Several clinical trials have failed to demonstrate a significant effect on outcome following human traumatic brain injury (TBI) despite promising results obtained in preclinical animal studies. These failures may be due in part to a misinterpretation of the findings obtained in preclinical animal models of TBI, a misunderstanding of the complexity of the human response to TBI, limited knowledge about the biological pathways that interact to contribute to good and bad outcomes after brain injury, and the effects of genomic variability and environment on individual recovery. Recent publications suggest that data obtained from gene expression profiling studies of complex neurological diseases such as stroke, multiple sclerosis (MS), Alzheimer’s and Parkinson’s may contribute to a more informed understanding of what affects outcome following TBI. These data may help to bridge the gap between successful preclinical studies and negative clinical trials in humans to reveal novel targets for therapy. Gene expression profiling has the capability to identify biomarkers associated with response to TBI, elucidate complex genetic interactions that may play a role in outcome following TBI, and reveal biological pathways related to brain health. This review highlights the current state of the literature on gene expression profiling for neurological disease and discusses its ability to aid in unraveling the variable human response to TBI and the potential for it to offer treatment strategies in an area where we currently have limited therapeutic options primarily based on supportive care.
Achiron, A., Feldman, A., Mandel, M., & Gurevich, M. ( 2007). Impaired expression of peripheral blood apoptotic-related gene transcripts in acute multiple sclerosis relapse. Annals of the New York Academy of Sciences, 1107, 155-167.
2.
Achiron, A., & Gurevich, M. ( 2006). Peripheral blood gene expression signature mirrors central nervous system disease: The model of multiple sclerosis. Autoimmunity Reviews, 5, 517-522.
3.
Achiron, A., Gurevich, M., Friedman, N., Kaminski, N., & Mandel, M. ( 2004). Blood transcriptional signatures of multiple sclerosis: Unique gene expression of disease activity. Annals of Neurology , 55, 410-417.
4.
Andersson, A., Ritz, C., Lindgren, D., Eden, P., Lassen, C., Heldrup, J., ... Fioretos, T. ( 2007). Microarray-based classification of a consecutive series of 121 childhood acute leukemias: Prediction of leukemic and genetic subtype as well as of minimal residual disease status. Leukemia, 21, 1198-1203.
5.
Arthur, A.T., Armati, P.J., Bye, C., Heard, R.N., Stewart, G.J., Pollard, J.D., ... Booth, D.R. ( 2008). Genes implicated in multiple sclerosis pathogenesis from consilience of genotyping and expression profiles in relapse and remission . BMC Medical Genetics, 9, 17.
6.
Baird, A.E. ( 2006). The blood option: Transcriptional profiling in clinical trials. Pharmacogenomics, 7, 141-144.
7.
Baker, J. ( 2007). Genomic Health, Inc. Pharmacogenomics , 8, 397-399.
8.
Barnes, M., Freudenberg, J., Thompson, S., Aronow, B., & Pavlidis, P. ( 2005). Experimental comparison and cross-validation of the Affymetrix and Illumina gene expression analysis platforms. Nucleic Acids Research, 33, 5914-5923.
9.
Basso, G., Case, C., & Dell’Orto, M. (2007). Diagnosis and genetic subtypes of leukemia combining gene expression and flow cytometry. Blood Cells, Molecules, and Diseases, 39, 164-168.
10.
Becker, K.G., Mattson, D.H., Powers, J.M., Gado, A.M., & Biddison, W.E. (1997). Analysis of a sequenced cDNA library from multiple sclerosis lesions. Journal of Neuroimmunology , 77, 27-38.
11.
Bomprezzi, R., Ringner, M., Kim, S., Bittner, M.L., Khan, J., Chen, Y., ... Trent, J.M. ( 2003). Gene expression profile in multiple sclerosis patients and healthy controls: Identifying pathways relevant to disease. Human Molecular Genetics, 12, 2191-2199.
12.
