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

轻度创伤性脑损伤是影响服役人员和退伍军人的重大健康问题 与战斗相关的爆炸暴露。持续的身体、认知、情感和行为缺陷 直接影响到许多退伍军人的健康和安全。众所周知，MTBI很难客观评估。它 导致神经元和轴突损伤，通常在损伤时观察到，并伴有复杂的继发性级联反应 导致脑白质退化。MTBI引起的病理改变包括髓鞘改变(例如，丢失 和聚集)和微出血(例如含铁血黄素或类血黄素的巨噬细胞)。髓鞘改变 破坏轴突运输、完整性和结构可塑性，并极大地减少信号转导。铁 积聚可能会导致一系列神经退行性疾病。不幸的是，传统的神经成像 技术无法准确评估髓鞘和铁，也无法显示大多数 MTBI病例。根据VA/DOD的定义，在mTBI患者中没有常规的影像表现。有限的 当前临床MRI和CT技术的诊断和预后价值突出表明迫切需要更多 先进的神经成像技术，有助于更好地检测和治疗监测脑外伤 退伍军人。 髓鞘成像技术可能有助于解决这一困境，特别是在髓鞘已成为 治疗。然而，目前的髓鞘成像技术是间接的，很大程度上是因为髓鞘具有极端的 短T2(&lt；&lt；1ms)，常规磁共振成像(MRI)序列无法检测到。铁 累积也倾向于降低T2*，并且很难用临床MRI技术准确地量化。 超短回波时间(UTE)MRI序列，回波时间(TES)比临床短100倍 序列允许直接检测来自髓鞘和铁超载的信号。三维短时间绝热反演 恢复UTE(STAIR-UTE)序列可以选择性地对髓鞘进行成像并对髓鞘T1、T2进行定量 质子密度(Pd)。3DUTE定量磁化率测绘(UTE-QSM)技术可以测绘铁 分配和量化铁含量。多组分驱动的T1和T2的平衡单脉冲观测 (McDESPOT)可以绘制髓鞘水图，提供髓鞘含量的间接测量。扩散张量成像 (DTI)已被用来评估轴突损伤。我们的目标是验证髓鞘和UTE的阶梯成像- 铁的QSM成像，与髓鞘水的mcDESPOT成像和轴突的DTI成像进行比较 人脑标本和受到开场低强度冲击波(LIB)(目标1)的小鼠，然后评估 退伍军人合并创伤性脑损伤的急救技术(目标2)。我们的中心假设是楼梯测量到的 髓鞘丢失和UTE-QSM测量的铁聚集与患者的神经功能较差有关 患有脑外伤的退伍军人。最终，我们希望这些新的MRI生物标记物可以帮助分化神经学- 和基于心理的症状，从而能够进行更有针对性的治疗。

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.