BBB dysfunction in post-stroke dementia

摘要 中风后痴呆是血管对认知功能的重要贡献， 损伤和痴呆。中风至少会使痴呆症的发病风险增加一倍。 十年后，即使在考虑了痴呆的其他血管危险因素和 脑卒中对认知功能的影响此外，近一半的老年人会发生无症状中风， 痴呆我们在野生型小鼠中建立了中风触发中风疤痕中的慢性神经炎症， 连接的大脑区域，这会导致延迟性认知衰退。在人类中， 在尸检中，约有一半的慢性中风幸存者的中风疤痕中存在神经炎症，即使在几十年后， 中风，这表明它可能也在人类中发挥作用。然而，目前还没有生物标志物可以 用于活体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 检验炎症诱导的中风和相连区域血管生成导致 不成熟的渗漏血管，即使在中风后很晚也会导致血脑屏障渗漏。我们将招募200名 在3个地点（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渗透性受损。在目标2中，我们会问， 不平衡血管生成的生物标志物在慢性卒中中失调。对于这两种情况，我们还将研究风险因素 他们的发展，以及他们如何与中风的大小，位置，性别，年龄和NIHSS。最后，在目标3中， 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功能下降，并确定其他MRI，血液和临床特征， 是有联系的。如果我们成功了，我们将确定，有慢性血脑屏障功能障碍， 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变化 中风后痴呆症的概念化，并将开辟新的治疗发展的途径。我们 预测模型也将有助于识别处于认知能力下降高风险的中风幸存者和/或选择 患者进行临床试验。因此，这将有助于我们更好地了解血管对认知功能的贡献。 损伤和痴呆。

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.