Cardoso, F., Van’t-Verr, L., Rutgers, E., Loi, S., Mook, S., & Piccart-Gebhart, M. (2008). Clinical application of the 70-gene profile: The MINDACT trial. Journal of Clinical Oncology, 26, 729-735.
13.
Chabas, D., Baranzini, S.E., Mitchell, D., Bernard, C.C., Rittling, S.R., Denhardt, D.T., ... Steinman, L. ( 2001). The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science, 294, 1731-1735.
14.
Chacon, M.R., Jensen, M.B., Sattin, J.A., & Zivin, J.A. ( 2008). Neuroprotection in cerebral ischemia: Emphasis on the SAINT trial. Current Cardiology Reports, 10, 37-42.
15.
Colangelo, V., Schurr, J., Ball, M.J., Pelaez, R.P., Bazan, N.G., & Lukiw, W.J. ( 2002). Gene expression profiling of 12633 genes in Alzheimer hippocampal CA1: Transcription and neurotrophic factor down-regulation and up-regulation of apoptotic and proinflammatory signaling. Journal of Neuroscience Research, 70, 462-473.
16.
De Benedittis, G., & De Santis, A. ( 1983). Chronic post-traumatic headache: Clinical, psychopathological features and outcome determinants. Journal of Neurosurgical Science, 27, 177-186.
17.
DeRisi, J., Penland, L., Brown, P.O., Bittner, M.L., Meltzer, P.S., Ray, M., ... Trent, J.M. ( 1996). Use of a cDNA microarray to analyse gene expression patterns in human cancer. Nature Genetics, 14, 457-460.
18.
Doppenberg, E.M., Choi, S.C., & Bullock, R. ( 2004). Clinical trials in traumatic brain injury: Lessons for the future. Journal of Neurosurgical Anesthesiology, 16, 87-94.
19.
Expression Analysis. (2007, October). Expression profiling of whole blood specimens on Illumina BeadChips (Technical note). Retrieved from http://www.expressionanalysis.com/images/uploads/tech_notes/Illumina_Blood_TechNote.pdf
20.
Fann, J.R., Katon, W.J., Uomoto, J.M., & Esselman, P.C. (1995). Psychiatric disorders and functional disability in outpatients with traumatic brain injuries. American Journal of Psychiatry, 152, 1493-1499.
21.
Ginsberg, S.D., Hemby, S.E., Lee, V.M., Eberwine, J.H., & Trojanowski, J.Q. (2000). Expression profile of transcripts in Alzheimer’s disease tangle-bearing CA1 neurons. Annals of Neurology, 48, 77-87.
22.
Goertsches, R., & Zettl, U.K. ( 2007). MS therapy research applying genome-wide RNA profiling of peripheral blood. International MS Journal, 14, 98-107.
23.
Grond-Ginsbach, C., Hummel, M., Wiest, T., Horstmann, S., Pfleger, K., Hergenhahn, M., ... Wagner, S. ( 2008). Gene expression in human peripheral blood mononuclear cells upon acute ischemic stroke. Journal of Neurology, 255, 723-731.
24.
Grunblatt, E., Mandel, S., Jacob-Hirsch, J., Zeligson, S., Amariglo, N., Rechavi, G., ... Youdim, M.B.H. ( 2004). Gene expression profiling of parkinsonian substantia nigra pars compacta; alterations in ubiquitin-proteasome, heat shock protein, iron and oxidative stress regulated proteins, cell adhesion/cellular matrix and vesicle trafficking genes. Journal of Neural Transmission , 111, 1543-1573.
25.
Grunblatt, E., Mandel, S., Maor, G., & Youdim, M.B. ( 2001). Gene expression analysis in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mice model of Parkinson’s disease using cDNA microarray: Effect of R-apomorphine . Journal of Neurochemistry, 78, 1-12.
26.
