Macrostructural and Microstructural Imaging Biomarkers of Traumatic Brain Injury

描述（由申请人提供）：创伤性脑损伤（TBI）是45岁以下美国人死亡和残疾的主要原因，并且在全球范围内的患病率正在上升。神经成像技术，如计算机断层扫描（CT）或磁共振成像（MRI）是重要的诊断工具，为临床管理急性脑外伤。然而，在急性TBI中，通过CT或MRI检测到的局灶性病变，如挫伤和轴突剪切损伤，往往不能预测TBI后的长期功能残疾，特别是在轻度病例中。本研究计划的目的是建立定量的宏观结构和微观结构成像生物标志物，以预测轻度脑损伤后患者的预后。宏观结构生物标记物使用基于变形的形态测量（DBM）对大脑进行连续高分辨率3D MR扫描来测量创伤后局灶性萎缩。显微结构生物标志物通过基于序列扩散张量成像（DTI）的定量纤维跟踪来测量创伤后白质完整性的下降。100例轻度TBI患者将分别在损伤后1个月、6个月和1年后分别在3台Tesla MR扫描仪上进行高分辨率3D结构MRI和DTI检查。将在40名年龄、性别和教育程度相匹配的健康对照受试者中与相同的成像方案进行比较。所有受试者将在MRI/DTI扫描的同一时间点进行神经认知和功能结果测试。在控制损伤严重程度的临床测量指标（包括格拉斯哥昏迷量表、无意识持续时间和创伤后失忆症持续时间）后，该假设将被验证，即连续MRI的DBM检测到的进行性局灶性萎缩的空间范围增加和/或连续DTI的进行性白质微结构损伤与损伤后一年更差的神经认知和功能结果相关。这些宏观结构和微观结构成像生物标志物也将分别与功能磁共振成像和3D磁共振光谱成像的功能和代谢成像数据相关联。如果这项研究成功地建立了TBI长期预后的定量宏观结构和微观结构成像生物标志物，那么它们可能会成为临床干预试验的替代终点。它们也可能为研究使TBI后预后恶化的遗传易感性因素提供内表型。为此，本研究将收集患者的DNA进行基因型分析。具体而言，我们将研究ApoE基因型是否影响局部脑萎缩和微结构白质损伤的程度。ApoE的等位基因变异已经被认为可以调节TBI后的临床结果，本研究将确定DBM和DTI是否可以为ApoE基因型对TBI结果的影响提供“中间表型”。公共卫生相关性：本研究计划的目的是将两种新的先进磁共振成像（MRI）技术应用于轻度创伤性脑损伤患者的研究：(1)基于变形的形态测量，(2)弥散张量成像。这项研究可能会促进对脑损伤的科学认识，并提高对脑震荡长期影响患者的诊断。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The objective of this research proposal is to apply two new advanced magnetic resonance imaging (MRI) technologies to the study of patients with mild traumatic brain injury: (1) deformation-based morphometry, and (2) diffusion tensor imaging. This research may advance the scientific understanding of brain injury as well as improve the diagnosis of patients suffering from the long-term effects of concussion.