Risk factor convergence in the development of lacunar strokes and vascular cognitive impairment and dementia

血管性认知障碍和痴呆(VCID)是仅次于 阿尔茨海默病(AD)。VCID是脑部小血管疾病(SVD)的后果之一。这根血管 紊乱会导致脑血流灌注不足，最终导致皮质和/或皮质下腔隙中风。空隙 中风可以是缺血性的或微出血性质的，并可能导致长期的身体残疾和死亡。 对目前的提案至关重要的是，腔隙中风是VCID的主要原因。高血压，高同型半胱氨酸血症， 糖尿病和高龄是SVD和由此导致的腔隙性中风的独立主要危险因素。这些 因素通常集中在腔隙中风风险最高和结局最差的个人身上。这个 目前的建议是由一个中心假设推动的，即在动物中结合导致SVD的主要人类风险因素 模型产生了一种协同效应，概括了人类疾病的病因，导致血管损伤， 导致缺陷性斯托克斯，最终导致VCID。进一步假设，将这些风险因素结合在一起有助于 腔隙性中风的合并以及由此导致的损伤增加加速了行为缺陷。在这 研究，将使用饮食诱导的高同型半胱氨酸血症的SVD模型在老年自发性高血压大鼠 (SHR)，这也会产生胰岛素抵抗表型。此外，我们还将进一步推动糖尿病的表型 1)高果糖饮食和2)通过使用低剂量的 链佐菌素。糖尿病的叠加将进一步检验我们的假设，即通过将更多的 独立危险因素SVD、、腔隙性脑梗塞、、VCID进展加快和加重。我们的 研究还将利用一种新的、非侵入性成像方式--多光谱光声断层扫描 (MSOT)，以识别和测量灌流/氧合缺陷区域，并将其与行为 与结构损伤的最终组织学分析的纵向结果。成功完成本建议书 将证明这些危险因素的组合概括了人类svd腔隙的后遗症。 在动物模型上梗死血管紧张性脑病。最终，这一强大且高度相关的漏洞的发展 卒中/VCID动物模型和成像技术将使靶点和先导化合物的临床前测试成为可能 腔隙性中风和VCID疗法。我们计划测试我们的中心假设，并实现我们的总体目标 通过追求以下具体目标：1)目标1：确定饮食诱导的高血压的协同效应 高同型半胱氨酸血症、小血管疾病的增龄、腔隙性中风和VCID，以及2)决定 胰岛素抵抗和糖尿病对高血压大鼠腔隙卒中和VCID的影响 高同型半胱氨酸血症--衰老。这项拟议的研究具有创新性，因为它代表了一项重大的突破 通过将重点从现状转移到调查如何将多个人类腔隙卒中和 VCID危险因素1)促进血管重塑和2)物理应激微血管系统可重现 在动物模型中，人类的状况会导致损伤的加速和加重。

Vascular cognitive impairment and dementia (VCID) is the second most common form of dementia after Alzheimer’s Disease (AD). VCID is one of the consequences of cerebral small-vessel disease (SVD). This vascular disorder produces cerebral perfusion deficits and, ultimately, cortical and/or subcortical lacunar strokes. Lacunar strokes can be ischemic or microhemorrhagic in nature and can result in long-term physical disabilities and death. Critical to the current proposal, lacunar strokes are a leading cause of VCID. Hypertension, hyperhomocysteinemia, diabetes and advanced age are independent, major risk factors for SVD and the resulting lacunar strokes. These factors are often clustered in individuals with both the highest risk for lacunar strokes and the worst outcomes. The current proposal is driven by the central hypothesis that combining major human risk factors for SVD in an animal model produces a synergistic effect that recapitulates the human disease etiology, giving rise to vascular injury that results in lacunar stokes and ultimately VCID. It is further hypothesized that combining these risk factors facilitates the coalescence of lacunar strokes and that the resulting augmentation of injury hastens behavioral deficits. In this study, will use the diet-induced hyperhomocysteinemia model of SVD in aged spontaneously hypertensive rats (SHR), which also produces an insulin-resistant phenotype. In addition, we will further drive the diabetic phenotype with 1) a high-fructose diet and 2) promoting a reduction in pancreatic beta cells through the use of the low-dose streptozocin. The superimposition of diabetes will further test our hypothesis that by combining a greater number of independent risk factors the progression of SVDlacunar infarcts VCID is accelerated and exacerbated. Our study will also leverage the use a novel, non-invasive imaging modality, multispectral optoacoustic tomography (MSOT), to identify and measure regions of perfusion/oxygenation deficits and correlate these with behavioral outcomes longitudinally and with final histological analysis of structural injury. Successful completion of this proposal will demonstrate that the combination of these risk factors recapitulates human sequelae of SVDlacunar infarctsVCID in an animal model. Ultimately, the development of this robust and highly relevant lacunar stroke/VCID animal model and imaging technique will permit pre-clinical testing of targets and lead compounds for lacunar stroke and VCID therapeutics. We plan to test our central hypothesis and accomplish our overall objective by pursuing the following Specific Aims: 1) Aim 1: Determine the synergistic effect of hypertension, diet-induced hyperhomocysteinemia, and aging on small-vessel disease, lacunar strokes and VCID in rats, and 2) Determine the impact of insulin-resistance and diabetes on lacunar strokes and VCID in a rat model of hypertension- hyperhomocysteinemia-aging. The proposed research is innovative because it represents a substantial departure from the status quo by shifting focus onto the investigation of how combining multiple human lacunar stroke and VCID risk factors that 1) promote vascular remodeling and 2) physically stress the microvasculature can recapitulate the human condition and result in acceleration and exacerbation of injury in an animal model.