Guo, L., Lobenhofer, E.K., Wang, C., Shippy, R., Harris, S.C., Zhang, L., ... Shi, L. ( 2006). Rat toxicogenomic study reveals analytical consistency across microarray platforms. Nature Biotechnology, 24, 1162-1169.
27.
Guttmacher, A.E., & Collins, F.S. ( 2002). Genomic medicine-a primer. New England Journal of Medicine, 347, 1512-1520.
28.
Hacia, J.G., Brody, L.C., Chee, M.S., Fodor, S.P., & Collins, F.S. ( 1996). Detection of heterozygous mutations in BRCA1 using high density oligonucleotide arrays and two-colour fluorescence analysis. Nature Genetics, 14, 441-447.
29.
Hauser, M.A., Li, Y.J., Xu, H., Noureddine, M.A., Shao, Y.S., Gullans, S.R., ... Vance, J.M. ( 2005). Expression profiling of substantia nigra in Parkinson disease, progressive supranuclear palsy, and frontotemporal dementia with parkinsonism. Archives of Neurology, 62, 917-921.
Hong, J., Zang, Y.C., Hutton, G., Rivera, V.M., & Zhang, J.Z. ( 2004). Gene expression profiling of relevant biomarkers for treatment evaluation in multiple sclerosis. Journal of Neuroimmunology , 152, 126-139.
32.
Iglesias, A.H., Camelo, S., Hwang, D., Villanueva, R., Stephanopoulos, G., & Dangond, F. ( 2004). Microarray detection of E2F pathway activation and other targets in multiple sclerosis peripheral blood mononuclear cells. Journal of Neuroimmunology, 150, 163-177.
33.
Jerne, N.K. ( 1985). The generative grammar of the immune system. Embo Journal, 4, 847-852.
34.
Kalman, J., Kitajka, K., Pakaski, M., Zvara, A., Juhasz, A., Vincze, G., ... Puskas, L.G. ( 2005). Gene expression profile analysis of lymphocytes from Alzheimer’s patients. Psychiatric Genetics, 15, 1-6.
35.
Kochanek, P.M., & Hallenbeck, J.M. (1992). Polymorphonuclear leukocytes and monocytes/macrophages in the pathogenesis of cerebral ischemia and stroke . Stroke, 23, 1367-1379.
36.
Koike, F., Satoh, J., Miyake, S., Yamamoto, T., Kawai, M., Kikuchi, S., ... Yamamura, T. ( 2003). Microarray analysis identifies interferon beta-regulated genes in multiple sclerosis. Journal of Neuroimmunology, 139, 109-118.
37.
Kukacka, J., Vajtr, D., Huska, D., Prusa, R., Houstava, L., Samal, F., ... Kizek, R. ( 2006). Blood metallothionein, neuron specific enolase, and protein S100B in patients with traumatic brain injury. Neuroendocrinology Letters, 27, 116-120.
38.
Langlois, J.A., Rutland-Brown, W., & Thomas, K.E. ( 2006). Traumatic brain injury in the United States: Emergency department visits, hospitalizations, and deaths. Atlanta, GA: Centers for Disease Control and Prevention, National Center for Injury Prevention and Control. Retrieved from http://www.cdc.gov/ncipc/pub-res/TBI_in_US_04/TBI_ED.htm
39.
Li, H.H., Lee, S.M., Cai, Y., Sutton, R.L., & Hovda, D.A. ( 2004). Differential gene expression in hippocampus following experimental brain trauma reveals distinct features of moderate and severe injuries. Journal of Neurotrauma, 21, 1141-1153.
40.
Lindberg, R.L., & Kappos, L. ( 2006). Transcriptional profiling of multiple sclerosis: Towards improved diagnosis and treatment. Expert Review of Molecular Diagnostics, 6, 843-855.
41.
Lipshutz, R.J., Fodor, S.P., Gingeras, T.R., & Lockhart, D.J. (1999). High density synthetic oligonucleotide arrays. Nature Genetics, 21, 20-24.
