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

开发患有创伤性脑损伤的退伍军人的髓磷脂和铁的 MRI 生物标志物

• 批准号: 10246748
• 负责人: Jiang Du
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10246748
• 关键词: 3-Dimensional; Affect; Anxiety; Axon; Axonal Transport; Behavioral; Blast Injuries; Brain; C57BL/6 Mouse; Cadaver; Clinical; Cognitive; Complex; Data; Demyelinations; Deposition; Detection; Diagnostic; Diffusion Magnetic Resonance Imaging; Emotional; Equilibrium; Evaluation; Exposure to; Goals; Health; Hemosiderin; Histology; Human; Image; Imaging Techniques; Injury; Iron; Iron Overload; Learning; Magnetic Resonance Imaging; Maps; Measures; Memory; Modeling; Monitor; Morphology; Motor Activity; Mus; Myelin; Nervous System Physiology; Neurodegenerative Disorders; Neurologic; Neurons; Neuropsychology; Pathologic; Physiologic pulse; Predisposition; Protons; Recording of previous events; Recovery; Reference Standards; Safety; Signal Transduction; Specimen; Structure; Symptoms; System; T2 weighted imaging; TBI treatment; Techniques; Therapeutic; Time; Traumatic Brain Injury; Veterans; Water; axon injury; base; behavior test; combat; density; executive function; macrophage; magnetic resonance imaging biomarker; mild traumatic brain injury; military veteran; mouse model; neuroimaging; prognostic value; psychologic; remyelination; research clinical testing; service member; targeted treatment; water diffusion; white matter

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.

轻度创伤性脑损伤（MTBI）是一个重大的健康问题，会影响服务成员和退伍军人 与战斗相关的爆炸。持续的身体，认知，情感和行为缺陷 直接影响许多退伍军人的健康和安全。众所周知，MTBI很难客观地评估。它 导致神经元和轴突损伤，通常在受伤时观察到，复杂的次级级联 导致白质变性。 MTBI诱导的病理变化包括髓磷脂的改变（例如，损失 和结块）和微毛（例如，炎性蛋白或嗜血蛋白含量巨噬细胞）。髓鞘改变 破坏轴突运输，完整性和结构可塑性，并大大降低信号转导。铁 积累可以导致许多神经退行性疾病。不幸的是，传统的神经影像学 技术无法准确评估髓鞘和铁，并且在大多数方面都无法表现出异常 MTBI案例。根据VA/DOD的定义，MTBI的人没有常规的成像发现。有限公司 当前临床MRI和CT技术的诊断和预后价值突出了迫切需要更多 高级神经影像学技术，以促进对MTBI的更好检测和治疗监测 资深人口。 髓磷脂成像技术可能有助于解决这一困境，尤其是髓鞘成为目标 治疗。但是，当前的髓鞘成像技术是间接的，主要是因为髓磷脂极为 短T2（<< 1 ms），无法通过常规磁共振成像（MRI）序列检测到。铁 累积也倾向于减少T2*，并且很难通过临床MRI技术准确地量化。 超短式回声时间（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磷脂和铁超载的信号。 3D短Tr绝热反转 恢复UTE（楼梯）序列允许选择性成像髓磷脂和髓磷脂T1，T2*的定量 和质子密度（PD）。 3D UTE定量敏感性映射（UTE-QSM）技术可以映射铁 分布和量化铁含量。多组分驱动的平衡单脉冲观察T1和T2 （McDespot）可以绘制髓鞘水，从而提供髓磷脂含量的间接度量。扩散张量成像 （DTI）已用于评估轴突损伤。我们的目标是验证髓磷脂和Ute-的楼梯成像 铁的QSM成像，将它们与髓鞘水的McDespot成像和轴突的DTI成像进行比较 人脑标本和受到开放场低强度爆炸（LIB）的小鼠（AIM 1），然后评估 MTBI退伍军人的UTE技术（AIM 2）。我们的中心假设是楼梯式测量 髓磷脂损失和UTE-QSM测量的铁积累与较差的神经功能相关 MTBI的退伍军人。最终，我们希望这些新的MRI生物标志物可以帮助分化神经系统 和基于心理的症状，从而可以进行更多针对性的治疗。