Laureate Institute for Brain Research, Tulsa, OK 74136, USA.
Oxley College of Health Sciences, The University of Tulsa, Tulsa, OK 74119, USA.
Brain. 2023 Oct 3;146(10):4262-4273. doi: 10.1093/brain/awad126.
The neurotrophic herpes virus cytomegalovirus is a known cause of neuropathology in utero and in immunocompromised populations. Cytomegalovirus is reactivated by stress and inflammation, possibly explaining the emerging evidence linking it to subtle brain changes in the context of more minor disturbances of immune function. Even mild forms of traumatic brain injury, including sport-related concussion, are major physiological stressors that produce neuroinflammation. In theory, concussion could predispose to the reactivation of cytomegalovirus and amplify the effects of physical injury on brain structure. However, to our knowledge this hypothesis remains untested. This study evaluated the effect of cytomegalovirus serostatus on white and grey matter structure in a prospective study of athletes with concussion and matched contact-sport controls. Athletes who sustained concussion (n = 88) completed MRI at 1, 8, 15 and 45 days post-injury; matched uninjured athletes (n = 73) completed similar visits. Cytomegalovirus serostatus was determined by measuring serum IgG antibodies (n = 30 concussed athletes and n = 21 controls were seropositive). Inverse probability of treatment weighting was used to adjust for confounding factors between athletes with and without cytomegalovirus. White matter microstructure was assessed using diffusion kurtosis imaging metrics in regions previously shown to be sensitive to concussion. T1-weighted images were used to quantify mean cortical thickness and total surface area. Concussion-related symptoms, psychological distress, and serum concentration of C-reactive protein at 1 day post-injury were included as exploratory outcomes. Planned contrasts compared the effects of cytomegalovirus seropositivity in athletes with concussion and controls, separately. There was a significant effect of cytomegalovirus on axial and radial kurtosis in athletes with concussion but not controls. Cytomegalovirus positive athletes with concussion showed greater axial (P = 0.007, d = 0.44) and radial (P = 0.010, d = 0.41) kurtosis than cytomegalovirus negative athletes with concussion. Similarly, there was a significant association of cytomegalovirus with cortical thickness in athletes with concussion but not controls. Cytomegalovirus positive athletes with concussion had reduced mean cortical thickness of the right hemisphere (P = 0.009, d = 0.42) compared with cytomegalovirus negative athletes with concussion and showed a similar trend for the left hemisphere (P = 0.036, d = 0.33). There was no significant effect of cytomegalovirus on kurtosis fractional anisotropy, surface area, symptoms and C-reactive protein. The results raise the possibility that cytomegalovirus infection contributes to structural brain abnormalities in the aftermath of concussion perhaps via an amplification of concussion-associated neuroinflammation. More work is needed to identify the biological pathways underlying this process and to clarify the clinical relevance of this putative viral effect.
神经滋养疱疹病毒巨细胞病毒是导致宫内和免疫功能低下人群神经病理学的已知原因。巨细胞病毒会因应激和炎症而被激活，这可能解释了它与免疫功能更轻微紊乱相关的轻微脑变化之间的新出现的关联。即使是轻度创伤性脑损伤，包括与运动相关的脑震荡，也是产生神经炎症的主要生理性应激源。从理论上讲，脑震荡可能使巨细胞病毒重新激活，并放大身体损伤对大脑结构的影响。但是，据我们所知，该假设尚未得到验证。本研究通过对运动员脑震荡和匹配的接触运动对照者的前瞻性研究，评估了巨细胞病毒血清阳性状态对白质和灰质结构的影响。遭受脑震荡的运动员（n = 88）在受伤后 1、8、15 和 45 天完成 MRI；匹配的未受伤运动员（n = 73）完成了类似的访问。通过测量血清 IgG 抗体确定巨细胞病毒血清阳性状态（n = 30 名脑震荡运动员和 n = 21 名对照者为血清阳性）。使用逆概率处理权重来调整运动员之间存在的混杂因素。使用扩散峰度成像指标评估白质微观结构，这些指标以前被证明对脑震荡敏感。使用 T1 加权图像定量平均皮质厚度和总表面积。将脑震荡相关症状、心理困扰和受伤后 1 天的 C-反应蛋白血清浓度作为探索性结局纳入其中。计划的对比分别比较了脑震荡运动员和对照组中巨细胞病毒血清阳性者的影响。巨细胞病毒对脑震荡运动员的轴向和径向峰度有显著影响，但对对照组没有影响。脑震荡阳性的巨细胞病毒运动员的轴向（P = 0.007，d = 0.44）和径向（P = 0.010，d = 0.41）峰度均大于脑震荡阴性的巨细胞病毒运动员。同样，巨细胞病毒与脑震荡运动员的皮质厚度之间存在显著关联，但与对照组无关。与脑震荡阴性的巨细胞病毒运动员相比，脑震荡阳性的巨细胞病毒运动员的右侧大脑半球平均皮质厚度降低（P = 0.009，d = 0.42），左侧大脑半球也表现出类似的趋势（P = 0.036，d = 0.33）。巨细胞病毒对峰度各向异性分数、表面积、症状和 C-反应蛋白没有显著影响。研究结果提示，巨细胞病毒感染可能通过加剧与脑震荡相关的神经炎症，导致脑震荡后的结构性脑异常。需要进一步研究以确定该过程的生物学途径，并阐明这种潜在病毒作用的临床意义。
