BBB dysfunction in post-stroke dementia

摘要 卒中后痴呆是血管对认知功能贡献的一个重要组成部分，但研究较少 损伤和痴呆症。中风使至少一年内罹患痴呆症的风险增加近一倍 十年后，即使在考虑了痴呆症的其他血管危险因素和初步影响后 中风对认知的损害。此外，近一半的老年患者会发生静止性中风，并与 痴呆症。我们在野生型小鼠中建立了中风会触发中风疤痕中的慢性神经炎症，并 相互连接的大脑区域，这会导致延迟性认知能力下降。在人类中，有 大约一半的慢性中风幸存者在尸检中发现中风疤痕中的神经炎症，即使是在几十年后也是如此 中风，这表明它可能也在人类身上发挥作用。然而，目前还没有生物标记物可以 在活人身上用于检测中风后谁有认知能力下降和痴呆症的风险。在此，我们建议 测试炎症诱导中风和相关区域血管生成导致 未成熟的血管渗漏，即使中风后很晚也会导致血脑屏障渗漏。我们将招募200人 慢性中风患者和3个地点的50名对照组(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Aim 1中测试基于MRI的成像生物标记物，并询问 中风后多年，血脑屏障通透性受到损害。在目标2中，我们会问一种血液是否 血管生成失衡的生物标志物在慢性卒中中调节失调。对于两者，我们还将考虑风险因素 以及它们与卒中大小、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记物是单独还是 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 是相关联的。如果我们成功了，我们将确定存在慢性血脑屏障功能障碍 并将其与血管生成失调联系起来，作为一种潜在的机制。这将是一个根本性的变化 中风后痴呆症是如何概念化的，并将为新的治疗方法开发开辟道路。我们的 预测模型也将有助于识别认知功能下降的高风险中风幸存者和/或选择 患者进行未来的临床试验。这将帮助我们更好地了解血管对认知的贡献 损伤和痴呆症。

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.