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急性血液神经丝轻链水平提示重复性轻度创伤性脑损伤小鼠一年的白质病理学和功能损伤。

Acute Blood Levels of Neurofilament Light Indicate One-Year White Matter Pathology and Functional Impairment in Repetitive Mild Traumatic Brain Injured Mice.

机构信息

Department of Acute Brain Injury, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

出版信息

J Neurotrauma. 2023 Jun;40(11-12):1144-1163. doi: 10.1089/neu.2022.0252. Epub 2023 Mar 13.

Abstract

Mild traumatic brain injury (mTBI) mostly causes transient symptoms, but repeated (r)mTBI can lead to neurodegenerative processes. Diagnostic tools to evaluate the presence of ongoing occult neuropathology are lacking. In a mouse model of rmTBI, we investigated MRI and plasma biomarkers of brain damage before chronic functional impairment arose. Anesthetized adult male and female C57BL/6J mice were subjected to rmTBI or a sham procedure. Sensorimotor deficits were evaluated up to 12 months post-injury in SNAP and Neuroscore tests. Cognitive function was assessed in the novel object recognition test at six and 12 months. Diffusion tensor imaging (DTI) and structural magnetic resonance imaging (MRI) were performed at six and 12 months to examine white matter and structural damage. Plasma levels of neurofilament light (NfL) were assessed longitudinally up to 12 months. Brain histopathology was performed at 12 months. Independent groups of mice were used to examine the effects of 2-, 7- and 14-days inter-injury intervals on acute plasma NfL levels and on hyperactivity. Twelve months after an acute transient impairment, sensorimotor functions declined again in rmTBI mice ( < 0.001 vs sham), but not earlier. Similarly, rmTBI mice showed memory impairment at 12 ( < 0.01 vs sham) but not at 6 months. White matter damage examined by DTI was evident in rmTBI mice at both six and 12 months ( < 0.001 vs sham). This was associated with callosal atrophy ( < 0.001 vs sham) evaluated by structural MRI. Plasma NfL at one week was elevated in rmTBI ( < 0.001 vs sham), and its level correlated with callosal atrophy at 12 months (Pearson r = 0.72,  < 0.01). Histopathology showed thinning of the corpus callosum and marked astrogliosis in rmTBI mice. The NfL levels were higher in mice subjected to short (2 days) compared with longer (7 and 14 days) inter-injury intervals ( < 0.05), and this correlated with hyperactivity in mice (Pearson r = 0.50; p < 0.05). These findings show that rmTBI causes white matter pathology detectable by MRI before chronic functional impairment. Early quantification of plasma NfL correlates with the degree of white matter atrophy one year after rmTBI and can serve to monitor the brain's susceptibility to a second mTBI, supporting its potential clinical application to guide the return to practice in sport-related TBI.

摘要

轻度创伤性脑损伤(mTBI)主要导致短暂性症状,但反复性(r)mTBI 可导致神经退行性过程。目前缺乏评估持续隐匿性神经病理学的诊断工具。在 r mTBI 的小鼠模型中,我们在慢性功能障碍出现之前,研究了 MRI 和血浆生物标志物来评估脑损伤。对麻醉的成年雄性和雌性 C57BL/6J 小鼠进行 r mTBI 或假手术处理。在 SNAP 和神经评分测试中,在受伤后 12 个月内评估感觉运动缺陷。在新物体识别测试中,在 6 个月和 12 个月时评估认知功能。在 6 个月和 12 个月时进行扩散张量成像(DTI)和结构磁共振成像(MRI),以检查白质和结构损伤。使用纵向方法评估血浆神经丝轻链(NfL)水平至 12 个月。在 12 个月时进行脑组织病理学检查。使用独立的小鼠组来研究 2 天、7 天和 14 天的损伤间隔对急性血浆 NfL 水平和过度活跃的影响。在急性短暂性损伤后 12 个月,r mTBI 小鼠的感觉运动功能再次下降( < 0.001 与假手术),但更早时没有。同样,r mTBI 小鼠在 12 个月( < 0.01 与假手术)时表现出记忆障碍,但在 6 个月时没有。在 r mTBI 小鼠中,在 6 个月和 12 个月时,通过 DTI 检查的白质损伤( < 0.001 与假手术)。这与通过结构 MRI 评估的胼胝体萎缩有关( < 0.001 与假手术)。在 r mTBI 中,一周时的血浆 NfL 升高( < 0.001 与假手术),并且其水平与 12 个月时的胼胝体萎缩相关(Pearson r=0.72, < 0.01)。组织病理学检查显示 r mTBI 小鼠的胼胝体变薄和明显的星形胶质增生。与较长(7 天和 14 天)损伤间隔相比,较短(2 天)损伤间隔的 NfL 水平更高( < 0.05),这与小鼠的过度活跃相关(Pearson r=0.50;p<0.05)。这些发现表明,r mTBI 在慢性功能障碍之前可通过 MRI 检测到白质病理学变化。早期定量血浆 NfL 与 r mTBI 后一年白质萎缩程度相关,可用于监测大脑对第二次 mTBI 的易感性,支持其在指导与运动相关的 TBI 恢复实践中的潜在临床应用。

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