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Detection of endophenotypes associated with neuropsychiatric deficiencies in a mouse model of tuberous sclerosis complex using diffusion tensor imaging
Brain Pathology ( IF 6.4 ) Pub Date : 2020-06-12 , DOI: 10.1111/bpa.12870 Christine Chin‐jung Hsieh, Yu‐Chun Lo, Ssu‐Ju Li, Ting‐Chun Lin, Ching‐Wen Chang, Ting‐Chieh Chen, Shih‐Hung Yang, Yi‐Chao Lee, You‐Yin Chen
Brain Pathology ( IF 6.4 ) Pub Date : 2020-06-12 , DOI: 10.1111/bpa.12870 Christine Chin‐jung Hsieh, Yu‐Chun Lo, Ssu‐Ju Li, Ting‐Chun Lin, Ching‐Wen Chang, Ting‐Chieh Chen, Shih‐Hung Yang, Yi‐Chao Lee, You‐Yin Chen
Tuberous sclerosis complex (TSC) is a rare hereditary disease, which results from the mutation of either TSC1 or TSC2, and its clinical features include benign tumors and dysfunctions in numerous organs, including the brain. Many individuals with TSC manifest neuropsychiatric symptoms, such as learning impairments, cognitive deficits and anxiety. Current pharmacological treatment for TSC is the use of mTOR inhibitors. However, they are not effective in treating neuropsychiatric symptoms. We previously used curcumin, a diet‐derived mTOR inhibitor, which possesses both anti‐inflammatory and antiproliferative properties, to improve learning and memory deficits in Tsc2+/− mice. Diffusion tensor imaging (DTI) provides microstructural information in brain tissue and has been used to study the neuropathological changes in TSC. In this study, we confirmed that the impaired recognition memory and increased anxiety‐like behavior in Tsc2+/− mice can be reversed by curcumin treatment. Second, we found altered fractional anisotropy and mean diffusivity in the anterior cingulate cortex and the hippocampus of the Tsc2+/− mice, which may indicate altered circuitry. Finally, the mTOR complex 1 hyperactivity was found in the cortex and hippocampus, coinciding with abnormal cortical myelination and increased glial fibrillary acidic protein expression in the hippocampal CA1 of Tsc2+/− mice, both of which can be rescued with curcumin treatment. Overall, DTI is sensitive to the subtle alterations that cannot be detected by conventional imaging, suggesting that noninvasive DTI may be suitable for longitudinally monitoring the in vivo neuropathology associated with the neuropsychiatric symptoms in TSC, thereby facilitating future clinical trials of pharmacological treatments.
中文翻译:
使用弥散张量成像检测结节性硬化症小鼠模型中与神经精神缺陷相关的内表型
结节性硬化症 (TSC) 是一种罕见的遗传性疾病,由TSC1或TSC2突变引起,其临床特征包括良性肿瘤和包括大脑在内的许多器官的功能障碍。许多患有 TSC 的人表现出神经精神症状,例如学习障碍、认知缺陷和焦虑。目前 TSC 的药物治疗是使用 mTOR 抑制剂。然而,它们不能有效治疗神经精神症状。我们以前使用姜黄素,一种饮食衍生的 mTOR 抑制剂,它具有抗炎和抗增殖的特性,来改善Tsc2 的学习和记忆缺陷+/-老鼠。弥散张量成像 (DTI) 提供脑组织的微观结构信息,并已用于研究 TSC 的神经病理学变化。在这项研究中,我们证实了姜黄素治疗可以逆转Tsc2 +/-小鼠中受损的识别记忆和增加的焦虑样行为。其次,我们发现Tsc2 +/-小鼠的前扣带回皮层和海马的各向异性分数和平均扩散率发生了改变,这可能表明电路发生了改变。最后,在皮层和海马中发现了 mTOR 复合物 1 过度活跃,这与Tsc2的海马 CA1 中异常的皮质髓鞘形成和胶质纤维酸性蛋白表达增加一致+/-小鼠,两者都可以通过姜黄素治疗获救。总体而言,DTI 对常规成像无法检测到的细微变化很敏感,这表明无创 DTI 可能适用于纵向监测与 TSC 中神经精神症状相关的体内神经病理学,从而促进未来的药物治疗临床试验。
更新日期:2020-06-12
中文翻译:
使用弥散张量成像检测结节性硬化症小鼠模型中与神经精神缺陷相关的内表型
结节性硬化症 (TSC) 是一种罕见的遗传性疾病,由TSC1或TSC2突变引起,其临床特征包括良性肿瘤和包括大脑在内的许多器官的功能障碍。许多患有 TSC 的人表现出神经精神症状,例如学习障碍、认知缺陷和焦虑。目前 TSC 的药物治疗是使用 mTOR 抑制剂。然而,它们不能有效治疗神经精神症状。我们以前使用姜黄素,一种饮食衍生的 mTOR 抑制剂,它具有抗炎和抗增殖的特性,来改善Tsc2 的学习和记忆缺陷+/-老鼠。弥散张量成像 (DTI) 提供脑组织的微观结构信息,并已用于研究 TSC 的神经病理学变化。在这项研究中,我们证实了姜黄素治疗可以逆转Tsc2 +/-小鼠中受损的识别记忆和增加的焦虑样行为。其次,我们发现Tsc2 +/-小鼠的前扣带回皮层和海马的各向异性分数和平均扩散率发生了改变,这可能表明电路发生了改变。最后,在皮层和海马中发现了 mTOR 复合物 1 过度活跃,这与Tsc2的海马 CA1 中异常的皮质髓鞘形成和胶质纤维酸性蛋白表达增加一致+/-小鼠,两者都可以通过姜黄素治疗获救。总体而言,DTI 对常规成像无法检测到的细微变化很敏感,这表明无创 DTI 可能适用于纵向监测与 TSC 中神经精神症状相关的体内神经病理学,从而促进未来的药物治疗临床试验。