Macrostructural and Microstructural Imaging Biomarkers of Traumatic Brain Injury

项目总结 创伤性脑损伤是45岁以下美国人死亡和残疾的主要原因，而且 全球范围内的流行率不断上升。神经成像技术，如计算机断层扫描(CT)或 磁共振成像(MRI)是临床治疗急性颅脑损伤的重要诊断手段。 然而，CT或MRI在急性颅脑损伤中发现的局灶性病变，如挫伤和轴索剪切 损伤，通常不能预测脑外伤后的长期功能障碍，特别是在轻微病例中。这个 本研究的目标是建立定量的宏观和微观结构成像 预测轻度脑外伤后患者预后的生物标志物。宏观结构生物标志物衡量的是后 应用系列高分辨率3D MR序列的形变形态计量学(DBM)研究创伤性局灶性萎缩 大脑。微结构生物标记物测量创伤后脑白质完整性的下降 基于序列扩散张量成像(DTI)的定量纤维跟踪。 100名轻型颅脑损伤患者将在3台特斯拉磁共振扫描仪上接受高分辨率3D结构MRI和DTI 伤后1个月、伤后6个月、伤后1年再复查。我们将进行比较 在40名年龄、性别和教育程度匹配的健康对照受试者中，采用相同的成像方案。全 受试者将在MRI/DTI的同一时间点接受神经认知和功能结果测试 扫描。这一假设将被检验，即通过检测到的进行性局灶性萎缩的空间范围增加 序列MRI的DBM和/或序列DTI上的进行性脑白质微结构损伤与病情恶化相关 在控制了临床损伤措施后，损伤后一年的神经认知和功能结果 严重程度包括格拉斯哥昏迷评分、昏迷持续时间和创伤后健忘持续时间。 这些宏观和微观成像生物标记物也将与功能和 分别使用功能磁共振成像和三维磁共振光谱成像的代谢成像数据。 如果拟议的调查成功地确定了这些量化的宏观结构和 微结构成像生物标记物可作为脑外伤患者远期疗效的替代指标 临床干预试验的终点。它们还可能产生用于遗传学研究的内表型。 导致脑外伤后预后恶化的易感因素。为了达到这个目的，病人的DNA将被储存 在本研究中进行了基因分型。具体地说，我们将检查载脂蛋白E基因是否会影响 局灶性脑萎缩程度及脑白质微结构损伤。载脂蛋白E的等位基因变体有 已经知道可以调节脑外伤后的临床结果，这项研究将确定DBM和DTI是否可以 为载脂蛋白E基因对脑损伤预后的影响提供“中间表型”。

PROJECT SUMMARY Traumatic brain injury (TBI) is the leading cause of death and disability in Americans under age 45, and is increasing in prevalence worldwide. Neuroimaging techniques such as computed tomography (CT) or magnetic resonance imaging (MRI) are important diagnostic tools for the clinical management of acute TBI. However, the focal lesions detected by CT or MRI in acute TBI, such as contusions and axonal shearing injuries, are often not predictive of long-term functional disability after TBI, especially in mild cases. The objective of this research proposal is to establish quantitative macrostructural and microstructural imaging biomarkers for predicting patient outcome after mild TBI. The macrostructural biomarker measures post- traumatic focal atrophy using deformation-based morphometry (DBM) of serial high-resolution 3D MR scans of the brain. The microstructural biomarker measures post-traumatic decreases in white matter integrity using quantitative fiber tracking based on serial diffusion tensor imaging (DTI). One hundred mild TBI patients will undergo high-resolution 3D structural MRI and DTI on 3 Tesla MR scanners at 1 month after injury, at 6 months after injury, and then again at 1 year after injury. Comparison will be made to the same imaging protocol in 40 age-, gender-, and education-matched healthy control subjects. All subjects will undergo neurocognitive and functional outcome tests at the same time points as the MRI/DTI scans. The hypothesis will be tested that increasing spatial extent of progressive focal atrophy detected by DBM of serial MRI and/or progressive white matter microstructural injury on serial DTI is correlated with worse neurocognitive and functional outcomes at one year after injury, after controlling for clinical measures of injury severity including Glasgow Coma Scale, duration of unconsciousness, and duration of post-traumatic amnesia. These macrostructural and microstructural imaging biomarkers will also be correlated with functional and metabolic imaging data using fMRI and 3D MR spectroscopic imaging, respectively. If the proposed investigation is successful in establishing these quantitative macrostructural and microstructural imaging biomarkers of long-term outcome in TBI, then they could potentially serve as surrogate endpoints for clinical intervention trials. They might also yield endophenotypes for studies of genetic susceptibility factors that worsen outcome after TBI. Towards this purpose, DNA will be banked from patients in this study for genotype analysis. Specifically, we will examine whether ApoE genotype influences the degree of regional brain atrophy and microstructural white matter injury. The allelic variants of ApoE are already known to modulate clinical outcome after TBI, and this study will determine if DBM and DTI can provide "intermediate phenotypes" for the effect of ApoE genotype on TBI outcome.