Low cerebral blood flow is a non-invasive biomarker of neuroinflammation after repetitive mild traumatic brain injury

• Type of Material: Article
• Authors: Sitara B. Sankar, Georgia Institute of Technology; Alyssa F. Pybus, Georgia Institute of Technology; Amanda Liew, Georgia Institute of Technology; Bharat Sanders, Georgia Institute of Technology; Kajol J. Shah, Georgia Institute of Technology; Levi B. Wood, Georgia Institute of Technology; Erin Buckley, Emory University
• Language: English
• Date: 2019-04-01
• Publisher: Elsevier Science Inc.
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.nbd.2018.12.018
• Title of Journal or Parent Work: Neurobiology of Disease
• Volume: 124
• Start Page: 544
• End Page: 554
• Grant/Funding Information: This work was supported by the National Institutes of Health [grant number R21NS104801] and start-up funds from the Woodruff School of Mechanical Engineering at Georgia Tech and from the Coulter Department of Biomedical Engineering at Georgia Tech and Emory.
• Keywords: Diffuse correlation spectroscopy; Science & Technology; Neurosciences; Players; Expression; Recovery; Neurosciences & Neurology; Cytokines; In-vitro; Kinase signaling; Cerebral blood flow; Life Sciences & Biomedicine; VEGF; Microglia; Activation; Mild traumatic brain injury; Pathways; Neuroinflammation
• Research Categories: Biology, Neuroscience; Health Sciences, Rehabilitation and Therapy; Engineering, Biomedical; Health Sciences, Medicine and Surgery

Abstract

Previous work has shown that non-invasive optical measurement of low cerebral blood flow (CBF) is an acute biomarker of poor long-term cognitive outcome after repetitive mild traumatic brain injury (rmTBI). Herein, we explore the relationship between acute cerebral blood flow and underlying neuroinflammation. Specifically, because neuroinflammation is a driver of secondary injury after TBI, we hypothesized that both glial activation and inflammatory signaling are associated with acute CBF and, by extension, with long-term cognitive outcome after rmTBI. To test this hypothesis, cortical CBF was non-invasively measured in anesthetized mice 4 h after 3 repetitive closed head injuries spaced once-daily, at which time brains were collected. Right hemispheres were fixed for immunohistochemical staining for glial activation markers Iba1 and GFAP while left hemispheres were used to quantify Iba1 and GFAP expression via Western blot as well as 32 cytokines and 21 phospho-proteins in the MAPK, PI3K/Akt, and NF-κB pathways using a Luminex multiplexed immunoassay. N = 8/7 injured/sham C57/black-6 adult male mice were studied. Within the injured group, CBF inversely correlated with Iba1 expression (R = −0.86, p <.01). Further, partial least squares regression analysis revealed significant correlations between CBF and expression of multiple pro-inflammatory cytokines, including RANTES and IL-17. Finally, within the injured group, phosphorylation of specific signals in the MAPK and NF-κB intracellular signaling pathways (e.g., p38 MAPK and NF-κB) were significantly positively correlated with Iba1. In total, our data indicate that acute cerebral blood flow after rmTBI is a biomarker of underlying neuroinflammatory pathology.