Developing MRI Biomarkers of Myelin and Iron in Veterans with Traumatic Brain Injury

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Mild traumatic brain injury (mTBI) is a significant health issue which affects service members and Veterans with combat-related exposure to blast. The sustained physical, cognitive, emotional, and behavioral deficits directly impact the health and safety of many Veterans. mTBI is notoriously difficult to evaluate objectively. It leads to neuronal and axonal damage, typically observed at the time of injury, with a complex secondary cascade leading to white matter degeneration. mTBI-induced pathological changes include myelin alterations (e.g., loss and clumping) and microhemorrhage (e.g., hemosiderin- or hematoidin-laden macrophages). Myelin alteration disrupts axonal transport, integrity, and structural plasticity and greatly reduces signal transduction. Iron accumulation can contribute to a host of neurodegenerative disorders. Unfortunately, conventional neuroimaging techniques are unable to accurately assess myelin and iron, and fail to show abnormalities in the majority of mTBI cases. By VA/DoD definitions, there are no conventional imaging findings in those with mTBI. The limited diagnostic and prognostic value of current clinical MRI and CT techniques highlights the urgent need for more advanced neuroimaging techniques to facilitate better detection and therapeutic monitoring of mTBI in the Veteran population. Myelin imaging techniques may help resolve this dilemma, especially as myelin has emerged as a target of treatment. However, current myelin imaging techniques are indirect, largely because myelin has an extremely short T2 (<< 1 ms) and cannot be detected with regular magnetic resonance imaging (MRI) sequences. Iron accumulation also tends to reduce T2* and is difficult to quantify accurately with clinical MRI techniques. Ultrashort echo time (UTE) MRI sequences with echo times (TEs) ~100 times shorter than those of clinical sequences allow direct detection of signals from myelin and iron overload. The 3D Short TR Adiabatic Inversion Recovery UTE (STAIR-UTE) sequence allows selective imaging of myelin and quantification of myelin T1, T2* and proton density (PD). The 3D UTE Quantitative Susceptibility Mapping (UTE-QSM) technique can map iron distribution and quantify iron content. Multicomponent-driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) can map myelin water, providing an indirect measure of myelin content. Diffusion tensor imaging (DTI) has been used to assess axonal damage. Our goal is to validate STAIR-UTE imaging of myelin and UTE- QSM imaging of iron, compare them with mcDESPOT imaging of myelin water and DTI imaging of axons in human brain specimens and in mice subjected to open-field low-intensity blast (LIB) (Aim 1), then evaluate the UTE techniques in Veterans with mTBI (Aim 2). Our central hypothesis is that the STAIR-UTE-measured myelin loss and UTE-QSM-measured iron accumulation are associated with worse neurological function in Veterans with mTBI. Ultimately, we hope these new MRI biomarkers may aid in the differentiation of neurological- and psychological-based symptoms, thus allowing for more targeted treatment.