Novel Strategies for Discovery, Validation and FDA Approval of Biomarkers for Acute and Chronic Brain Injury

Abstract

The proposed chapter outlines novel approaches that provide an infrastructure for discovery and validation of new biomarkers of acute brain injury. Approaches to validation can be also applied to existing biomarkers of brain injury in order to provide more rigorous assessment of their clinical utility. Importantly, there are currently no biomarkers of brain injury approved by Food and Drug Administration (FDA). The chapter reviews approaches critical for securing FDA approval of biomarkers of brain injury and disease, focusing on traumatic brain injury (TBI). The chapter reviews proteomics techniques applied for the first time to discovery of biomarkers of central nervous system (CNS). These techniques include refined mass spectrometry technology and high throughput immunoblot techniques. Output from these approaches can identify potential candidate biomarkers employing systems biology and data mining methods that will also be described. Once potential biomarkers have been identified, it is important to provide information on their clinical utility for diagnosis, management and prognosis of patients exposed to brain injuries. This section of the chapter will review both preclinical and clinical methods for biomarker validation. Preclinical models discussed include rodent models of closed head injury such as the controlled cortical impact (CCI) device. Consideration will also be given to the design and results from human clinical trials validating biomarkers of mild, moderate and severe traumatic brain injury (TBI). Human studies will include detailed analyses of the biokinetics of different biomarkers in order to understand their utility in acute, subacute and chronic phases of TBI. Consideration will also be given to relationships between levels of biomarkers and magnitude of acute injury, CT imaging profiles, occurrence of secondary insults and long term outcome. To achieve practical clinical utility, it is important to develop highly sensitive and specific assays for individual biomarkers. Enzyme-linked immunosorbent assays (ELISAs) are the current choice for clinical use, since this assay technology provides reliable, quantitative and accurate data. ELISA technologies relevant to biomarker measurement will be discussed. Once ELISA assays for individual biomarkers have been developed, these assays need to be transferred to devices that are appropriate for the clinical application and medical