BBB dysfunction in post-stroke dementia

脑卒中后痴呆的血脑屏障功能障碍

• 批准号: 10701068
• 负责人: MARION S BUCKWALTER
• 金额: $ 69.93万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701068
• 关键词: Accounting; Age; Aging; Angiogenic Factor; Angiogenic Proteins; Autopsy; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Vessels; Blood brain barrier dysfunction; Brain; Brain region; Bypass; Cardiac; Cardiovascular system; Cells; Characteristics; Chronic; Cicatrix; Clinical; Clinical Trials; Cognition; Cognitive; Data; Data Element; Data Set; Dementia; Development; Enzyme-Linked Immunosorbent Assay; Extravasation; Functional disorder; Future; Human; Image; Impaired cognition; Individual; Inflammation; Ipsilateral; Learning; Lesion; Link; Location; Longitudinal cohort study; MRI Scans; Magnetic Resonance Imaging; Measures; Modeling; Multicenter Studies; Mus; Operative Surgical Procedures; Participant; Pathway interactions; Patient Selection; Pericytes; Persons; Phase; Plasma; Plasma Proteins; Platelet-Derived Growth Factor B; Proteins; Proteomics; Radiology Specialty; Risk; Risk Factors; Site; Stroke; Testing; Universities; Vascular Dementia; Wild Type Mouse; angiogenesis; aptamer; blood-brain barrier permeabilization; cerebral atrophy; chronic stroke; cognitive testing; comparison control; contrast enhanced; dementia risk; experimental study; follow-up; high risk; imaging biomarker; improved; machine learning model; medical schools; neuroinflammation; novel therapeutics; post stroke; post stroke cognitive impairment; post stroke dementia; predictive modeling; primary outcome; prospective; recruit; risk prediction; secondary outcome; sex; stroke survivor; therapy development; vascular cognitive impairment and dementia; vascular factor; vascular risk factor

Abstract Post-stroke dementia is an important and understudied component of the vascular contributions to cognitive impairment and dementia. Having a stroke approximately doubles the risk of incident dementia for at least a decade afterwards, even after accounting for other vascular risk factors of dementia and the initial effects of the stroke lesion on cognition. Also, silent strokes occur in nearly half of all aging individuals and are associated with dementia. We established in wildtype mice that stroke triggers chronic neuroinflammation in the stroke scar and connected brain regions, and that this causes delayed-onset cognitive decline. In humans, there is neuroinflammation in the stroke scar in about half of all chronic stroke survivors on autopsy, even decades after stroke, suggesting it may play a role in people as well. However, there are no biomarkers that can currently be used in living humans to detect who is at risk of cognitive decline and dementia after stroke. Here we propose to test the hypothesis that inflammation-induced angiogenesis in the stroke and connected regions results in immature leaky vessels that cause blood-brain barrier leakage even very late after stroke. We will recruit 200 participants with chronic stroke and 50 controls at 3 sites (Stanford School of Medicine, Columbia University, and the University of Manchester). We will test an MRI-based imaging biomarker in Aim 1 and ask whether blood-brain barrier permeability is compromised for years after stroke. In Aim 2 we will ask whether a blood biomarker of imbalanced angiogenesis is dysregulated in chronic stroke. For both, we will also look at risk factors for their development and how they relate to stroke size, location, sex, age, and NIHSS. Finally, in Aim 3 we will use both traditional multivariable and machine learning models to ask whether each biomarker separately or together predicts cognitive decline after stroke, and to identify other MRI, blood, and clinical characteristics that are associated. If we are successful, we will establish that there is chronic blood-brain barrier dysfunction after stroke and link it to dysregulated angiogenesis as a potential mechanism. This would be a fundamental change in how post-stroke dementia is conceptualized and would open avenues for novel therapy development. Our predictive models will also be useful to identify stroke survivors at high risk of cognitive decline and/or to select patients for future clinical trials. This will thus help us better understand vascular contributions to cognitive impairment and dementia.

抽象的 中风后痴呆症是对认知贡献的重要组成部分 障碍和痴呆症。中风大约使出现痴呆症的风险翻了一番 此后的十年，即使考虑了其他痴呆症的其他血管危险因素和最初影响 认知的中风病变。同样，在所有老龄化的人中，近一半都会发生无声中风，并且与 失智。我们在野生型小鼠中建立了触发的小鼠，从而触发了中风疤痕和 连接的大脑区域，这会导致延迟发病的认知能力下降。在人类中 几十年后，甚至几十年后 中风，表明它也可能在人们中发挥作用。但是，目前没有生物标志物 用于活着的人来检测谁在中风后有认知能力下降和痴呆症的风险。在这里我们建议 检验以下假设，即炎症诱导的中风和相关区域的血管生成导致 中风后很晚才导致血脑屏障泄漏的未成熟泄漏血管。我们将招募200 3个地点的慢性中风和50个对照的参与者（哥伦比亚大学斯坦福大学医学院， 和曼彻斯特大学）。我们将在AIM 1中测试基于MRI的成像生物标志物，并询问是否 中风后多年，血脑屏障的渗透率被损害。在AIM 2中，我们会问是否有血 慢性中风中血管生成不平衡的生物标志物失调。对于这两者，我们还将研究风险因素 为了开发以及它们与中风规模，位置，性别，年龄和NIHSS的关系。最后，在目标3中，我们将 使用传统的多变量和机器学习模型询问每个生物标志物是单独或 共同预测中风后的认知能力下降，并确定其他MRI，血液和临床特征 相关。如果我们成功，我们将确定在 中风并将其与血管生成失调，作为潜在机制。这将是一个基本变化 在中风后痴呆症的概念上，将为新的治疗发展开辟途径。我们的 预测模型也将对识别具有认知能力下降和/或选择高风险的中风幸存者很有用 未来临床试验的患者。因此，这将有助于我们更好地了解认知的血管贡献 障碍和痴呆症。