Stroke Connectome MRI biomarkers for VCID risk assessment

项目总结 血管对认知损害和痴呆的贡献(VCID)是四种阿尔茨海默病之一 和相关痴呆症(ADRDS)。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，其中四分之三是中风 的中风发生在65岁及以上的人群中。卒中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，经济负担数十亿美元。卒中后 痴呆症被定义为中风后6个月内开始的即刻和或延迟性认知能力下降。 因此，卒中后认知障碍和痴呆被认为是主要的VCID。然而， 与中风有关的潜在疾病生物学还没有完全了解。有确凿的证据表明AD病理 经常与中风等脑血管疾病共存，并有许多共同的危险因素，导致 认知衰退的相加或协同效应。然而，也有区别的是，早期- 中风后痴呆的发病依赖于中风和大脑韧性之间的复杂相互作用，而不是 迟发性卒中后痴呆依赖于严重的小血管疾病，而不是由复发的中风引起的 或并发AD病理。然而，目前还没有可靠区分生物标志物的报道。 神经退行性疾病和脑血管疾病之间的关系。理解两者之间的关系 因此，疾病仍然是一个高度优先的问题，以实现以潜在机制为目标并减少总体 VCID的负担。本项目的具体目标是调查血浆中 磷酸化tau(p-tau)和载脂蛋白𝜖𝜖-4基因(Apoe4)在预测卒中后血管紧张性脑缺血进展中的作用。 P-tau代表大脑中淀粉样蛋白负荷的程度，APOE4与发展为阿尔茨海默病的风险有关。我们的 中心假设是淀粉样蛋白负荷、载脂蛋白4遗传风险和中风之间的交互作用会更好 解释为什么一部分中风患者继续发展为VCID的潜在病理。具体目标： 描述VCID风险因素、认知储备、血浆生物标志物之间的特定关系(p- Tau，APOE4)，中风后6个月和12个月的大脑健康和认知功能。圆满完成 该项目将提供目前缺乏对VCID之间复杂生物学关系的科学理解 风险因素、血液和中风核磁共振生物标记物，这是中风后认知能力下降的生物学基础。 与PET扫描或腰椎穿刺术相比，基于血液的生物标记物检测更容易进行，而且复杂程度更低 用于评估大脑中的淀粉样蛋白负荷。因此，拟议的项目预计将产生重大影响 卒中后VCID对分子和遗传生物标志物领域的影响结果将奠定一个强有力的 为建立准确的诊断、预后和未来有助于积极改变的临床研究奠定基础 疾病进展和减轻中风后VCID患者的疾病负担。

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.