Jingfei Shi1,2, Wenlu Li2, Fang Zhang2, Ji Hyun Park2, Hong An1,2, Shuzhen Guo2, Yunxia Duan1, Di Wu1,2, Kazuhide Hayakawa2, Eng H Lo2, Xunming Ji1,3,4. 1. Cerebrovascular and Neuroscience Research Institute (J.S., H.A., Y.D., D.W., X.J.), Capital Medical University, Beijing, China. 2. Neuroprotection Research Laboratories, Departments of Neurology and Radiology, Massachusetts General Hospital, Harvard Medical School, Boston (J.S., W.L., F.Z., J.H.P., H.A., S.G., D.W., K.H., E.H.L.). 3. Departments of Neurosurgery, Xuanwu Hospital (X.J.), Capital Medical University, Beijing, China. 4. Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders (X.J.), Capital Medical University, Beijing, China.
Abstract
Background and Purpose: Inflammatory mediators in blood have been proposed as potential biomarkers in stroke. However, a direct relationship between these circulating factors and brain-specific ischemic injury remains to be fully defined. Methods: An unbiased screen in a nonhuman primate model of stroke was used to find out the most responsive circulating biomarker flowing ischemic stroke. Then this phenomenon was checked in human beings and mice. Finally, we observed the temporospatial responsive characteristics of this biomarker after ischemic brain injury in mice to evaluate the direct relationship between this circulating factor and central nervous system–specific ischemic injury. Results: In a nonhuman primate model, an unbiased screen revealed CCL2 (C-C motif chemokine ligand 2) as a major response factor in plasma after stroke. In mouse models of focal cerebral ischemia, plasma levels of CCL2 showed a transient response, that is, rapidly elevated by 2 to 3 hours postischemia but then renormalized back to baseline levels by 24 hours. However, a different CCL2 temporal profile was observed in whole brain homogenate, cerebrospinal fluid, and isolated brain microvessels, with a progressive increase over 24 hours, demonstrating a mismatch between brain versus plasma responses. In contrast to the lack of correlation with central nervous system responses, 2 peripheral compartments showed transient profiles that matched circulating plasma signatures. CCL2 protein in lymph nodes and adipose tissue was significantly increased at 2 hours and renormalized by 24 hours. Conclusions: These findings may provide a cautionary tale for biomarker pursuits in plasma. Besides a direct central nervous system response, peripheral organs may also contribute to blood signatures in complex and indirect ways.
Background and Purpose: Inflammatory mediators in blood have been proposed as potential biomarkers in stroke. However, a direct relationship between these circulating factors and brain-specific ischemic injury remains to be fully defined. Methods: An unbiased screen in a nonhuman primate model of stroke was used to find out the most responsive circulating biomarker flowing ischemic stroke. Then this phenomenon was checked in human beings and mice. Finally, we observed the temporospatial responsive characteristics of this biomarker after ischemic brain injury in mice to evaluate the direct relationship between this circulating factor and central nervous system–specific ischemic injury. Results: In a nonhuman primate model, an unbiased screen revealed CCL2 (C-C motif chemokine ligand 2) as a major response factor in plasma after stroke. In mouse models of focal cerebral ischemia, plasma levels of CCL2 showed a transient response, that is, rapidly elevated by 2 to 3 hours postischemia but then renormalized back to baseline levels by 24 hours. However, a different CCL2 temporal profile was observed in whole brain homogenate, cerebrospinal fluid, and isolated brain microvessels, with a progressive increase over 24 hours, demonstrating a mismatch between brain versus plasma responses. In contrast to the lack of correlation with central nervous system responses, 2 peripheral compartments showed transient profiles that matched circulating plasma signatures. CCL2 protein in lymph nodes and adipose tissue was significantly increased at 2 hours and renormalized by 24 hours. Conclusions: These findings may provide a cautionary tale for biomarker pursuits in plasma. Besides a direct central nervous system response, peripheral organs may also contribute to blood signatures in complex and indirect ways.
Entities:
Keywords:
adipose tissue; biomarker; brain; central nervous system; ischemic stroke
Authors: Seyoung Lee; Hannah X Chu; Hyun Ah Kim; Nicola C Real; Saeed Sharif; Stephen B Fleming; Andrew A Mercer; Lyn M Wise; Grant R Drummond; Christopher G Sobey Journal: Stroke Date: 2014-12-23 Impact factor: 7.914
Authors: Xian Shuang Liu; Zheng Gang Zhang; Rui Lan Zhang; Sara R Gregg; Lei Wang; Toh Yier; Michael Chopp Journal: J Neurosci Res Date: 2007-08-01 Impact factor: 4.164