Department of Child Development, United Graduate School of Child Development, Osaka University, Osaka, Japan; Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.
Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine, Osaka, Japan.
Neuroimage Clin. 2023;37:103288. doi: 10.1016/j.nicl.2022.103288. Epub 2022 Dec 12.
Neuroinflammation contributes to the severity of various neurological disorders, including epilepsy. Tuberous sclerosis complex (TSC) is a condition that results in the overactivation of the mammalian target of rapamycin (mTOR) pathway, which has been linked to the activation of microglia responsible for neuroinflammation. To clarify the involvement of neuroinflammation in the neuropathophysiology of TSC, we performed a positron emission tomography (PET) study using the translocator protein (TSPO) radioligand, [C] DPA713, and investigated microglial activation in relation to neurological manifestations, especially epilepsy and cognitive function.
This cross-sectional study included 18 patients with TSC (6 in the no-seizure group, 6 in the refractory seizure group, and 6 in the mTOR-inhibitor [mTOR-i] group). All participants underwent [C] DPA713-PET. PET results were superimposed with a 3D T2-weighted fluid-attenuated inversion-recovery (FLAIR) and T1-weighted image (T1WI) to evaluate the location of cortical tubers. Microglial activation was assessed using the standardized uptake value ratio (SUVr) of DPA713 binding. The volume ratio of the DPA713-positive area to the intracranial volume (volume ratio of DPA713/ICV) was calculated to evaluate the extent of microglial activation. A correlation analysis was performed to examine the relationship between volume ratio of DPA713/ICV and severity of epilepsy and cognitive function.
Most cortical tubers with hyperintensity on FLAIR and hypo- or isointensity on T1WI showed microglial activation. The extent of microglial activation was significantly greater in the refractory seizure group than in the no-seizure or mTOR-i groups (p < 0.001). The extent of microglial activation in subjects without mTOR-i treatment correlated positively with epilepsy severity (r = 0.822, P = 0.001) and negatively with cognitive function (r = -0.846, p = 0.001), but these correlations were not present in the mTOR-i group (r = 0.232, P = 0.658, r = 0.371, P = 0.469, respectively).
Neuroinflammation is associated with the severity of epilepsy and cognitive dysfunction in brains with TSC. mTOR-i may suppress the extent of neuroinflammation in TSC. Investigating the spread of microglial activation using TSPO-PET in these patients may help to predict the progression of neuropathy by assessing the degree of neuroinflammation and therefore be useful for determining how aggressive the treatment should be and in assessing the effectiveness of such treatment in patients with TSC.
神经炎症与各种神经疾病（包括癫痫）的严重程度有关。结节性硬化症（TSC）是一种导致哺乳动物雷帕霉素靶蛋白（mTOR）通路过度激活的疾病，该通路与负责神经炎症的小胶质细胞的激活有关。为了阐明神经炎症在 TSC 神经病理生理学中的作用，我们使用转位蛋白（TSPO）放射性配体[C] DPA713 进行了正电子发射断层扫描（PET）研究，并研究了与神经表现，尤其是癫痫和认知功能相关的小胶质细胞激活。
本横断面研究纳入了 18 名 TSC 患者（无癫痫发作组 6 名，难治性癫痫发作组 6 名，mTOR 抑制剂（mTOR-i）组 6 名）。所有参与者均接受了[C] DPA713-PET 检查。将 PET 结果与三维 T2 加权液体衰减反转恢复（FLAIR）和 T1 加权图像（T1WI）叠加，以评估皮质结节的位置。使用 DPA713 结合的标准化摄取值比（SUVr）评估小胶质细胞激活。计算 DPA713 阳性区域与颅内体积的体积比（DPA713/ICV 的体积比），以评估小胶质细胞激活的程度。进行了相关性分析，以检查 DPA713/ICV 体积比与癫痫严重程度和认知功能之间的关系。
FLAIR 上呈高信号且 T1WI 上呈低信号或等信号的大多数皮质结节显示出小胶质细胞激活。难治性癫痫发作组的小胶质细胞激活程度明显高于无癫痫发作组或 mTOR-i 组（p<0.001）。无 mTOR-i 治疗的受试者的小胶质细胞激活程度与癫痫严重程度呈正相关（r=0.822，P=0.001），与认知功能呈负相关（r=-0.846，p=0.001），但在 mTOR-i 组中未观察到这些相关性（r=0.232，P=0.658，r=0.371，P=0.469）。
神经炎症与 TSC 大脑中癫痫发作的严重程度和认知功能障碍有关。mTOR-i 可能抑制 TSC 中小胶质细胞激活的程度。使用 TSPO-PET 研究这些患者的小胶质细胞激活的传播情况，通过评估神经炎症的程度，可能有助于预测神经病变的进展，从而有助于确定治疗的侵袭性，并评估 TSC 患者治疗的有效性。
