miR132/212调控神经保护因子预测老年抑郁症转归的纵向随访研究

Late-Life Depression (LLD) brings heavy disease burden. It is an important public health problem. LLD have separately outcomes, including dementia, remission and partial recovery, which indicates the heterogeneous LLD has sub-types. To date, the LLD outcomes can not be predicted, so that LLD patients might be wrongly treated. Evidences showed microRNA132/212-Sirt1 could connect the Blood Brain-Derived neurotrophic factor (BDNF) and S100β levels. They participated in the occurrence and progression of depression, aging and dementia. Our preliminary study showed LLD patients with high dementia risk had different changing pattern in serum BDNF and S100β levels. Furthermore, the levels in older adults were related to the atrophy of front lobe. These results supported our hypothesis that LLD is the result of neuroprotective attenuation under the impact of “aging-disease”, and indicated that BDNF-miR132/212-Sirt1-S100β pattern might work as peripheral markers to predict the outcomes of LLD. In the study, we plan to recruit 200 LLD patients and 200 community dwelling health elders, measure their blood neuroprotective factors, along with the MRI scan, APOE gene types measurement and clinical neuro-psychological test. Our aim is to build up a predicting model for LLD outcomes, provide evidences for LLD's precision medicine and further mechanism exploration.

老年抑郁症（LLD）疾病负担沉重，是重要的公共卫生问题。其治疗结局不一，说明LLD的异质性显著。当前缺乏有效的生物学标记物区分LLD以预测其转归，致使贻误治疗时机。有证据表明，衰老相关因子miR132/212-Sirt1可衔接脑源性神经营养因子（BDNF）与S100β蛋白，参与了抑郁症、老化、痴呆的发生发展。为此我们提出LLD在“老龄-疾病”作用下神经保护削弱的假设。前期我们的研究显示，痴呆高危的LLD患者血清BDNF、S100β水平变化符合我们的预警假设，并与大脑前额叶的萎缩相关，提示BDNF-miR132/212-Sirt1-S100β这一神经保护因子系列作为外周标记物预测LLD转归的可能性。本研究将以社区老人为对照，检测200例LLD患者上述神经保护因子，纵向随访三年，结合头颅MRI、载脂蛋白E基因分型与临床评估，建立LLD的转归预测模型并予以验证，为精准医疗与病因研究奠定基础。

老年抑郁症(LLD)占60岁以上老年人年致残率的5.7%,是重要的公共卫生问题。其治疗结局不一，说明LLD的异质性显著。当前精神疾病的诊断仍是临床医师通过家属的对患者症状行为的描述，结合量表评估结果所做的主观判断，缺乏敏感有效的生物学指标，必然导致高误诊率及漏诊率，进而延误最佳治疗时机，造成不良的预后。本研究通过衰老相关因子miR132/212-Sirt1可衔接脑源性神经营养因子(BDNF)与 S100β蛋白，免疫炎症因子结合头颅MRI、载脂蛋白E基因分型与临床评估，从多方面观察其在抑郁症、老化、痴呆的发生发展。我们的研究显示，⑴通过随访我们可以发现老年人抑郁症的转归可大体归纳为4个方面:治愈或临床 痊愈、转为慢性抑郁或有残留症状、进展为各种类型的神经认知障碍、自杀或死亡。⑵虽然在老年抑郁症患者急性期存在BDNF与 S100β蛋白增高，但受抗抑郁药影响，与抑郁症状改善关联较弱。⑶miRNA132在抑郁症发作期增高，缓解期趋向正常，可能与老年抑郁症转归的关联。⑷通过进一步比较老年抑郁症患者与痴呆高危患者血浆免疫因子，提示两者均存在免疫反应异常，然而在老年抑郁症患者中大多免疫相关因子表达量减少而痴呆高危患者中则恰恰相反，相比之下老年抑郁症免疫特征似乎与阿尔茨海默症患者表现更为类似，进一步证明老年抑郁症可能是痴呆的风险因素，⑸IL-6联合血沉等多指标显示对两者较好的区分效果, 预测老年抑郁症诊断准确率为84.8%，灵敏度为83.3%，特异86.4%.研究的最终目的是为LLD患者寻找早期诊断的生物指标和早期干预的理论依据。我们的早期动物研究和临床研究数据支持miRNA132参与疾病的转归，也揭示了免疫炎症在LLD与阿尔茨海默病的关联性。