Pathobiology of Vascular Cognitive Impairment

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， 更同质的人群，这将有助于临床试验。SIVDshow中的病理学研究 血管周围基底膜增厚，纤维素样坏死和玻璃样变性继发于 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 受伤后的重建我们已经证明，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，MMP破坏血管周围的基质， 开放血脑屏障（BBB）。此外，MMPs分解髓磷脂，这可能有助于 SIVD中可见血管脱髓鞘。最近，我们报道了MMPs水平的增加， VCI患者的CSF，而不是阿尔茨海默病（AD）患者。我们假设基质金属蛋白酶是 由缺血/缺氧脑细胞分泌并有助于VCI的病理生物学。具体目标是：1） 基于多模式测试开发SIVD评级量表，包括临床评价、磁共振成像、磁共振成像和磁共振成像。 共振成像（MRI）和多体素质子波谱（1H-MRS），神经心理学测试，以及 CSF研究; 2）通过将CSF和血液中的MMPs编入索引以确定CSF中MMPs的来源， 白蛋白; 3）用钆-DTPA增强定性确定BBB的参与， 用Patlak图解法定量地测量开口并将开口与MMP水平相关联;以及4） 以盲法将MMP水平与SIVD评定量表的结果相关联， 经患者长期随访证实。这些研究将确定蛋白酶介导的 SIVD的进展形式的炎症，并可能导致新的治疗，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.