A disbalance of matrix metalloproteinases and their inhibitors in the cerebrospinal fluid from patients with cerebral amyloid angiopathy

Abstract

Background: Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are involved in extracellular matrix (ECM) modelling and regulation of basement membrane integrity. A chronic disbalance in the expression and activity of these proteinases and their inhibitors in favor of MMPs can lead to excessive degradation of the ECM, dysfunction of the blood-brain barrier (BBB) and subsequent (micro)bleeds. Cerebral amyloid angiopathy (CAA) is characterized by accumulation of the amyloid-β (Aβ) protein in cerebral vessel walls and decreased BBB integrity, and is a major cause of intracerebral hemorrhage and cognitive decline. Currently, diagnosis of CAA is based on neuroimaging, but there is a need for alternative methods as these neuroimaging methods are not optimal for detection of CAA during life at an early stage. Previously, Aβ40 levels in the cerebrospinal fluid (CSF) have been suggested as promising biomarker for CAA. We hypothesize that a disbalance in MMP/TIMP expression is associated with CAA and is reflected in the CSF, and may besides Aβ40, be a potential biomarker candidate for detection of CAA at an early stage. In this study, we aimed to quantify levels of MMPs, TIMPs and Aβ proteins in the CSF to gain more insight in the pathophysiology of CAA and to establish their potential biomarker value for CAA. Method:We used immunoassays to quantify MMP-14, TIMP-1 and Aβ40 levels in CSF in a group of controls (n=40) and CAA patients (n=28). Result:The MMP-14/TIMP-1 ratio was decreased in CAA (0.016 ± 0.005) vs. controls (0.022 ± 0.008; p=0.0007), which was a stronger difference than observed for either MMP-14 (not significant: p=0.53) or TIMP-1 (p=0.0027) alone, or for Aβ40 (p=0.038).The difference of the MMP-14/TIMP-1 ratio was robust and remained after correction for age and total protein levels. Conclusion:Our results suggest that a disbalance in the expression of MMP-14 and TIMP-1 in CSF is associated with CAA, and may be a promising biomarker both to identify CAA, with a higher diagnostic value than CSF Aβ40, as well as to obtain more insight into the pathophysiological processes in CAA.