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Lipids, Lipoproteins, and Cardiovascular Risk Factors |
Department of Pathology and Immunology, Division of Laboratory Medicine, Washington University School of Medicine, St. Louis, MO.
aAddress correspondence to this author at: Department of Pathology and Immunology, Division of Laboratory Medicine, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8118, St. Louis, MO 63110. Fax 314-454-5208; e-mail ladenson{at}labmed.wustl.edu.
Background: The diagnosis of diseases leading to brain injury, such as stroke, Alzheimer disease, and Parkinson disease, can often be problematic. In this study, we pursued the discovery of biomarkers that might be specific and sensitive to brain injury.
Methods: We performed gene array analyses on a mouse model to look for biomarkers that are both preferentially and abundantly produced in the brain. Via bioinformatics databases, we identified the human homologs of genes that appeared abundant in brain but not in other tissues. We then confirmed protein production of the genes via Western blot of various tissue homogenates and assayed for one of the markers, visinin-like protein 1 (VLP-1), in plasma from patients after ischemic stroke.
Results: Twenty-nine genes that were preferentially and abundantly expressed in the mouse brain were identified; of these 29 genes, 26 had human homologs. We focused on 17 of these genes and their protein products on the basis of their molecular characteristics, novelty, and/or availability of antibodies. Western blot showed strong signals in brain homogenates for 13 of these proteins. Tissue specificity was tested by Western blot on a human tissue array, and a sensitive and quantitative sandwich immunoassay was developed for the most abundant gene product observed in our search, VLP-1. VLP-1 was detected in plasma of patients after stroke and in cerebrospinal fluid of a rat model of stroke.
Conclusions: The use of relative mRNA production appears to be a valid method of identifying possible biomarkers of tissue injury. The tissue specificity suggested by gene expression was confirmed by Western blot. One of the biomarkers identified, VLP-1, was increased in a rat model of stroke and in plasma of patients after stroke. More extensive, prospective studies of the candidate biomarkers identified appear warranted.
The following articles in journals at HighWire Press have cited this article:
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  O. F. Laterza, L. Lim, P. W. Garrett-Engele, K. Vlasakova, N. Muniappa, W. K. Tanaka, J. M. Johnson, J. F. Sina, T. L. Fare, F. D. Sistare, et al. Plasma MicroRNAs as Sensitive and Specific Biomarkers of Tissue Injury Clin. Chem., November 1, 2009; 55(11): 1977 - 1983. [Abstract] [Full Text] [PDF]
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 C. Foerch, J. Montaner, K. L. Furie, M. M. Ning, and E. H. Lo Invited Article: Searching for oracles?: Blood biomarkers in acute stroke Neurology, August 4, 2009; 73(5): 393 - 399. [Abstract] [Full Text] [PDF]
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 E. S. Weiss, K. K.W. Wang, J. G. Allen, M. E. Blue, L. U. Nwakanma, M. C. Liu, M. S. Lange, J. Berrong, M. A. Wilson, V. L. Gott, et al. Alpha II-Spectrin Breakdown Products Serve as Novel Markers of Brain Injury Severity in a Canine Model of Hypothermic Circulatory Arrest Ann. Thorac. Surg., August 1, 2009; 88(2): 543 - 550. [Abstract] [Full Text] [PDF]
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H.-G. Bernstein and K.-H. Braunewell Some Notes on Visinin-Like Protein 1 and Alzheimer Disease Clin. Chem., May 1, 2009; 55(5): 1041 - 1043. [Full Text] [PDF]
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M. M. Verbeek and M. G.M. Olde Rikkert Cerebrospinal Fluid Biomarkers in the Evaluation of Alzheimer Disease Clin. Chem., October 1, 2008; 54(10): 1589 - 1591. [Full Text] [PDF]
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J.-M. Lee, K. Blennow, N. Andreasen, O. Laterza, V. Modur, J. Olander, F. Gao, M. Ohlendorf, and J. H. Ladenson The Brain Injury Biomarker VLP-1 Is Increased in the Cerebrospinal Fluid of Alzheimer Disease Patients Clin. Chem., October 1, 2008; 54(10): 1617 - 1623. [Abstract] [Full Text] [PDF]
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 W. Whiteley, M.-C. Tseng, and P. Sandercock Blood Biomarkers in the Diagnosis of Ischemic Stroke: A Systematic Review Stroke, October 1, 2008; 39(10): 2902 - 2909. [Abstract] [Full Text] [PDF]
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K. Jeyaseelan, K. Y. Lim, and A. Armugam MicroRNA Expression in the Blood and Brain of Rats Subjected to Transient Focal Ischemia by Middle Cerebral Artery Occlusion Stroke, March 1, 2008; 39(3): 959 - 966. [Abstract] [Full Text] [PDF]
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N. Rifai and R. E. Gerszten Biomarker Discovery and Validation Clin. Chem., September 1, 2006; 52(9): 1635 - 1637. [Full Text] [PDF]
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