2.5×. A: Cerebral section from a 74-y-old ND individual with ApoE ɛ3/ɛ3 genotype, who died as the result of metastatic prostate cancer. The WM appears homogeneously stained without noticeable dilated periarterial spaces. B: Shows a section from an 80-y-old AD patient with ApoE ɛ4/ɛ4 genotype. The numerous arteries with enlarged perivascular spaces are evident throughout the entire extent of the WM, whereas the GM is comparatively free of these alterations. The paler blotches in the WM represent areas of myelin rarefaction.
Figure 4
Figure 4
Perivascular spaces in Alzheimer’s disease white matter. Row A: The fine periarterial spaces are not normally visible at light microscopic level. Magnifications: left and center 100×; right 200×. Row B: The periarterial spaces appear to be slightly dilated. Magnifications: left 200×; center and right 100×. Rows C, D, and E demonstrate a series of severely distended perivascular spaces. The centrally located arteries apparently have a normal morphology. All captions were taken at 100×. All histological slides were stained with hematoxylin and eosin.
Figure 5
Figure 5
Quantitative and statistical analyses among the 3 variables investigated in this study: cortical Aβ concentrations, number of dilated perivascular spaces (état criblé–like lesions), and ratio of perivascular space diameter/blood vessel diameter. In the 3 left panels, ▪ and □ histograms represent the total numbers of ND and AD individuals and these populations divided by Apo E genotype, respectively. The 3 panels on the right side of the figure demonstrate the linear correlations and P values among the 3 studied variables. A: The total levels of cortical Aβ in ND and AD subjects. P value represents the 2-tailed unpaired Student t-test probability. * and ** represent P < 0.05 and P < 0.01, respectively, in post-hoc analysis (Newman-Keuls Multiple Comparison Test) after 1-way analysis of variance demonstrated that there was a significant difference among the AD subgroups. B: The average number of WM enlarged perivascular spaces (état criblé–like lesions) in the ND and AD groups. P value represents the 2-tailed unpaired Student t-test probability. C: Mean ratios of perivascular space diameter/blood vessel diameter observed in ND and AD cohorts. P value represents the 2-tailed unpaired Student t-test probability. D: Linear correlation (R = 0.97) between the mean number of WM enlarged perivascular spaces and average levels of cortical Aβ when the AD and control subjects were grouped by Apo E genotype. E: Linear correlation between the ratio of perivascular space diameter to blood vessel diameter and the total levels of cortical Aβ (R = 0.55; P < 0.001). F: Linear correlation between the mean number of WM enlarged perivascular spaces and the ratio of perivascular space diameter to blood vessel diameter (R = 0.70; P < 0.001).
Figure 6
Figure 6
Diagram suggesting the morphological changes that lead to enlargement of WM perivascular spaces. A: Under normal conditions, the brain’s interstitial fluid is collected by the patent periarterial spaces around the blood vessels of the WM, GM, and leptomeninges. B: The leptomeningeal and perforating cortical arteries supplying the brain GM and WM are surrounded by heavy amyloid deposits that destroy the vascular walls and block the perivascular spaces at the level of the cerebral cortex and leptomeninges. This obstruction results in WM congestion and stasis of interstitial fluid with simultaneous dilation of the WM perivascular spaces. The greater density and rigidity and lesser compliance of the GM matter leave this tissue substantially less affected than the WM.
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