title: Cerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes cortical microinfarcts.
abstract: Cortical microinfarcts (CMIs) observed in brains of patients with Alzheimer's disease tend to be located close to vessels afflicted with cerebral amyloid angiopathy (CAA). CMIs in Alzheimer's disease are preferentially distributed in the arterial borderzone, an area most vulnerable to hypoperfusion. However, the causal association between CAA and CMIs remains to be elucidated. This study consists of two parts: (1) an observational study using postmortem human brains (n = 31) to determine the association between CAA and CMIs, and (2) an experimental study to determine whether hypoperfusion worsens CAA and induces CMIs in a CAA mouse model. In postmortem human brains, the density of CMIs was 0.113/cm(2) in mild, 0.584/cm(2) in moderate, and 4.370/cm(2) in severe CAA groups with a positive linear correlation (r = 0.6736, p < 0.0001). Multivariate analysis revealed that, among seven variables (age, disease, senile plaques, neurofibrillary tangles, CAA, atherosclerosis and white matter damage), only the severity of CAA was a significant multivariate predictor of CMIs (p = 0.0022). Consistent with the data from human brains, CAA model mice following chronic cerebral hypoperfusion due to bilateral common carotid artery stenosis induced with 0.18-mm diameter microcoils showed accelerated deposition of leptomeningeal amyloid β (Aβ) with a subset of them developing microinfarcts. In contrast, the CAA mice without hypoperfusion exhibited very few leptomeningeal Aβ depositions and no microinfarcts by 32 weeks of age. Following 12 weeks of hypoperfusion, cerebral blood flow decreased by 26% in CAA mice and by 15% in wild-type mice, suggesting impaired microvascular function due to perivascular Aβ accumulation after hypoperfusion. Our results suggest that cerebral hypoperfusion accelerates CAA, and thus promotes CMIs.
authors.affiliation: Department of Neurology, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo, Kyoto 606-8507, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Toru
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Raj N
authors.initials: RN
authors.lastname: Kalaria
authors.forename: Hideto
authors.initials: H
authors.lastname: Senzaki
authors.forename: Takakuni
authors.initials: T
authors.lastname: Maki
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Hase
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kitamura
authors.forename: Kazuo
authors.initials: K
authors.lastname: Washida
authors.forename: Mahito
authors.initials: M
authors.lastname: Yamada
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Ito
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tomimoto
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ihara
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology*; D000818:Animals; D050197:Atherosclerosis / Q000473:pathology; D001921:Brain / Q000098:blood supply* / Q000473:pathology; D020520:Brain Infarction / Q000209:etiology / Q000473:pathology*; D016657:Cerebral Amyloid Angiopathy / Q000209:etiology / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D016874:Neurofibrillary Tangles / Q000473:pathology; D058225:Plaque, Amyloid / Q000473:pathology