Pathobiology of Vascular Cognitive Impairment

描述（由申请人提供）：血管性认知障碍（VCI）是一种异质性疾病，是痴呆的主要原因。选择患有小血管疾病，皮质下缺血性血管性痴呆（SIVD）的患者，提供了一个更均匀的人群，这将促进临床试验。SIVD的病理研究显示血管周围的基底膜增厚伴纤维蛋白样坏死和透明质病继发于高血压、糖尿病和先天性血管疾病。缺血/缺氧导致基质降解金属蛋白酶（MMPs）的产生，作为损伤后炎症反应和组织重塑的一部分。我们的研究表明，对反应性星形胶质细胞和巨噬细胞/小胶质细胞中的MMPs进行VCI免疫染色的患者脑组织中，MMPs破坏血管周围的基质并打开血脑屏障（BBB）。此外，MMPs会分解髓磷脂，这可能导致SIVD中的血管脱髓鞘。最近，我们报道在VCI患者的脑脊液中发现MMPs水平升高，但在阿尔茨海默病（AD）患者中没有发现。我们假设MMPs是由缺血/缺氧的脑细胞分泌的，并参与了VCI的病理生物学。具体目标是：1)开发基于多模态测试的SIVD评分量表，包括临床评估、磁共振成像（MRI）和多体素质子谱（1H-MRS）、神经心理测试和脑脊液研究；2)通过将脑脊液和血液中的MMPs与白蛋白结合，确定CSF中MMPs的来源；3}用钆- dtpa增强定性地确定血脑屏障的受损伤，用Patlak图形法定量地确定血脑屏障的受损伤，并将开口与MMP水平相关联；4)以盲法将MMPs水平与SIVD评分量表结果联系起来，SIVD评分量表已通过对患者的长期随访验证。这些研究将确定蛋白酶介导的炎症在进行性SIVD中的作用，并可能导致抑制蛋白酶的新疗法。

DESCRIPTION (provided by applicant): Vascular cognitive impairment (VCI) is a heterogeneous disorder that is a major cause of dementia. Selection of patients with small vessel disease, subcortical ischemic vascular dementia (SIVD), provides a more homogenous population that would facilitate clinical trials. Pathological studies in SIVD show thickening of the basal lamina around blood vessels with fibrinoid necrosis and hyalinosis secondary to hypertension, diabetes mellitus, and congenital vascular diseases. Ischemia/hypoxia leads to the production of matrix-degrading metalloproteinases (MMPs) as part of both an inflammatory response and tissue remodeling after injury. We have shown that brain tissues from patients with VCI immunostain for MMPs in reactive astrocytes and macrophage/microglia cells, MMPs disrupt the matrix around blood vessels and open the blood-brain barrier (BBB). In addition, MMPs break down myelin, which could contribute to the vascular demyelination seen in SIVD. Recently, we reported that increased levels of MMPs are found in the CSF of patients with VCI, but not in patients with Alzheimer's disease (AD). We hypothesize that MMPs are secreted by ischemic/hypoxic brain cells and contribute to the pathobiology of VCI. The specific aims are: 1) to develop a SIVD rating scale based on rnultimodal testing, including clinical evaluation, magnetic resonance imaging (MRI) and multivoxel proton spectroscopy (1H-MRS), neuropsychological testing, and CSF studies; 2) to identify the source of MMPs in the CSF by indexing the MMPs in the CSF and blood to albumin; 3} to determine the involvement of the BBB qualitatively with Gadolinium-DTPA enhancement and quantitatively with the Patlak Graphical Method and to correlate the opening with MMP levels; and 4) to correlate the levels of MMPs in a blinded fashion with the results of the SIVD rating scale that has been validated by long-term follow-up of the patients. These studies will determine the role of protease-mediated nflammation in the progressive form of SIVD, and could lead to novel treatments to suppress proteases.