The Influence of Chronic Cerebral Hypoperfusion on Cognitive Function and Amyloid β Metabolism in APP Overexpressing Mice

Cognitive impairment resulting from cerebrovascular insufficiency has been termed vascular cognitive impairment, and is generally accepted to be distinct from Alzheimer's disease resulting from a neurodegenerative process. However, it is clear that this simple dichotomy may need revision in light of the apparent occurrence of several shared features between Alzheimer's disease and vascular cognitive impairment. Nevertheless, it still remains largely unknown whether the burden of vascular- and Alzheimer-type neuropathology are independent or interdependent. Therefore, we investigated whether chronic cerebral hypoperfusion influences cognitive ability or amyloid β deposition in amyloid precursor protein (APP) overexpressing transgenic mice

Cerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes cortical microinfarcts

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/cm2 in mild, 0.584/cm2 in moderate, and 4.370/cm2 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

非降圧量のテルミサルタンはPPAR-γ活性化作用を部分的に介してマウス慢性脳低灌流モデルの認知機能障害を軽減する

京都大学0048新制・課程博士博士(医学)甲第15939号医博第3524号新制||医||985(附属図書館)28518京都大学大学院医学研究科医学専攻(主査)教授 宮本 享, 教授 河野 憲二, 教授 中尾 一和学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDA

Animal Models of Chronic Cerebral Hypoperfusion: From Mouse to Primate

Vascular cognitive impairment (VCI) or vascular dementia occurs as a result of brain ischemia and represents the second most common type of dementia after Alzheimer&rsquo;s disease. To explore the underlying mechanisms of VCI, several animal models of chronic cerebral hypoperfusion have been developed in rats, mice, and primates. We established a mouse model of chronic cerebral hypoperfusion by narrowing the bilateral common carotid arteries with microcoils, eventually resulting in hippocampal atrophy. In addition, a mouse model of white matter infarct-related damage with cognitive and motor dysfunction has also been established by asymmetric common carotid artery surgery. Although most experiments studying chronic cerebral hypoperfusion have been performed in rodents because of the ease of handling and greater ethical acceptability, non-human primates appear to represent the best model for the study of VCI, due to their similarities in much larger white matter volume and amyloid &beta; depositions like humans. Therefore, we also recently developed a baboon model of VCI through three-vessel occlusion (both the internal carotid arteries and the left vertebral artery). In this review, several animal models of chronic cerebral hypoperfusion, from mouse to primate, are extensively discussed to aid in better understanding of pathophysiology of VCI

Adrenomedullin: A vasoactive agent for sporadic and hereditary vascular cognitive impairment

Adrenomedullin (AM) is an endogenous peptide mainly secreted from endothelial cells, which has multiple physiological actions such as anti-inflammation, vasodilation, vascular permeability regulation and angiogenesis. Blood AM levels are upregulated in a variety of pathological states including sepsis, severe COVID-19, acute ischemic stroke and vascular cognitive impairment with white matter changes, likely serving as a compensatory biological defense response against infection and ischemia. AM is currently being tested in clinical trials for ulcerative colitis, Crohn's disease, severe COVID-19 for its anti-inflammatory properties and in ischemic stroke for its additional angiogenic action. AM has been proposed as a therapeutic option for vascular cognitive impairment as its arteriogenic and angiogenic properties are thought to contribute to a slowing of cognitive decline in mice after chronic cerebral hypoperfusion. As AM promotes differentiation of oligodendrocyte precursor cells into mature oligodendrocytes under hypoxic conditions, AM could also be used in the treatment of CADASIL, where reduced oxygen delivery is thought to lead to the death of hypoxia-prone oligodendrocytes. AM therefore holds potential as an innovative therapeutic drug, which may regenerate blood vessels, while controlling inflammation in cerebrovascular diseases

