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. 2021 Oct;41(10):2524-2533.
doi: 10.1177/0271678X211012110. Epub 2021 May 5.

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

Fang Yu  1   2 , Aisha Saand  2 , Changhong Xing  3   4 , Jong Woo Lee  5 , Liangge Hsu  6 , Octavia P Palmer  2   7 , Vanessa Jackson  2 , Lu Tang  8 , MingMing Ning  9 , Rose Du  10 , Patrick M Kochanek  11 , Eng H Lo  4 , Sherry H-Y Chou  1   2   4   5   12
Affiliations

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

Fang Yu et al. J Cereb Blood Flow Metab. 2021 Oct.

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.

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Conflict of interest statement

Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Chou, S, Ning, M, and Lo, EH are co-inventors on MITOCHONDRIAL BIOMARKERS OF, AND THERAPEUTICS AQ15 FOR, CNS INJURY AND DISEASE filed in the United States Patent and Trademark Office as Application 62/3817.

Figures

Figure 1.
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.
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.
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.
Figure 4.
Relationships between lipocalin-2 (LCN2) and MMP-9 in CSF (a) and in blood (plasma) (b).
See this image and copyright information in PMC

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