The blood-brain barrier (BBB) shields the brain from systemic influences, and actively participates to the control of central nervous system homeostasis. Loss of BBB function is common in a variety of neurological disorders. Depending on the neurological condition involved and given the fact that the BBB also prevents entry of useful chemotherapeutic agents, BBB openings may be both advantageous and damaging. The exact time course of BBB failure, and its etiological contribution to disease progression is poorly understood mainly because reliable peripheral markers are not available and since golden radiologic standards of BBB are yet to be determined. The discovery of imaging strategies or surrogate markers of BBB function were identified a top priority for this Program announcement. Our preliminary results suggest that peripheral measurements of specific brain or CSF proteins (e.g. S100P) are reproducible, less invasive and less costly alternative to contrast CT/MRI or CSF sampling for determining BBB integrity. A surrogate, readily available, non-radiologic marker for impaired BBB function may be of significant value in identifying patients with a variety of neurological disorders, including metastatic brain tumors, gliomas, stroke, multiple sclerosis, head injury, etc. We developed a multi-step routine that allows detection of plasma proteins prior to and after BBB opening. Many questions remain unanswered. Is S100P the only useful peripheral marker of BBB function? What is the time course of the marker's accumulation? How do putative markers correlated with different MRI/CT patterns believed to be associated with BBB leakage? We will use molecular and protein-detection techniques to discover new markers of BBB intactness or leakage and to test the hypothesis that an increased plasma-to CSF ratio of S100P or other BBB markers correlates temporally and qualitatively with radiological measures of BBB impairment. Finally, we will validate the usefulness of these markers in the early detection of recurrent brain tumors or metastases, to specifically address one of the mandates of this PA.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BDCN-L (90))
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Jacobs, Tom P
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Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
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Marchi, Nicola; Granata, Tiziana; Ghosh, Chaitali et al. (2012) Blood-brain barrier dysfunction and epilepsy: pathophysiologic role and therapeutic approaches. Epilepsia 53:1877-86
Ghosh, Chaitali; Marchi, Nicola; Desai, Nirav K et al. (2011) Cellular localization and functional significance of CYP3A4 in the human epileptic brain. Epilepsia 52:562-71
Ghosh, Chaitali; Puvenna, Vikram; Gonzalez-Martinez, Jorge et al. (2011) Blood-brain barrier P450 enzymes and multidrug transporters in drug resistance: a synergistic role in neurological diseases. Curr Drug Metab 12:742-9
Marchi, Nicola; Teng, Qingshan; Ghosh, Chaitali et al. (2010) Blood-brain barrier damage, but not parenchymal white blood cells, is a hallmark of seizure activity. Brain Res 1353:176-86
Falcone, Tatiana; Mishra, Leenu; Carlton, Erin et al. (2010) Suicidal behavior in adolescents with first-episode psychosis. Clin Schizophr Relat Psychoses 4:34-40
Marchi, Nicola; Fan, Qingyuan; Ghosh, Chaitali et al. (2009) Antagonism of peripheral inflammation reduces the severity of status epilepticus. Neurobiol Dis 33:171-81
Marchi, Nicola; Betto, Giulia; Fazio, Vincent et al. (2009) Blood-brain barrier damage and brain penetration of antiepileptic drugs: role of serum proteins and brain edema. Epilepsia 50:664-77
Hossain, M; Sathe, T; Fazio, V et al. (2009) Tobacco smoke: a critical etiological factor for vascular impairment at the blood-brain barrier. Brain Res 1287:192-205
Mazzone, Peter J; Marchi, Nicola; Fazio, Vince et al. (2009) Small vessel ischemic disease of the brain and brain metastases in lung cancer patients. PLoS One 4:e7242
Falcone, Tatiana; Carlton, Erin; Janigro, Damir et al. (2008) Self-harm during first-episode psychosis. Br J Psychiatry 193:167;author reply 167

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