Development of MR Biomarkers of Brain Injury in Acute and Chronic mTBI

描述（由申请人提供）： 创伤性脑损伤（TBI）每年影响超过170万人，其中大多数病例为轻度（mTBI），包括从伊拉克和阿富汗返回的30多万军人。此外，15-30%的mTBI受试者具有在损伤后3个月不消退的症状，并且可能导致永久性残疾。鉴于这些事实，早期发现脑损伤 对于确定那些最有可能出现不良结果的人至关重要。然而，由于常规CT/MRI不敏感，临床诊断无特异性，因此mTBI难以诊断。然而，最近的技术发展使得诸如扩散张量成像（DTI）、磁敏感加权成像（SWI）和磁共振波谱（MRS）的测量成为可能。我们通过患者特异性特征、自由水校正和光谱编辑MRS进一步推进了这些方法。结合这些新工具将使mTBI的“虚拟活检”成为可能，以间接表征不同的组织成分（即，神经元， 轴突、神经递质、神经胶质细胞、髓磷脂）以及TBI病理学的不同方面（急性微出血、水肿、炎症、神经胶质增生和变性）。这种多模式方法将能够开发损伤的生物标志物，并采用纵向设计，以绘制损伤后的大脑变化，包括神经认知恢复和持续性脑震荡后症状（PPCS）的演变。在该提案中，将招募48名急性mTBI患者和30名匹配的骨科对照，并在创伤后1周、3个月和6个月在VA Boston Healthcare System的TBI和应激障碍转化研究中心（TRACTS）接受成像和临床/认知评价。此外，将使用相同硬件上的相同成像方案从先前采集的数据中选择96名mTBI退伍军人（1/2原始/1/2无原始，有/无PPCS）和48名退伍军人对照，并在年龄、性别和社会经济状况方面与急性样本匹配。我们的策略是根据急性期的神经影像学标志物，结合联合收割机多模式成像来提供mTBI预后。我们的目标是：1）使用先进的患者特异性损伤多模态成像特征检测与PPCS相关的脑异常; 2）绘制mTBI从损伤到恢复或PPCS的纵向过程; 3）识别与PPCS相比恢复的多模态成像预测因子。使用纵向数据，我们将根据先验假设和经验推导的算法对恢复与PPCS进行预测。这些预测因子将被推广到VA人群，在那里将识别常见和独特的损伤模式，使成像预测因子成为手术室中有价值的工具，并成为确定治疗干预措施的第一步。基于初步结果和先前的研究，我们预期VA和急性mTBI中的PPCS将显示与胶质增生、轴突变性和慢性神经炎症相关的改变的成像标志物，尽管异常的位置和严重程度将不同。我们还预期急性mTBI患者在损伤过程的早期将不同于对照组，并且作为一个组将表现出轴突损伤、小脉管系统出血、髓鞘损伤增加、血管源性水肿和炎症增加，使用扩散指数和N-乙酰天冬氨酸（NAA; MRS神经元标记物）减少和谷氨酸（Glu;兴奋性毒性的MRS标记物）评估。我们预测，脑损伤将开始恢复正常的受试者，这表明大脑恢复的阶段。对于那些在6个月时没有恢复的患者，我们预计在扩散指数上会看到更多的神经胶质增生、轴突变性和炎症证据，也反映在MRS指数上的胆碱、Glu和谷胱甘肽变化中。1周时炎症过程、广泛轴突损伤和胶质增生多模式成像标志物的组合将预测6个月时的不良恢复和临床PPCS，而早期阶段的白色物质再生的证据将是良好恢复的最强预测因素之一。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) affects more than 1.7 million each year, with most cases being mild (mTBI) including more than 300,000 service members returning from Iraq and Afghanistan. Moreover, 15-30% of mTBI subjects have symptoms that do not resolve 3 months post-injury and which can lead to permanent disability. In view of these facts, early detection of brain injury is critical to identifying those who are most at risk for poor outcome. Unfortunately mTBI is difficult to diagnose because conventional CT/MRI is not sensitive and clinical diagnosis is non-specific. Recent technical developments, however, have enabled measurements such as diffusion tensor imaging (DTI), susceptibility weighted imaging (SWI), and magnetic resonance spectroscopy (MRS). We have advanced these methods further with patient specific profiles, free-water correction, and spectral edited MRS. Combining these novel tools will make possible a "virtual biopsy" of mTBI to characterize, indirectly, different tissue components (i.e., neurons, axons, neurotransmitters, glial cells, myelin), as well as different aspects of TBI pathology (acute micro-hemorrhage, edema, inflammation, gliosis, and degeneration). This multi-modal approach will enable the development of biomarkers of injury, and with a longitudinal design, to chart brain changes following injury, including the evolution of neurocognitive recovery and persistent post-concussive symptoms (PPCS). In this proposal, 48 acute mTBI patients and 30 matched orthopedic controls will be recruited and will undergo imaging and clinical/cognitive evaluation at 1 week, 3 and 6 months post-injury at the Translational Research Center for TBI and Stress Disorders (TRACTS), VA Boston Healthcare System. In addition, 96 mTBI Veterans (1/2 blast/1/2 no blast, with/without PPCS), and 48 Veteran controls will be selected from previously acquired data using an identical imaging protocol on the same hardware and matched to the acute sample on age, gender, and socio-economic status. Our strategy is to combine multi-modal imaging to provide prognosis of mTBI outcome, based on neuroimaging markers at the acute stage. Our aims are: 1) to detect brain abnormalities associated with PPCS using advanced patient-specific multimodal imaging profiles of injury; 2) to chart the longitudinal course of mTBI from injury to recovery or PPCS; and 3) to identify multimodal imaging predictors of recovery versus PPCS. Using longitudinal data, we will make predictions about recovery versus PPCS based on a priori hypotheses and an empirically derived algorithm. These predictors will be generalized to the VA population, where common and unique patterns of injury will be identified, making imaging predictors a valuable tool in theater, and a first ste in determining treatment interventions. Based on preliminary results and prior studies, we that expect PPCS in VA and acute mTBI will show altered imaging markers associated with gliosis, and with axonal degeneration and chronic neuroinflammation, although the location and severity of abnormalities will be different. We also expect acute mTBI patients will differ from controls, early in the course of injury, and as a group will evince axonal injury, small vasculature hemorrhage, increased myelin injury, vasogenic edema, and increased inflammation, assessed using diffusion indices, and decreased N-acetyl aspartate (NAA; MRS neuronal marker), and increased glutamate (Glu; MRS marker of excitotoxicity). We predict that brain injury will begin to normalize in subjects who recover, suggesting a staging of brain recovery. For those who do not recover at 6 months, we expect to see greater evidence of gliosis, axonal degeneration and inflammation, on diffusion indices, also reflected in choline, Glu, and glutathione changes on MRS indices. A combination of inflammatory processes, extensive axonal damage and gliosis multimodal imaging markers at 1 week, will predict poor recovery and clinical PPCS at 6 months, while evidence of white matter regeneration at early stages will be among the strongest predictors of good recovery.