42.
Loring, J.F., Wen, X., Lee, J.M., Seilhamer, J., & Somogyi, R. ( 2001). A gene expression profile of Alzheimer’s disease . DNA Cell Biology, 20, 683-695.
43.
Lu, A., Tang, Y., Ran, R., Clark, J.F., Aronow, B.J., & Sharp, F.R. ( 2003). Genomics of the periinfarction cortex after focal cerebral ischemia. Journal of Cerebral Blood Flow and Metabolism, 23, 786-810.
44.
Maas, A.I., Marmarou, A., Murray, G.D., Teasdale, S.G., & Steyerberg, E.W. (2007). Prognosis and clinical trial design in traumatic brain injury: The IMPACT study. Journal of Neurotrauma, 24, 232-238.
45.
Maes, O.C., Xu, S., Yu, B., Chertkow, H.M., Wang, E., & Schipper, H.M. (2007). Transcriptional profiling of Alzheimer blood mononuclear cells by microarray. Neurobiology of Aging, 28, 1795-1809.
46.
Maouche, S., Poirier, O., Godefroy, T., Olaso, R., Gut, I., Collet, J.P., ... Cambien, F. ( 2008). Performance comparison of two microarray platforms to assess differential gene expression in human monocyte and macrophage cells . BMC Genomics, 9, 302.
47.
Marciano, P.G., Eberwine, J.H., Ragupathi, R., Saatman, K.E., Meaney, D.F., & McIntosh, T.K. (2002). Expression profiling following traumatic brain injury: A review. Neurochemical Research, 27, 1147-1155.
48.
Michael, D.B., Byers, D.M., & Irwin, L.N. ( 2005). Gene expression following traumatic brain injury in humans: Analysis by microarray. Journal of Clinical Neuroscience, 12, 284-290.
49.
Microarray platform comparisons-Commentary on Barnes et al. (2005) (White paper). (2006). Retrieved from the Affymetrix web-site at http://www.affymetrix.com/support/technical/whitepapers.affx
50.
Miller, R.M., Callahan, L.M., Casaceli, C., Chen, L., Kiser, G.L., Chui, B., ... Federoff, H.J. ( 2004). Dysregulation of gene expression in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse substantia nigra. Journal of Neuroscience, 24, 7445-7454.
Miller, R.M., & Federoff, H.J. (2006). Microarrays in Parkinson’s disease: A systematic approach. NeuroRx, 3, 319-326.
53.
Miller, R.M., Kiser, G.L., Kaysser-Kranich, T.M., Lockner, R.J., Palaniappan, C., & Federoff, H.J. (2006). Robust dysregulation of gene expression in substantia nigra and striatum in Parkinson’s disease . Neurobiology of Disease, 21, 305-313.
54.
Moore, D.F., Li, H., Jeffries, N., Wright, V., Cooper, R.A. Jr., Elkahloun, A., ... Baird, A.E. ( 2005). Using peripheral blood mononuclear cells to determine a gene expression profile of acute ischemic stroke: A pilot investigation . Circulation, 111, 212-221.
55.
Natale, J.E., Knight, J.B., Cheng, Y., Rome, J.E., & Gallo, V. ( 2004). Metallothionein I and II mitigate age-dependent secondary brain injury. Journal of Neuroscience Research, 78, 303-314.
56.
Neuberger, M.S. ( 2008). Antibody diversification by somatic mutation: From Burnet onwards. Immunology and Cell Biology, 86, 124-132.
57.
Paintlia, A.S., Paintlia, M.K., Singh, A.K., Stanislaus, R., Gilg, A.G., Barbosa, E., ... Singh, I. ( 2004). Regulation of gene expression associated with acute experimental autoimmune encephalomyelitis by Lovastatin. Journal of Neuroscience Research, 77, 63-81.
58.
