Development of immunoassays for highly sensitive diagnostic monitoring of traumatic brain injury using novel astroglial injury-defined biomarkers

ABSTRACT Traumatic brain injuryTBIis an expanding public health epidemic with complex pathophysiology that is difficult to diagnose and thus treatTBI blood testing should provide simplereliablereal timeobjective diagnostic monitoring and outcome prediction across the entire severity spectrumNeurotrauma biomarkers with insight into underlying TBI processes can address these needsAt UCLADrWanner s team has discovered and confirmed new Astrocyte Injury DefinedAIDbiomarkers for improved TBI patient assessmentAldolase CALDOCand brain lipid binding proteinBLBPare elevated hyper acutely and over prolonged periods after TBIThey are also robustly present after mild TBIThese two markers are linked to trauma specific cell membrane woundingmechanoporationand glial fiber damageIn contrastnew small breakdown productsBDPsof GFAP are selective for cell death and associate with lesions and poor outcomeThe work s long term objective is to improve TBI assessment by profiling biofluid signatures for specific TBI manifestations using biomarkers defined by cellular trauma processesThis project proposes the development and validation of diagnostically usefulnoninvasive AID biomarker assays for improved clinical stratification of TBI patientsThe first aim is to design and optimize enzyme linked immunosorbent and electrochemiluminescence based platform assaysAn already created ALDOC assay prototype will be fully authenticatedwhile assays for BLBP and small GFAP BDPs are being developedusing best performing antibody pairsAID markers have high brain selectivity that will be validated in tissue panelsAssay targets will be definedand affinity for biomarker BDPs determinedAssay accuracy will be optimized for TBI discrimination and distinction from healthy and non TBI trauma controlsThe second aim will clinically validate AID biomarkers and determine their longitudinal biofluid kineticsTransition between cerebrospinal fluid and circulation will be monitored and degradation determined after severe TBIDiagnostic performance of AID markers will then be assessed in a large mild TBI cohort and correlated with lesion presence and symptomatic recoveryMild TBI AID marker signals will be differentiated from healthy and orthopedic trauma controlsCritical concussion diagnosis is addressed by measuring AID markers in two well defined cohorts of concussed football players alongside healthy controlsnon concussed and chronically impact exposed playersAID marker blood levels will be correlated with MR imaging for diffuse white matter damageblood brain barrier permeability and blood flow changesDifferent trauma kinetics and sensitivities of ALDOCBLBPand GFAP with its BDPs complement each other in multivariate analysesoffering superior assessmentThusAID markers will improve diagnostic performance because they reflect acute traumatic tissue wounding and compromise in addition to tissue lossThis work will benefit neurotrauma research and translationas these novel tests have great potential to improve patient stratification in clinical trials and diagnostic monitoring of mild TBI patients NARRATIVE Because of great symptom complexity and unpredictable recovery path of traumatic brain injury patientsinexpensive tools for simple and reliablereal time diagnostic monitoring of TBI are still lackingThis project will develop novel blood tests using new biomarkers that report on temporary brain tissue wounding and compromise that is typical for concussions and distinct from tissue lossThe new tests have the potential to improve patient classification and careprevent repeated injures and predict outcomebenefitting a wide range of patients such as the elderlychildrenathletesmilitary personnel and accident victims