CSF lipocalin-2 increases early in subarachnoid hemorrhage are associated with neuroinflammation and unfavorable outcome

Abstract

Lipocalin-2 mediates neuro-inflammation and iron homeostasis in vascular injuries of the central nervous system (CNS) and is upregulated in extra-CNS systemic inflammation. We postulate that cerebrospinal fluid (CSF) and blood lipocalin-2 levels are associated with markers of inflammation and functional outcome in subarachnoid hemorrhage (SAH). We prospectively enrolled 67 SAH subjects, serially measured CSF and plasma lipocalin-2, matrix metallopeptidase 9 (MMP-9), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) on post-SAH days 1-5 and assessed outcome by modified Rankin Scale (mRS) every 3 months. Unfavorable outcome is defined as mRS > 2. Twenty non-SAH patients undergoing lumbar drain trial were enrolled as controls. Lipocalin-2 was detectable in the CSF and significantly higher in SAH compared to controls (p < 0.0001). Higher CSF LCN2 throughout post-SAH days 1-5 was associated with unfavorable outcome at 3 (p = 0.0031) and 6 months (p = 0.014). Specifically, higher CSF lipocalin-2 on post-SAH days 3 (p = 0.036) and 5 (p = 0.016) were associated with unfavorable 3-month outcome. CSF lipocalin-2 levels positively correlated with CSF IL-6, TNF-α and MMP-9 levels. Higher plasma lipocalin-2 levels over time were associated with worse 6-month outcome. Additional studies are required to understand the role of lipocalin-2 in SAH and to validate CSF lipocalin-2 as a potential biomarker for SAH outcome.

Keywords: Lipocalin-2; aneurysmal subarachnoid hemorrhage; cerebrospinal fluid; inflammation; long-term neurofunctional outcome.

Figure 1.

CSF lipocalin-2 (LCN2) levels and SAH functional outcomes at 3-month (a) and 6-month (b) and CSF lipocalin-2 levels relative to SAH clinical severity measured by Hunt Hess grade (c) and SAH radiological severity measured by modified Fisher grade (d) (*p < 0.017, ^#p < 0.05, ^#### p < 0.0001). All data are presented as mean ± standard deviation (SD).

Figure 2.

Plasma lipocalin-2 (LCN2) levels and SAH functional outcomes at 3-month (a) and 6-month (b) and plasma lipocalin-2 levels relative to SAH clinical severity measured by Hunt Hess grade (c) and radiographic severity measured by modified Fisher grade (d) (^#p < 0.05, ^### p < 0.001). All data are presented as mean ± standard deviation (SD).

Figure 3.

Associations between CSF lipocalin-2 (LCN2) and IL-6 on post-SAH days 1 (a), 3 (b) and 5 (c) and between CSF LCN2 and TNF-α on post-SAH days 1 (d), 3 (e) and 5 (f).

Figure 4.

Relationships between lipocalin-2 (LCN2) and MMP-9 in CSF (a) and in blood (plasma) (b).