Stroke Connectome MRI biomarkers for VCID risk assessment

项目摘要 血管对认知障碍和痴呆的贡献（VCID）是四种阿尔茨海默病之一 和相关痴呆症（ADRD）。VCID研究调查了一系列血管疾病和 血管危险因素对认知的影响。美国每年有61万人首次中风， 65岁及以上的人群中发生中风的比例为10%。中风后认知障碍和痴呆症非常普遍 （约30%），是美国成年人残疾的主要原因，经济负担达数十亿美元。卒中后 痴呆被定义为在中风后6个月内开始的立即和/或延迟的认知能力下降。 因此，卒中后认知障碍和痴呆被认为是主要的VCID。但 与中风相关的潜在疾病生物学尚未完全了解。有充分的证据表明AD病理学 通常与脑血管疾病（如中风）并存，有许多共同的风险因素，导致 对认知能力下降有累加或协同作用。但是，也有一个区别，即“早期”。 中风后痴呆的发病取决于中风和大脑恢复力之间复杂的相互作用， “迟发性卒中后痴呆”取决于严重的小血管疾病，而不是复发性卒中 或并发AD病理。然而，还没有生物标志物被报道可靠地区分 神经退行性疾病和脑血管疾病之间的联系了解两者之间的关系 因此，疾病仍然是一个高度优先事项，以便能够针对基本机制， VCID的负担。本项目的具体目标是研究基于血浆的 磷酸化tau蛋白（p-tau）和载脂蛋白ε4基因（APOE 4）在预测卒中后VCID进展中的作用。 p-tau代表大脑中淀粉样蛋白负荷的程度，APOE 4与发展AD的风险有关。我们 中心假设是淀粉样蛋白负荷、APOE 4遗传风险和中风之间的相互作用更好地解释了 解释为什么一部分中风患者会发展为VCID的潜在病理学。具体目标： 描述VCID风险因素、认知储备、血浆生物标志物（p- tau，APOE 4），脑健康和认知功能在中风后6个月和12个月。成功完成 该项目将提供目前缺乏科学的理解之间的复杂的生物学关系VCID 风险因素、血液和卒中MRI生物标志物，这些是卒中后认知能力下降的生物学基础。 与PET扫描或腰椎穿刺相比，基于血液的生物标志物检测更容易获得，且不太复杂 用于评估大脑中的淀粉样蛋白负荷。因此，预计该项目将产生重大影响。 对卒中后VCID的分子和遗传生物标志物领域的影响。结果将奠定一个强大的 为建立准确的诊断，预后和未来的临床研究奠定了基础，这些研究可以帮助积极改变 疾病进展和减少中风后VCID给患者带来的疾病负担。

PROJECT SUMMARY Vascular Contributions to Cognitive Impairments and Dementia (VCID) is one of the four Alzheimer’s Disease and Related Dementias (ADRDs). VCID research investigates the effects of a range of vascular disease and vascular risk factors on cognition. Every year 610,000 people in the US have first-time strokes and three-quarters of strokes occur in people aged 65 and older. Post-stroke cognitive impairment and dementia is highly prevalent (~30%) and is a major cause of adult disability in the US, with economic burden in the billions. Post-stroke dementia is defined as an immediate and or delayed cognitive decline that begins within 6 months after a stroke. Therefore, post-stroke cognitive impairments and dementia is recognized as a major VCID. However, the underlying disease biology linked to stroke is not fully understood. There is robust evidence that AD pathology often coexists with cerebrovascular disorders such as stroke, with many risk factors being shared, resulting in additive or synergistic effects on cognitive decline. However, there is also a distinction made between ‘early- onset post-stroke dementia’ which depends on the complex interplay between stroke and brain resilience, versus ‘late-onset post-stroke dementia’ which depends on severe small vessel disease, rather than by recurrent stroke or concurrent AD pathology. However no biological biomarkers have yet been reported to reliably differentiate between neurodegenerative and cerebrovascular disease. Understanding the relationships between the two diseases therefore remains a high priority to enable targeting of underlying mechanisms and reducing the overall burden of VCID. The specific goal of this project is to investigate the utility of blood-plasma based phosphorylated-tau (p-tau) and apolipoprotein 𝜖𝜖-4 gene (APOE4) in predicting progression to post-stroke VCID. p-tau represents the extent of amyloid burden in the brain and APOE4 is linked to risk for developing AD. Our central hypothesis is that interactions between amyloid burden, APOE4 genetic risk, and stroke would better explain the underlying pathology of why a subset of stroke patients go on to develop VCID. Specific Aim: Characterize specific relationships between VCID risk factors, cognitive reserve, blood plasma biomarkers (p- tau, APOE4), brain health and cognitive function at 6 and 12-months after stroke. Successful completion of the project will provide currently lacking scientific understanding of the intricate biological relationships among VCID risk factors, blood, and stroke MRI biomarkers, which underlie the biology of cognitive decline after a stroke. Blood-based biomarker testing is more accessible, and less complex compared to PET scan or lumbar puncture for assessing amyloid burden in the brain. Therefore, the proposed project is expected to exert a significant influence on the field of molecular and genetic biomarkers of post stroke VCID. The results will lay a strong foundation for building accurate diagnosis, prognosis, and future clinical studies that can aid in positively altering disease progression and reducing the burden of illness on patients due to post stroke VCID.