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Abstract：
BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a reversible CNS disease characterized by disturbed cerebrospinal fluid (CSF) dynamics. Changes in the extracellular matrix (ECM) composition might be involved in the pathophysiology of iNPH. The aim of this study was to explore possible differences between lumbar and ventricular CSF concentrations of the ECM markers brevican and neurocan, matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase-1 (TIMP-1) and their relation to clinical symptoms in iNPH patients before and after shunt surgery.
METHODS: Paired lumbar and ventricular CSF was collected from 31 iNPH patients, before and four months after shunt surgery. CSF was analysed for concentrations of tryptic peptides originating from brevican and neurocan using a mass spectrometry-based panel, and for MMP-1, -2, -9, -10 and TIMP-1 using fluorescent or electrochemiluminescent immunoassays.
RESULTS: Brevican and neurocan peptide levels were not influenced by CSF origin, but MMP-1, -2, -10 and TIMP-1 were increased (p ≤ 0.0005), and MMP-9 decreased (p ≤ 0.0003) in lumbar CSF compared with ventricular CSF. There was a general trend of ECM proteins to increase following shunt surgery. Ventricular TIMP-1 was inversely correlated with overall symptoms (rho = - 0.62, p < 0.0001). CSF concentrations of the majority of brevican and neurocan peptides were increased in iNPH patients with a history of cardiovascular disease (p ≤ 0.001, AUC = 0.84-0.94) compared with those without.
CONCLUSIONS: Levels of the CNS-specific proteins brevican and neurocan did not differ between the lumbar and ventricular CSF, whereas the increase of several CNS-unspecific MMPs and TIMP-1 in lumbar CSF suggests contribution from peripheral tissues. The increase of ECM proteins in CSF following shunt surgery could indicate disturbed ECM dynamics in iNPH that are restored by restitution of CSF dynamics.
METHODS: Paired lumbar and ventricular CSF was collected from 31 iNPH patients, before and four months after shunt surgery. CSF was analysed for concentrations of tryptic peptides originating from brevican and neurocan using a mass spectrometry-based panel, and for MMP-1, -2, -9, -10 and TIMP-1 using fluorescent or electrochemiluminescent immunoassays.
RESULTS: Brevican and neurocan peptide levels were not influenced by CSF origin, but MMP-1, -2, -10 and TIMP-1 were increased (p ≤ 0.0005), and MMP-9 decreased (p ≤ 0.0003) in lumbar CSF compared with ventricular CSF. There was a general trend of ECM proteins to increase following shunt surgery. Ventricular TIMP-1 was inversely correlated with overall symptoms (rho = - 0.62, p < 0.0001). CSF concentrations of the majority of brevican and neurocan peptides were increased in iNPH patients with a history of cardiovascular disease (p ≤ 0.001, AUC = 0.84-0.94) compared with those without.
CONCLUSIONS: Levels of the CNS-specific proteins brevican and neurocan did not differ between the lumbar and ventricular CSF, whereas the increase of several CNS-unspecific MMPs and TIMP-1 in lumbar CSF suggests contribution from peripheral tissues. The increase of ECM proteins in CSF following shunt surgery could indicate disturbed ECM dynamics in iNPH that are restored by restitution of CSF dynamics.
摘要：
背景：特发性常压性脑积水（iNPH）是一种可逆的CNS疾病，其特征是脑脊液（CSF）动力学紊乱。细胞外基质（ECM）组成的变化可能与iNPH的病理生理学有关。这项研究的目的是探索ECM标志物brevican和neurocan的腰椎和心室CSF浓度之间可能的差异，基质金属蛋白酶(MMPs)和金属蛋白酶组织抑制因子-1(TIMP-1)及其与iNPH患者分流手术前后临床症状的关系
方法：收集31例iNPH患者的腰脑室脑脊液，分流手术之前和之后四个月.使用基于质谱的面板分析CSF中源自brevican和neurocan的胰蛋白酶肽的浓度，和MMP-1、-2、-9、-10和TIMP-1使用荧光或电化学发光免疫测定。
结果：Brevican和Neurocan肽水平不受CSF来源的影响，但MMP-1，-2，-10和TIMP-1增加（p≤0.0005），与心室CSF相比，腰CSF中的MMP-9降低（p≤0.0003）。分流手术后ECM蛋白有增加的一般趋势。心室TIMP-1与总体症状呈负相关（rho=-0.62，p<0.0001）。与没有心血管疾病病史的iNPH患者相比，大多数brevican和neurocan肽的CSF浓度增加（p≤0.001，AUC=0.84-0.94）。
结论：中枢神经系统特异性蛋白brevican和neurora的水平在腰椎和心室CSF之间没有差异，而腰椎CSF中几种CNS非特异性MMPs和TIMP-1的增加提示外周组织有贡献。分流手术后CSF中ECM蛋白的增加可能表明iNPH中ECM动力学受到干扰，可通过恢复CSF动力学而恢复。
方法：收集31例iNPH患者的腰脑室脑脊液，分流手术之前和之后四个月.使用基于质谱的面板分析CSF中源自brevican和neurocan的胰蛋白酶肽的浓度，和MMP-1、-2、-9、-10和TIMP-1使用荧光或电化学发光免疫测定。
结果：Brevican和Neurocan肽水平不受CSF来源的影响，但MMP-1，-2，-10和TIMP-1增加（p≤0.0005），与心室CSF相比，腰CSF中的MMP-9降低（p≤0.0003）。分流手术后ECM蛋白有增加的一般趋势。心室TIMP-1与总体症状呈负相关（rho=-0.62，p<0.0001）。与没有心血管疾病病史的iNPH患者相比，大多数brevican和neurocan肽的CSF浓度增加（p≤0.001，AUC=0.84-0.94）。
结论：中枢神经系统特异性蛋白brevican和neurora的水平在腰椎和心室CSF之间没有差异，而腰椎CSF中几种CNS非特异性MMPs和TIMP-1的增加提示外周组织有贡献。分流手术后CSF中ECM蛋白的增加可能表明iNPH中ECM动力学受到干扰，可通过恢复CSF动力学而恢复。
