Matrix metalloproteinases are associated with increased blood-brain barrier opening in vascular cognitive impairment.
Matrix metalloproteinases are associated with increased blood-brain barrier opening in vascular cognitive impairment.
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DOI：
10.1161/strokeaha.110.600825
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发表时间：
2011-05
期刊：
影响因子：
8.3
通讯作者：
Rosenberg GA
中科院分区：
文献类型：
--
作者：
Candelario-Jalil E;Thompson J;Taheri S;Grossetete M;Adair JC;Edmonds E;Prestopnik J;Wills J;Rosenberg GA
皮质下缺血性血管病（SIVD）是由小血管疾病引起的血管性认知功能障碍（VCI）的主要形式。基质金属蛋白酶（MMP）是一种中性蛋白酶，在神经炎症条件下破坏血脑屏障（BBB）并降解髓鞘碱性蛋白。VCI患者的脑组织和CSF中MMPs水平升高。我们假设SIVD患者CSF中MMPs增加，这与CSF白蛋白增加有关。我们研究了60名疑似VCI患者。25例被归类为SIVD，而其他组包括阿尔茨海默病AD和VCI混合（MX）、多发性卒中（MI）和脑白质疏松（LA）（当存在白色病变且VCI诊断不确定时）。采用凝胶酶谱法测定脑脊液和血浆中MMP-2和MMP-9的含量，并以脑脊液和血浆白蛋白为指标。用荧光法测定MMP-3活性。我们发现，与对照组相比，全组患者（SIVD、MI、MX和LA）CSF中的MMP-2指数降低（p<0.001），对照组的CSF是在脊髓麻醉期间获得的。VCI组MMP-3活性明显高于对照组（P<0.01）。在SIVD中，MMP-2指数与Qalb呈负相关，而与MMP-9指数无相关性。结合MMP-2指数和MMP-3活性将SIVD患者与对照组区分开来，具有高度特异性（p<0.0005）。我们的研究结果支持MMPs与CSF白蛋白增加相关的假设，并表明它们可能有助于SIVD的病理生理学。
Subcortical ischemic vascular disease (SIVD) is a major form of vascular cognitive impairment (VCI) due to small vessel disease. Matrix metalloproteinases (MMPs) are neutral proteases that disrupt the blood-brain barrier (BBB) and degrade myelin basic protein under conditions of neuroinflammation. Brain tissues and CSF of patients with VCI have increased levels of MMPs. We hypothesized that patients with SIVD have increased MMPs in the CSF, which are associated with increased CSF albumin. We studied 60 patients with suspected VCI. Twenty-five were classified as SIVD, while other groups included mixed Alzheimer’s disease AD and VCI (MX), multiple strokes (MI), and leukoaraiosis (LA) when white matter lesions were present and the diagnosis of VCI was uncertain. MMP-2 and MMP-9 in CSF and plasma were measured by gel zymography and indexed to CSF and plasma albumin. MMP-3 activity was measured by fluorescent assay. We found reduced MMP-2 index (p<0.001) in the CSF for the full group of patients (SIVD, MI, MX and LA) compared to controls, whose CSF was obtained during spinal anesthesia. MMP-3 activity was increased in VCI compared to controls (p<0.01). In SIVD, MMP-2 index showed a negative correlation with Qalb, which was absent with the MMP-9 index. Combining MMP-2 index and MMP-3 activity separated the SIVD patients from the controls with high specificity (p<0.0005). Our results support the hypothesis that MMPs are associated with increased CSF albumin and suggest that they may contribute to the pathophysiology of SIVD.