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: 10426261
• 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/10426261
• 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; Diffusion Magnetic Resonance Imaging; Emotional; Equilibrium; Evaluation; Exposure to; Goals; Health; Hemorrhage; Hemosiderin; Histology; Human; Image; Imaging Techniques; Injury; Iron; Iron Overload; Learning; Macrophage; Magnetic Resonance Imaging; Maps; Measures; Memory; Modeling; Monitor; Morphology; Motor Activity; Mus; Myelin; Myelin Water Imaging; Nervous System Physiology; Neurodegenerative Disorders; Neurologic; Neurons; Neuropsychology; Pathologic; Physiologic pulse; Predisposition; Protons; Recording of previous events; Recovery; Reference Standards; Safety; Signal Transduction; Specimen; Symptoms; System; Techniques; Therapeutic; Time; Traumatic Brain Injury; Veterans; Water; axon injury; behavior test; combat; density; diagnostic value; executive function; magnetic resonance imaging biomarker; mild traumatic brain injury; military veteran; mouse model; neuroimaging; prognostic value; psychologic; remyelination; research clinical testing; service member; targeted treatment; 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）是影响服务人员和退伍军人的重要健康问题 与战斗有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很难客观评估。它 导致神经元和轴突损伤，通常在损伤时观察到，具有复杂的次级级联反应 导致白色物质变性。mTBI诱导的病理变化包括髓磷脂改变（例如，损失 和结块）和微出血（例如，含铁血黄素或装载血色素的巨噬细胞）。髓鞘改变 破坏轴突运输、完整性和结构可塑性，并大大降低信号转导。铁 积累可导致许多神经变性疾病。不幸的是，传统的神经成像 技术不能准确评估髓磷脂和铁，并且不能显示大多数人的异常。 mTBI病例。根据VA/DoD定义，mTBI患者无常规影像学表现。有限 目前临床MRI和CT技术的诊断和预后价值突出了迫切需要更多的 先进的神经成像技术，以促进更好地检测和治疗监测mTBI在 退伍军人 髓磷脂成像技术可能有助于解决这一难题，特别是髓磷脂已成为靶点。 治疗然而，目前的髓磷脂成像技术是间接的，主要是因为髓磷脂具有非常大的 短T2（<< 1 ms），不能用常规磁共振成像（MRI）序列检测。铁 累积也倾向于降低T2*，并且难以用临床MRI技术精确地量化。 超短回波时间（UTE）MRI序列，回波时间（TE）比临床短约100倍 序列允许直接检测来自髓磷脂和铁过载的信号。三维短TR绝热反演 Recovery UTE（STAIR-UTE）序列允许选择性髓鞘成像和定量髓鞘T1、T2* 质子密度（PD）3D UTE定量易感性映射（UTE-QSM）技术可以映射铁 分布和量化铁含量。T1和T2的多分量驱动平衡单脉冲观测 （mcDESPOT）可以绘制髓磷脂水，提供髓磷脂含量的间接测量。扩散张量成像 (DTI)被用来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，并与髓鞘水的mcDESPOT成像和轴突的DTI成像进行比较。 人脑标本和小鼠进行开放场低强度冲击波（LIB）（目的1），然后评估 UTE技术在mTBI退伍军人中的应用（目标2）。我们的中心假设是， 髓鞘丢失和UTE-QSM测量的铁积累与神经功能恶化相关， 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疾病， 和基于心理的症状，从而允许更有针对性的治疗。