Patterson, T.A., Lobenhofer, E.K., Fulmer-Smentek, S.B., Collins, P.J., Chu, T.M., Bao, W., ... Wolfinger, R.D. ( 2006). Performance comparison of one-color and two-color platforms within the MicroArray Quality Control (MAQC) project. Nature Biotechnology, 24, 1140-1150.
59.
Poulsen, C.B., Penkowa, M., Borup, R., Nielsen, F.C., Caceres, M., Quintana, A., ... Hidalgo, J. ( 2005). Brain response to traumatic brain injury in wild-type and interleukin-6 knockout mice: A microarray analysis. Journal of Neurochemistry, 92, 417-432.
60.
Ramanathan, M., Weinstock-Guttman, B., Nguyen, L.T., Badgett, D., Miller, C., Patrick, K., ... Jacobs, L. ( 2001). In vivo gene expression revealed by cDNA arrays: The pattern in relapsing-remitting multiple sclerosis patients compared with normal subjects. Journal of Neuroimmunology, 116, 213-219.
61.
Ritenour, A.E., & Baskin, T.W. ( 2008). Primary blast injury: Update on diagnosis and treatment . Critical Care Medicine, 36, S311-S317.
62.
Saatman, K.E., Duhaime, A.C., Bullock, R., Maas, A.I., Valadka, A., & Manley, G.T. ( 2008). Classification of traumatic brain injury for targeted therapies. Journal of Neurotrauma, 25, 719-738.
63.
Satoh, J., Nakanishi, M., Koike, F., Onoue, H., Aranami, T., Yamamoto, T., ... Yamamura, T. ( 2006). T cell gene expression profiling identifies distinct subgroups of Japanese multiple sclerosis patients. Journal of Neuroimmunology, 174, 108-118.
64.
Schena, M., Shalon, D., Davis, R.W., & Brown, P.O. ( 1995). Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science, 270, 467-470.
65.
Schena, M., Shalon, D., Heller, R., Chai, A., Brown, P.O., & Davis, R.W. ( 1996). Parallel human genome analysis: Microarray-based expression monitoring of 1000 genes. Proceedings of the National Academy of Sciences of the USA, 93, 10614-10619.
66.
Scherzer, C.R., Eklund, A.C., Morse, L.J., Liao, Z., Locascio, J.J., Fefer, D., ... Gullans, S.R. ( 2007). Molecular markers of early Parkinson’s disease based on gene expression in blood. Proceedings of the National Academy of Sciences of the USA, 104, 955-960.
67.
Sharp, F.R., Lit, L., Xu, H., Apperson, M., Walker, W., Wong, B., ... Glauser, T.A. ( 2006). Genomics of brain and blood: Progress and pitfalls. Epilepsia, 47, 1603-1607.
68.
Sharp, F.R., Xu, H., Lit, L., Walker, W., Apperson, M., Gilbert, D.L., ... Ran, R. ( 2006). The future of genomic profiling of neurological diseases using blood. Archives of Neurology, 63, 1529-1536.
69.
Sharp, F.R., Xu, H., Lit, L., Walker, W., Pinter, J., Apperson, M., ... Vero, P. ( 2007). Genomic profiles of stroke in blood. Stroke, 38, 691-693.
70.
Shi, L., Reid, L.H., Jones, W.D., Shippy, R., Warrington, J.A., Baker, S.C., ... Slikker, W. Jr. (2006). The MicroArray Quality Control (MAQC) project shows inter- and intraplatform reproducibility of gene expression measurements. Nature Biotechnology, 24, 1151-1161.
71.
Sturzebecher, S., Wandinger, K.P., Rosenwald, A., Sathyamoorthy, M., Tzou, A., Mattar, P., ... McFarland, H.F. ( 2003). Expression profiling identifies responder and non-responder phenotypes to interferon-beta in multiple sclerosis. Brain , 126, 1419-1429.
72.
