## 2 Mechanisms of Cognitive Dysfunction
### Matrix Metalloproteinase-9  
Matrix metalloproteinases (MMPs) are a family of zinc- and calcium-dependent endoproteinases that mediate degradation and remodeling of the extracellular matrix proteins [56,57]. MMPs are secreted as inactive proenzymes and are activated extracellularly by various mechanisms [58]. The entire process is precisely regulated at the level of gene transcription, activation of the precursor proenzymes and inhibition by their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs) [59]. In the immune system, MMP-9 is secreted by several immunocompetent cell types (granulocytes, lymphocytes and monocytes), with neutrophils being one of the richest cellular sources of MMP-9 [58,60]. There is evidence in human and animal stroke models that activation of MMPs, specifically MMP-9, can degrade components of the basal lamina such as type IV collagen, fibronectin and laminin and contribute to proteolysis of the basal lamina and subsequent disruption of the BBB [61,62]. MMP-9 is inhibited by TIMP-1, a glycoprotein that forms a complex with MMP-9 to inhibit its proteolytic activity [63]. _Ex vivo_ analyses of autopsied human brain tissue showed the following: (i) increased in total MMP-9 (pro-MMP9 and active MMP-9) in the microvessels; (ii) majority of the infiltrated cells surrounding the microvessels being MMP-9\({}^{+}\) neutrophils; and (iii) type IV collagen degradation colocalizing with MMP-9\({}^{+}\) neutrophils within areas of hemorrhagic and non-hemorrhagic infarcted brain tissue [62]. Neutrophil depletion in a rat model of intracerebral hemorrhage demonstrated reduced MMP-9 expression and BBB breakdown [60]. Baseline MMP-9 and MMP-9/TIMP-1 ratio have been shown to be predictive of hyperintense acute reperfusion injury, a neuroimaging marker of BBB disruption in humans, at 24 h [61]. Further, in a cross-sectional study of patients with neuropsychiatric optica and multiple sclerosis, serum MMP-9 levels correlated with Q albumin and the Kurtzke's Expanded Disability Status Scale score [57]. Hence, there is evidence that MMP-9 mediates BBB disruption and it may play a role in the neuroinflammation-memory process of CNS diseases. Recent evidence has implicated MMP-9 in the pathogenesis of a variety of autoimmune diseases [64]. Peripheral blood mononuclear cells (PBMCs) from SLE patients have been shown to express higher levels of MMP-9 mRNA and pro-MMP-9 protein compared to healthy controls [65]. However, data from cross-sectional studies evaluating serum MMP-9 levels in SLE patients has been heterogeneous. Total serum MMP-9 levels were higher in SLE patients in one study, lower in SLE patients in two studies and similar to healthy controls in another study [63,64,66,67]. The activity of serum MMP-9 was higher compared to healthy controls in one study but lower in another [63,68]. These discrepancies could be due to different techniques employed to measure MMP-9 levels and activity or the presence of MMP-9 promoter polymorphisms in SLE patients [67]. In contrast, serum and CSF MMP-9 levels have been consistently shown to be elevated in patients with NPSLE. In a cross-sectional study evaluating SLE patients with _a priori_ defined cognitive dysfunction, serum MMP-9 levels were higher in the following groups: (i) patients with NPSLE manifestations (\(73.2\pm 46.1\) ng/mL) compared to patients without (\(42.8\pm 26.8\) ng/mL); and (ii) patients with cognitive dysfunction (\(80.8\pm 45.8\) ng/mL) compared to those without (\(48.6\pm 34.2\) ng/mL) [64]. Further, serum MMP-9 levels correlated with volumes of T2-weighted lesions on brain MRI in SLE patients [64]. CSF MMP-9 levels were higher in SLE patients with NPSLE (\(240\pm 60\) pg/mL) than in SLE patients without NPSLE (\(100\pm 20\) pg/mL) and healthy controls (\(0.28\pm 0.16\) pg/mL) [69]. CSF MMP-9 levels also correlated with CSF levels of tau andgial fibrillary acid protein, markers of neuronal degeneration and astrocytic degeneration respectively, in SLE patients [69].