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）是痴呆的第二种最常见形式， 阿尔茨海默病（AD）。VCID是脑小血管病（SVD）的后果之一。这种血管 疾病产生脑灌注缺陷，并最终导致皮质和/或皮质下腔隙性中风。腔隙性 中风本质上可以是缺血性或微出血性的，并且可以导致长期的身体残疾和死亡。 对目前的建议至关重要的是，腔隙性中风是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及其导致的腔隙性卒中的独立主要危险因素。这些 这些因素通常集中在腔隙性中风风险最高和结果最差的个体中。的 目前的建议是由中心假设驱动的，即在动物中结合主要的人类SVD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，引起血管损伤， 导致腔隙性斯托克斯并最终导致VCID。进一步假设，结合这些风险因素有助于 腔隙性中风的合并以及由此导致的损伤的加重加速了行为缺陷。在这 本研究将采用饮食诱导的高同型半胱氨酸血症的老年自发性高血压大鼠SVD模型 (SHR)，其也产生胰岛素抗性表型。此外，我们将进一步推动糖尿病表型 1）高果糖饮食和2）通过使用低剂量的果糖来促进胰腺β细胞的减少， 链脲霉素。糖尿病的叠加将进一步验证我们的假设，即通过结合更多的 独立的危险因素，SVD和腔隙性梗死的进展是加速和加剧的。我们 这项研究还将利用一种新型的非侵入性成像方式，多光谱光声断层扫描， （MSOT），以识别和测量灌注/氧合缺陷的区域，并将这些与行为 纵向结果和结构损伤的最终组织学分析。成功完成本提案 将证明这些风险因素的组合概括了SVD腔隙性心脏病的人类后遗症， 在动物模型中，最终，这个强大的和高度相关的空白的发展， 中风/VCID动物模型和成像技术将允许临床前测试靶和先导化合物， 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 1）目的1：确定高血压、饮食诱导的高血压和高血压相关性的协同作用。 高同型半胱氨酸血症和衰老对大鼠小血管疾病、腔隙性中风和VCID的影响，以及2）确定 胰岛素抵抗和糖尿病对高血压大鼠模型腔隙性脑卒中和VCID影响 高同型半胱氨酸血症-衰老拟议的研究是创新的，因为它代表了一个实质性的偏离 通过将重点转移到如何将多个人类腔隙性中风和 VCID风险因素，1）促进血管重塑和2）物理应力微血管可以概括 人类状况并导致动物模型中损伤的加速和恶化。

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.