Sundstrom, A., Nilsson, L.G., Cruts, M., Adolfsson, R., Van Broeckhoven, C., & Nyberg, L. ( 2007). Fatigue before and after mild traumatic brain injury: Pre-post-injury comparisons in relation to apolipoprotein E. Brain Injury, 21, 1049-1054.
73.
Tajouri, L., Fernandez, F., & Griffiths, L.R. (2007). Gene expression studies in multiple sclerosis. Current Genomics, 8, 181-189.
74.
Tang, Y., Gilbert, D.L., Glauser, T.A., Hershey, A.D., & Sharp, F.R. ( 2005). Blood gene expression profiling of neurologic diseases: A pilot microarray study. Archives of Neurology, 62, 210-215.
75.
Tang, Y., Lu, A., Aronow, B.J., & Sharp, F.R. ( 2001). Blood genomic responses differ after stroke, seizures, hypoglycemia, and hypoxia: Blood genomic fingerprints of disease. Annals of Neurology, 50, 699-707.
76.
Tang, Y., Lu, A., Aronow, B.J., Wagner, K.R., & Sharp, F.R. ( 2002). Genomic responses of the brain to ischemic stroke, intracerebral haemorrhage, kainate seizures, hypoglycemia, and hypoxia. European Journal of Neuroscience, 15, 1937-1952.
77.
Tang, Y., Lu, A., Ran, R., Aronow, B.J., Schorry, E.K., Hopkin, R.J., ... Sharp, F.R. ( 2004). Human blood genomics: Distinct profiles for gender, age and neurofibromatosis type 1. Brain Research. Molecular Brain Research, 132, 155-167.
78.
Tang, Y., Nee, A.C., Lu, A., Ran, R., & Sharp, F.R. ( 2003). Blood genomic expression profile for neuronal injury . Journal of Cerebral Blood Flow Metabolism, 23, 310-319.
79.
Tang, Y., Schapiro, M.B., Franz, D.N., Patterson, B.J., Hickey, F.J., Schorry, E.K., ... Sharp, F.R. ( 2004). Blood expression profiles for tuberous sclerosis complex 2, neurofibromatosis type 1, and Down’s syndrome. Annals of Neurology, 56, 808-814.
80.
Tang, Y., Xu, H., Du, X., Lit, L., Walker, W., Lu, A., ... Sharp, F.R. ( 2006). Gene expression in blood changes rapidly in neutrophils and monocytes after ischemic stroke in humans: A microarray study. Journal of Cerebral Blood Flow Metabolism, 26, 1089-1102.
81.
von Gertten, C., Flores Morales, A., Holmin, S., Mathiesen, T., & Nordqvist, A.C. (2005). Genomic responses in rat cerebral cortex after traumatic brain injury. BMC Neuroscience , 6, 69.
82.
Whitney, L.W., Becker, K.G., Tresser, N.J., Caballero-Ramos, C.I., Munson, P.J., Prabhu, V.V., ... Biddison, W.E. ( 1999). Analysis of gene expression in mutiple sclerosis lesions using cDNA microarrays. Annals of Neurology, 46, 425-428.
83.
Whitney, L.W., Ludwin, S.K., McFarland, H.F., & Biddison, W.E. (2001). Microarray analysis of gene expression in multiple sclerosis and EAE identifies 5-lipoxygenase as a component of inflammatory lesions. Journal of Neuroimmunology , 121, 40-48.
84.
Woo, Y., Affourtit, J., Daigle, S., Viale, A., Johnson, K., Naggert, J., ... Churchill, G. ( 2004). A comparison of cDNA, oligonucleotide, and Affymetrix GeneChip gene expression microarray platforms. Journal of Biomolecular Techniques, 15, 276-284.
85.
Zhou, Y.W., Zhang, Y.G., & Deng, W.N. ( 2002). A primary study on the ARP-SRP gene expression profiling of brain injury by cDNA microarray (in Chinese). Fa Yi Xue Za Zhi, 18, 146-149.
