Pathobiology of Vascular Cognitive Impairment

血管认知障碍(VCI)是一种异质性疾病，是痴呆的主要原因之一。 小血管疾病--皮质下缺血性血管性痴呆(SIVD)患者的选择 更多同质的人群，这将促进临床试验。SIVD中的病理学研究 血管周围基底膜增厚，继发纤维素样坏死和玻璃体增生症 高血压、糖尿病和先天性血管疾病。缺血/缺氧导致产生 基质降解金属蛋白酶(MMPs)作为炎症反应和组织的一部分 损伤后的重塑。我们已经证明了来自VCI患者的脑组织中MMPs的免疫染色 反应性星形胶质细胞和巨噬细胞/小胶质细胞，MMPs破坏血管周围的基质和 打开血脑屏障(BBB)。此外，MMPs分解髓鞘，这可能有助于 在SIVD中可见血管脱髓鞘。最近，我们报告说，在 VCI患者的脑脊液，而阿尔茨海默病(AD)患者的脑脊液中不存在。我们假设MMP是 由缺血/缺氧的脑细胞分泌，参与了VCI的病理生物学过程。具体目标是：1) 开发基于多模式测试的SIVD评定量表，包括临床评估、磁学 磁共振成像(MRI)和多体素质子波谱(1H-MRS)，神经心理测试，以及 脑脊液研究；2)通过索引脑脊液和血液中的MMPs来确定脑脊液中MMPs的来源 白蛋白；3)定性确定血脑屏障参与Gd-DTPA增强和 用Patlak图解法定量，并将开口与基质金属蛋白酶水平相关联；4) 将MMPs水平与SIVD评定量表的结果进行盲法关联 通过对患者的长期随访进行验证。这些研究将确定蛋白水解酶的作用 在SIVD的进行性形式的炎症，并可能导致新的治疗方法，以抑制蛋白酶。

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 SIVDshow 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.