Relationship between elevated cerebrospinal fluid levels of plasminogen activator inhibitor 1 and neuronal destruction in patients with neuropsychiatric systemic lupus erythematosus

Abstract

Objective. A homeostatic imbalance between coagulation and fibrinolysis might occur intrathecally in neuropsychiatric systemic lupus erythematosus (NPSLE). However, there are no published data on levels of fibrinolytic factors in the cerebrospinal fluid (CSF) of patients with NPSLE. The present study was undertaken to assess CSF levels of fibrinolytic molecules, including urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), D-dimer, and plasminogen activator inhibitor 1 (PAI-1), in SLE patients with clinically verified neuropsychiatric involvement and to compare these levels with those in SLE patients without neuropsychiatric involvement and in healthy subjects.Methods. Levels of uPA, tPA, and PAI-1 were assessed in CSF from 94 patients with SLE (33 who had NPSLE, 56 who did not have NPSLE, and 5 who were positive for antiphospholipid antibody [not included in the NPSLE or non-NPSLE group]) and from 53 agematched controls. Patients were evaluated clinically, with magnetic resonance imaging of the brain, analyses of neuronal/glial degradation products in CSF, and neuropsychiatric testing.Results. In the group of patients with NPSLE, intrathecal PAI-1 levels were significantly elevated compared with levels in SLE patients without overt neuropsychiatric involvement (P < 0.05) and in healthy controls (P < 0.001). In contrast, intrathecal levels of uPA did not differ significantly. Intrathecal levels of PAI-1 correlated significantly with CSF levels of interleukin-6 (IL-6) (r ‫؍‬ 0.34, P < 0.001) and IL-8 (r ‫؍‬ 0.33, P < 0.001). Importantly, increased PAI-1 and D-dimer levels were observed in SLE patients who had pathologically elevated levels of glial fibrillary acidic protein, neurofilament triplet protein, and tau protein in CSF.Conclusion. Intrathecal release of PAI-1 is increased in patients with NPSLE. This results in impaired fibrinolysis, which might contribute to neuronal and astrocytic damage in NPSLE.

Neuropsychiatric Systemic Lupus Erythematosus

“…Furthermore, CSF levels of IL-6 and IL-8, which are found to be elevated in NPSLE, are both significantly correlated with MMP-9 levels. Similarly, intrathecal levels of PAI-1 have been found to be significantly elevated in patients with NPSLE comparing to those without NPSLE and healthy controls [69]. The intrathecal levels of PAI-1 also correlated with CSF levels of proinflammatory cytokines, IL-6 and IL-8, in addition to association with neuronal damage markers, glial fibrillary acidic protein and neurofilament triplet protein.…”

Cognitive Dysfunction in Systemic Lupus Erythematosus: A Case for Initiating Trials

“…Among the multiple other cytokines associated with NPSLE, IL‐6 and IL‐8 have the most plausible association with neuronal damage, given their presence in CSF in association with proteins that are indicative of neuronal and astrocytic damage . Other inflammatory mediators, such as TWEAK , CCL2 , myelin‐associated neurite outgrowth inhibitor , matrix metalloproteinase 9 , lipocalin 2 , anti–α‐internexin , and the renin–angiotensin system , are also associated with CD in SLE.…”

Pathogenesis of neurocognitive and neuropsychiatric manifestations in childhood-onset lupus: an overview

“…111,112 Raised intra-thecal Plasminogen activator inhibitor (PAI-1) levels in NPSLE correlate with increased CSF levels of pro-inflammatory cytokines and markers of neuronal damage. 113 The metalloproteinase, MMP-9, is known to play a key role in disruption of the BBB, with elevated levels seen in the serum and CSF. 114,115 Neuropeptides such as oxytocin, vasopressin, corticotropin-releasing factor, neuropeptide Y, substance P and calcitonin gene-related peptide have also been linked, with decreased levels of the latter three in the hippocampus found in a few studies in lupusprone mice, 116 and elevated serum levels of neuropeptide Y levels in SLE patients, irrespective of steroid treatment, in another study.…”