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 中风后痴呆是血管对认知的贡献的一个重要且尚未得到充分研究的组成部分 损伤和痴呆。中风至少在一段时间内使发生痴呆症的风险增加一倍 十年后，即使考虑了痴呆症的其他血管危险因素以及 中风对认知的损害。此外，近一半的老年人会发生无症状中风，并且与以下因素有关： 失智。我们在野生型小鼠中证实，中风会引发中风疤痕中的慢性神经炎症，并且 连接的大脑区域，这会导致迟发性认知能力下降。在人类身上，有 在尸检中，大约一半的慢性中风幸存者的中风疤痕中存在神经炎症，甚至在几十年后也是如此 中风，表明它也可能在人类中发挥作用。然而，目前还没有任何生物标志物可以 用于活人检测谁有中风后认知能力下降和痴呆的风险。在此我们建议 检验以下假设：中风和连接区域中炎症诱导的血管生成导致 不成熟的渗漏血管甚至在中风后很晚也会导致血脑屏障渗漏。我们将招募200名 3 个地点的慢性中风参与者和 50 名对照者（斯坦福大学医学院、哥伦比亚大学、 和曼彻斯特大学）。我们将在目标 1 中测试基于 MRI 的成像生物标志物，并询问是否 中风后数年，血脑屏障的通透性都会受到损害。在目标 2 中，我们将询问血是否 慢性中风中血管生成不平衡的生物标志物失调。对于两者，我们还将研究风险因素 了解它们的发展以及它们与中风大小、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来询问每个生物标志物是否单独或 共同预测中风后认知能力下降，并确定其他 MRI、血液和临床特征 是相关联的。如果我们成功了，我们将确定术后存在慢性血脑屏障功能障碍。 中风并将其与血管生成失调联系起来作为一种潜在机制。这将是一个根本性的改变 中风后痴呆症是如何概念化的，并将为新疗法的开发开辟途径。我们的 预测模型也将有助于识别认知能力下降高风险的中风幸存者和/或选择 患者用于未来的临床试验。因此，这将帮助我们更好地了解血管对认知的贡献 损伤和痴呆。