種々のレクチン染色によるヒト膀胱癌の免疫組織化学的解析

51例の膀胱癌症例の組織型の内訳は, 移行上皮癌(TCC) 44例(G1 15例;G2 17例;G3 12例), 扁平上皮癌(SCC) 7例であり, ホルマリンないしカルノア液にて固定後に以下の10種類のレクチン染色を行った。concanavalin agglutinin (Con A), soybean agglutinin (SBA), Lotus tetragonolobus agglutinin (LTA), Dolichos biflorus agglutinin (DBA), peanut agglutinin (PNA), Ricinus communis agglutinin 1 (RCA1), Ulex europaeus agglutinin 1, 2 (UEA-1, 2), wheat germ agglutinin (WGA), Pisum sativum agglutinin (PEA)。カルノア固定で, TCCでCon A, UEA-1, WGA, UEA-2では正の相関傾向が, DBAでは負の相関傾向が見られタ。ホルマリン固定では, RCA1にのみある程度の正の相関傾向を認めたA lectin immunohistochemical analysis of 51 human bladder carcinomas, including 44 cases of transitional cell carcinoma (TCC) (G1, 15 cases; G2, 17 cases; G3, 12 cases) and 7 cases of squamous cell carcinoma (SCC), was performed. Tissues were obtained by cold punch biopsies, fixed in Carnoy's or 10% formalin solution, stained for binding of 10 different lectins, and evaluated under the light microscope. The lectins used were concanavalin agglutinin (Con A), soybean agglutinin (SBA), Lotus tetragonolobus agglutinin (LTA), Dolichos biflorusa agglutinin (DBA), peanut agglutinin (PNA), Ricinus communis agglutinin I (RCA1), Ulex europaeus agglutinin I, II (UEA-I, II), wheat germ agglutinin (WGA), and Pisum sativum agglutinin (PEA). TCC prepared with Carnoy's fixation tended to show moderately positive Con A, UEA-I, and WGA reactions for G1, and strongly positive reactions for G2 and G3 lesions. UEA-II was mainly negative in G1, but tended to increase to become moderate in G3. DBA tended to show a moderately positive reaction in G1 and G2, but was mainly negative in G3. With formalin fixation, only RCA1 demonstrated grade specific variation, tendency to react moderately in the G1 and G2 cases, and strongly in G3. There were no further differences among the histopathological grades of TCC for other lectins. Thus, Carnoy's fixation appears superior for distinguishing between grades of lesions. SCC tended to react more strongly than TCC with all the various lectins except PEA, independent of fixation

A multicenter, single-arm, phase II clinical trial of adrenomedullin in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common form of hereditary cerebral small vessel disease (SVD), currently lacks disease-modifying treatments. Adrenomedullin (AM), a vasoactive peptide with angiogenic, vasodilatory, anti-inflammatory, and anti-oxidative properties, shows potential effects on the neuro-glial-vascular unit. Objective: The AdrenoMedullin for CADASIL (AMCAD) study aims to assess the efficacy and safety of AM in patients with CADASIL. Sample size: Overall, 60 patients will be recruited. Methods: The AMCAD is a multicenter, investigator-initiated, single-arm phase II trial. Patients with a confirmed CADASIL diagnosis, based on NOTCH3 genetic testing, will receive an 8-h AM treatment (15 ng/kg/min) for 14 days following a baseline assessment (from day 1 to day 14). Follow-up evaluations will be performed on days 15, 28, 90, and 180. Study outcomes: The primary endpoint is the cerebral blood flow change rate in the frontal cortex, evaluated using arterial spin labeling magnetic resonance imaging, from baseline to day 28. Summary statistics, 95% confidence intervals, and a one-sample t-test will be used for analysis. Conclusion: The AMCAD study aims to represent the therapeutic potential of AM in patients with CADASIL, addressing an unmet medical need in this challenging condition. Clinical Trial Registration: jRCT 2,051,210,117 (https://jrct.niph.go.jp/en-latest-detail/jRCT2051210117)

Selective white matter abnormalities in a novel rat model of vascular dementia.

Rats subjected to bilateral common carotid artery (CCA) occlusion or 2-vessel occlusion (2VO) have been used as animal models of subcortical ischemic vascular dementia. However, this model possesses an inherent limitation in that cerebral blood flow (CBF) drops too sharply and substantially after ligation of CCAs. To circumvent such hypoxic-ischemic conditions, we tested implantation of the ameroid constrictor device on bilateral CCAs of male Wistar-Kyoto rats and more precisely replicated chronic cerebral hypoperfusion by gradual narrowing of the CCAs (2-vessel gradual occlusion; 2VGO). The acute cerebral blood flow reduction and resultant inflammatory responses observed in the 2VO rats were eliminated in the 2VGO rats. Thus, chronic cerebral hypoperfusion was segregated, and induced selective white matter changes with relatively preserved neurovascular coupling and substantially less metabolic and histological derangements in the gray matter including the hippocampus. This led to significant spatial working memory impairment of a magnitude similar to the 2VO rats at 28 days postoperation. The 2VGO model may more closely mimic cognitive impairment subsequent to selective white matter damage