Division of Neurocritical Care, Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
J Neurotrauma. 2023 Jan;40(1-2):74-85. doi: 10.1089/neu.2022.0178. Epub 2022 Sep 13.
Traumatic brain injury (TBI) causes significant white matter injury, which has been characterized by various rodent and human clinical studies. The exact time course of imaging changes in a pediatric brain after TBI and its relation to biomarkers of injury and cellular function, however, is unknown. To study the changes in major white matter structures using a valid model of TBI that is comparable to a human pediatric brain in terms of size and anatomical features, we utilized a four-week-old pediatric porcine model of injury with controlled cortical impact (CCI). Using diffusion tensor imaging differential tractography, we show progressive anisotropy changes at major white matter tracts such as the corona radiata and inferior fronto-occipital fasciculus between day 1 and day 30 after injury. Moreover, correlational tractography shows a large part of bilateral corona radiata having positive correlation with the markers of cellular respiration. In contrast, bilateral corona radiata has a negative correlation with the plasma biomarkers of injury such as neurofilament light or glial fibrillary acidic protein. These are expected correlational findings given that higher integrity of white matter would be expected to correlate with lower injury biomarkers. We then studied the magnetic resonance spectroscopy findings and report decrease in a N-acetylaspartate/creatinine (NAA/Cr) ratio at the pericontusional cortex, subcortical white matter, corona radiata, thalamus, genu, and splenium of corpus callosum at 30 days indicating injury. There was also an increase in choline/creatinine ratio in these regions indicating rapid membrane turnover. Given the need for a pediatric TBI model that is comparable to human pediatric TBI, these data support the use of a pediatric pig model with CCI in future investigations of therapeutic agents. This model will allow future TBI researchers to rapidly translate our pre-clinical study findings into clinical trials for pediatric TBI.
创伤性脑损伤（TBI）会导致明显的白质损伤，这已被各种啮齿动物和人类临床研究所证实。然而，小儿脑 TBI 后影像学变化的确切时间进程及其与损伤生物标志物和细胞功能的关系尚不清楚。为了使用与小儿大脑大小和解剖特征相当的 TBI 有效模型研究主要白质结构的变化，我们利用了一个 4 周大的小儿猪模型，采用了皮质控制冲击（CCI）。通过扩散张量成像差异轨迹，我们在主要白质束（如放射冠和下额枕束）中显示出在损伤后第 1 天至第 30 天之间的进行性各向异性变化。此外，相关轨迹显示双侧放射冠的很大一部分与细胞呼吸标志物呈正相关。相比之下，双侧放射冠与损伤的血浆生物标志物如神经丝轻链或神经胶质纤维酸性蛋白呈负相关。这些是预期的相关发现，因为更高的白质完整性预计与更低的损伤生物标志物相关。然后，我们研究了磁共振波谱学的发现，并报告了在 30 天时，损伤区域的皮质下白质、放射冠、丘脑、膝部和胼胝体压部的 N-乙酰天冬氨酸/肌酐（NAA/Cr）比值下降，表明存在损伤。这些区域的胆碱/肌酐比值也增加，表明膜快速周转。鉴于需要一个与小儿 TBI 相当的儿科 TBI 模型，这些数据支持在未来的治疗剂研究中使用 CCI 的小儿猪模型。该模型将使未来的 TBI 研究人员能够将我们的临床前研究结果快速转化为小儿 TBI 的临床试验。
