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) 是影响现役军人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，并伴有复杂的二级级联反应 导致白质退化。 mTBI 引起的病理变化包括髓磷脂改变（例如，髓磷脂缺失） 和结块）和微出血（例如，含铁血黄素或富含血红素的巨噬细胞）。髓磷脂改变 破坏轴突运输、完整性和结构可塑性，并大大减少信号转导。铁 积累会导致一系列神经退行性疾病。不幸的是，传统的神经影像学 技术无法准确评估髓磷脂和铁，并且无法显示大多数的异常情况 转移性脑损伤病例。根据 VA/DoD 的定义，mTBI 患者没有常规影像学表现。有限的 当前临床 MRI 和 CT 技术的诊断和预后价值凸显了迫切需要更多 先进的神经影像技术有助于更好地检测和治疗监测 mTBI 退伍军人人口。 髓磷脂成像技术可能有助于解决这一困境，特别是当髓磷脂已成为治疗目标时 治疗。然而，目前的髓磷脂成像技术是间接的，很大程度上是因为髓磷脂具有极其 T2 短（<< 1 ms），无法通过常规磁共振成像 (MRI) 序列检测到。铁 积累也往往会降低 T2*，并且很难用临床 MRI 技术准确量化。 超短回波时间 (UTE) MRI 序列的回波时间 (TE) 比临床序列短约 100 倍 序列允许直接检测来自髓磷脂和铁过载的信号。 3D 短 TR 绝热反演 恢复 UTE (STAIR-UTE) 序列可对髓磷脂进行选择性成像并对髓磷脂 T1、T2* 进行定量 和质子密度（PD）。 3D UTE 定量磁化率图谱 (UTE-QSM) 技术可以绘制铁图谱 分布和量化铁含量。 T1 和 T2 的多组分驱动平衡单脉冲观察 (mcDESPOT) 可以绘制髓磷脂水图，提供髓磷脂含量的间接测量。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 STAIR-UTE 成像- 铁的 QSM 成像，与髓磷脂水的 mcDESPOT 成像和轴突的 DTI 成像进行比较 人脑样本和接受开放场低强度爆炸 (LIB) 的小鼠（目标 1），然后评估 UTE 技术用于患有 mTBI 的退伍军人（目标 2）。我们的中心假设是 STAIR-UTE 测量的 髓磷脂损失和 UTE-QSM 测量的铁积累与神经功能较差有关 患有 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区分神经系统 - 和基于心理的症状，从而可以进行更有针对性的治疗。