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【神经科学前沿技术培训系列】详见文末
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审阅︱乐卫东
责编︱王思珍
神经退行性疾病（Neurodegenerative diseases，NDs）是以神经元和胶质细胞进行性功能障碍为特征的神经系统疾病，导致其在中枢和/或周围神经系统中的结构和功能退化。既往对NDs的研究往往忽视了小脑的作用，越来越多的临床和生物学证据表明小脑与NDs之间存在重要联系。传统上，小脑被认为是控制运动的结构，例如运动、步态、姿势和平衡。然而，近年来越来越多的研究强调了小脑的非运动功能，包括认知、行为和情感处理。小脑可能通过多种机制参与NDs的发生和发展，包括神经退行性变、神经炎症、氧化应激和代谢改变等。靶向小脑的治疗方式在治疗神经退行性疾中可能是有价值的。1. 阿尔茨海默病（Alzheimer’s disease，AD）和小脑
既往对于AD的研究主要集中于大脑和海马，但新兴的研究揭示了小脑在AD中的作用。AD小脑表现出典型的Aβ和Tau病理，并且小脑可能与认知和行为变化有关。我们团队之前的研究揭示了在AD模型小鼠出现病理变化之前小脑就已经出现电生理改变[1]。在早期阶段，小脑可能起到代偿作用，减缓临床症状的进展[2, 3]。AD小脑表现出显著的线粒体功能障碍、氧化应激和代谢紊乱，并且可能发生在疾病早期[4, 5]。此外，在AD小脑中观察到浦肯野细胞的丢失、颗粒细胞的减少、小胶质细胞的激活和星形胶质细胞的增殖[6, 7]。小脑结构和功能的变化可能与疾病进展有关，并可能有助于AD的早期诊断。2. 帕金森病（Parkinson’s disease，PD）和小脑
在PD中，小脑中存在α-synuclein和多巴胺能功能障碍[8]。PD患者表现出明显的小脑灰质萎缩[9]。PD患者的小脑变化可能与临床症状和疾病分期有关，随着疾病的进展，小脑体积逐渐缩小[10]。PD患者小脑也与运动和精神症状有关[11-13]。神经递质变化和代谢改变发生在PD小脑中，与疾病进展相关[14, 15]。小脑在PD中受到影响，并与疾病进展相关。3. 肌萎缩侧索硬化症（Amyotrophic lateral sclerosis，ALS）和小脑
ALS 的特征性病理变化包括谷氨酸兴奋性毒性、蛋白质错误折叠和异常聚集、炎症、细胞凋亡、线粒体功能障碍和氧化应激[16]。在ALS患者中观察到小脑显着萎缩[17]。ALS 患者小脑中可以发现浦肯野细胞丢失、星形胶质细胞增加和小胶质细胞活化[18, 19]。ALS 患者小脑氧化应激和炎症加剧[20]。小脑受ALS典型病理的影响，表现出结构和功能异常，并且与临床症状有关。4. C型尼曼-匹克病和小脑
小脑在C型尼曼-匹克病的早期阶段受到严重影响[21]。小脑体积减少与患者临床症状的严重程度有关[22]。浦肯野细胞死亡发生在C型尼曼-匹克病患者的小脑中，随着疾病的进展而细胞死亡增加[23]。C型尼曼-匹克病模型小鼠小脑早期出现小胶质细胞激活和星形胶质细胞的显著增加[24, 25]。5. 亨廷顿病（Huntington’s disease，HD）和小脑
突变的亨廷顿蛋白在HD患者小脑中显著过表达[26]。HD患者小脑的灰质和白质体积都显著减少，表现出明显的萎缩[27]。HD患者的小脑萎缩发生在疾病早期，与疾病进展和临床症状有关[28, 29]。HD患者的小脑中存在神经退行性变和代谢紊乱[30, 31]。6. 额颞叶痴呆（Frontotemporal dementia，FTD）和小脑
FTD 以家族性和散发性形式存在，其中C9orf72突变是最常见的原因。C9orf72-FTD小脑中六核苷酸重复扩增与疾病严重程度相关[32]。在FTD中，小脑与行为和认知障碍有关[33]。FTD小脑表现出明显的萎缩，并且与疾病症状和进展相关[34, 35]。小脑相关治疗方法可促进NDs的治疗并改善临床症状。小脑磁刺激可有效调节AD患者的胆碱能活性[36]。对小脑的经颅电刺激可以改善PD患者的步态障碍[37]。小脑的经颅交流电刺激可以减少PD患者的静止性震颤[38]。小脑的经颅直流电刺激是增强PD运动学习的潜在干预措施[39]。小脑的靶向治疗对NDs具有巨大治疗潜力，需要进一步研究小脑相关治疗方法对NDs的价值。小脑相关治疗方法可能为治疗这些疾病提供有前途且安全的选择。
在既往NDs的相关的研究中，小脑通常没有得到足够的关注。目前表明，小脑在NDs中起着关键作用。首先，小脑在NDs中受到影响。小脑萎缩发生在NDs中，并与疾病的严重程度相关。甚至于在疾病的早期阶段，小脑就出现萎缩。不同类型的NDs可能表现出不同的小脑改变。特定小脑区域的受累可能导致特定症状。其次，小脑可能起到储备和代偿作用，减缓疾病进展。但是，这种代偿能力可能会在疾病晚期丢失。最后，NDs中的小脑会出现各种病理和生化变化，主要是神经退行性变、神经炎症、线粒体功能障碍、代谢紊乱和神经递质变化。小脑磁刺激和电刺激、物理疗法、干细胞疗法和药物治疗可能有助于这些疾病的治疗。总之，小脑对NDs的早期诊断、治疗和预防疾病进展具有重要价值。
原文链接：https://doi.org/10.1016/j.isci.2024.111194转载须知：“逻辑神经科学”特邀稿件，且作者授权发布；本内容著作权归作者和“逻辑神经科学”共同所有；欢迎个人转发分享，未经授权禁止转载，违者必究。
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