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Abstract
Cerebral amyloid angiopathy (CAA) affects brain parenchymal and leptomeningeal arteries and arterioles but sometimes involves capillaries (capCAA) with spread of the amyloid into the surrounding neuropil, that is, dyshoric changes. We determined the relationship between capCAA and larger vessel CAA, β amyloid (Aβ) plaques, neurofibrillary changes, inflammation, and apolipoprotein E (APOE) in 22 cases of dyshoric capCAA using immunohistochemistry. The dyshoric changes contained predominantly Aβ1-40, whereas dense bulblike deposits adjacent to the capillary wall contained mostly Aβ1-42. There was an inverse local correlation between Aβ plaque load and capCAA severity (p = 0.01), suggesting that Aβ transport between the neuropil and the circulation may be mechanistically involved. Deposits of hyperphosphorylated tau and ubiquitin and clusters of activated microglia, resembling the changes around Aβ plaques, were found around capCAA but were absent around larger vessel CAA. In 14 cases for which APOE genotype was available, there was a high APOE-ε4 allele frequency (54%; 43% homozygous). The severity of CapCAA increased with the number of ε4-alleles; and APOE4 seemed to colocalize with capCAA by immunohistochemistry. These results suggest that capCAA is pathologically and possibly pathogenetically distinct from larger vessel CAA, and that it is associated with a high APOE-ε4 allele frequency.
Key Words: Alzheimer, Capillary cerebral amyloid angiopathy, Cerebral amyloid angiopathy, Dementia, Dyshoric, Neuroinflammation.
INTRODUCTION
Sporadic cerebral amyloid angiopathy (CAA) is characterized by deposits of β-amyloid (Aβ) in meningeal and parenchymal arteries, arterioles, and to a lesser extent, brain capillaries (1). Cerebral amyloid angiopathy is a common finding at autopsy, and its incidence increases with age and occurs in 70% to 100% of Alzheimer disease (AD) patients (2, 3). Cerebral amyloid angiopathy may occur in any region of the brain and spreads in a characteristic pattern starting in the neocortex, where the occipital lobe is a predilection site; it may involve other brain areas, including the thencephalon, striatum, and cerebellum (4, 5).
Sporadic CAA can be classified into CAA-type 1, involving cortical capillaries in addition to leptomeningeal and cortical arteries and arterioles, and CAA-type 2, not involving cortical capillaries (6). Capillary CAA (CapCAA) can occur in any stage of CAA-type 1 and correlates with severity of AD pathology, whereas larger vessel CAA does not (7, 8). A remarkably high apolipoprotein E-ε4 (APOE-ε4) allele frequency...