Supplementary file 1_Hippocampal dysmetabolism contributes to cognitive loss in autoimmune encephalitis and focal temporal epilepsy.docx

IntroductionAutoimmune encephalitis (AE) is associated with severe cognitive disability. Brain metabolic dysfunction has been linked to encephalopathy in neurodegenerative disorders; however, its role in the development of cognitive loss in AE has not been studied. We hypothesized that cognitively impaired patients with AE will demonstrate altered brain metabolism and immune activation, and these measures will correlate with cognitive scores.
MethodsThe hippocampal and cortical metabolites related to neuronal integrity, oxidative metabolism, and glial activation were assessed using single-voxel proton magnetic resonance spectroscopy (1H-MRS) in patients with AE, non-lesional temporal lobe epilepsy (TLE) and control subjects. Metabolite levels were correlated with neuropsychological test scores.
ResultsWe recruited patients with post-acute AE (n = 12), non-lesional TLE (n = 12), and control subjects (n = 11). Subjective cognitive complaints were reported by 83.3% of AE and all TLE patients. AE patients had fewer seizures and used fewer anti-seizure medications than TLE patients (p = 0.04, t-test and p = 0.03, post-hoc test). On neuropsychological testing, moderate and severe cognitive impairment was revealed in 58.3% of patients with AE and 41.6% of patients with TLE. Hippocampal myo-inositol (M-Ins) concentrations were higher in patients compared to control subjects, with a trend toward increase in AE and TLE relative to control (p = 0.046, ANOVA; p = 0.09 and p = 0.07 for AE and TLE vs. control, respectively; post-hoc tests). The concentration of creatine (tCr) and total choline (tCho) were significantly higher in patients with TLE compared to the controls (tCr: p = 0.007; tCh: p = 0.04; post-hoc tests). Elevated M-Ins in AE was associated with better attention but worse memory recognition scores (R2 = 0.38, p = 0.04 and R2 = 0.50, p = 0.02, respectively); higher tCr levels correlated with faster processing speed (R2 = 0.38; p = 0.04). The higher concentrations of tCr, tCho, and M-Ins in TLE have selectively correlated with worse measures of attention, processing speed, language, and memory.
ConclusionsAlthough AE and TLE patients report similar cognitive issues, their hippocampal metabolic signatures differ. The disease-specific changes in the measures of hippocampal inflammation and neuronal integrity can inform trajectories for cognitive recovery and be targeted therapeutically.

引言
自身免疫性脑炎（Autoimmune Encephalitis, AE）与严重的认知功能障碍密切相关。脑代谢功能异常已被证实与神经退行性疾病中的脑病相关，但目前尚未有研究探讨其在自身免疫性脑炎患者认知减退发生发展中的作用。本研究假设，合并认知受损的自身免疫性脑炎患者会表现出脑代谢与免疫激活状态的改变，且这些指标与认知评分存在相关性。

方法
本研究采用单体素质子磁共振波谱（Single-voxel Proton Magnetic Resonance Spectroscopy, 1H-MRS），对自身免疫性脑炎患者、非病灶性颞叶癫痫（Temporal Lobe Epilepsy, TLE）患者及健康对照受试者中与神经元完整性、氧化代谢及神经胶质激活相关的海马及皮层代谢物进行检测，并将代谢物水平与神经心理学测试评分进行相关性分析。

结果
本研究共纳入急性后期自身免疫性脑炎患者12例、非病灶性颞叶癫痫患者12例及健康对照受试者11例。83.3%的自身免疫性脑炎患者及全部颞叶癫痫患者均报告了主观认知主诉。与颞叶癫痫患者相比，自身免疫性脑炎患者的癫痫发作次数更少、抗癫痫药物使用量更少（t检验：p=0.04；事后检验：p=0.03）。神经心理学测试结果显示，58.3%的自身免疫性脑炎患者及41.6%的颞叶癫痫患者存在中度至重度认知功能受损。与健康对照相比，所有患者的海马肌醇（Myo-inositol, M-Ins）浓度均更高，自身免疫性脑炎与颞叶癫痫患者的肌醇浓度均呈现出较对照升高的趋势（方差分析：p=0.046；自身免疫性脑炎、颞叶癫痫与对照组比较的事后检验分别为p=0.09、p=0.07）。与健康对照相比，颞叶癫痫患者的肌酸（Creatine, tCr）及总胆碱（Total Choline, tCho）浓度显著升高（肌酸：p=0.007；总胆碱：p=0.04；事后检验）。自身免疫性脑炎患者升高的肌醇浓度与更好的注意力表现及更差的记忆再认评分相关（决定系数R²=0.38，p=0.04；R²=0.50，p=0.02）；更高的肌酸水平与更快的信息处理速度相关（R²=0.38，p=0.04）。颞叶癫痫患者升高的肌酸、总胆碱及肌醇浓度则分别与更差的注意力、信息处理速度、语言功能及记忆表现相关。

结论
尽管自身免疫性脑炎与颞叶癫痫患者报告的认知问题相似，但二者的海马代谢特征存在差异。海马炎症与神经元完整性相关指标的疾病特异性变化，可为认知恢复轨迹提供参考，并可作为治疗靶向目标。