双相障碍临床超高危人群大脑结构纵向改变与临床转归的关系、机制和影响因素

Bipolar disorder (BP) is a recurrent disabling mental illness, with a lifetime prevalence of 1-4%.Recently clinical staging models that cut across the dichotomous category of the present classification systems have been proposed for BP, with emphases on the stages that are prior to the official onset, which are high-risk and ultra-high-risk stages. During high-risk stage, individuals with risk factors (e.g. genetic susceptibility) manifest no or non-specific symptoms. While in the ultra-high-risk (UHR) stage (exchangeable with clinically ultra-high-risk), individuals manifest both genetic susceptibility and sub-threshold syndromes...More recently, our research on the UHR stage of BP suggested that UHR individuals manifested abnormal brain structures (i.e. increased gray matter volumes in the left superior frontal cortex, right posterior cingulated cortex, middle and inferior occipital cortex, and the left superior parietal cortex, and the left parietal cortex) that were distinguishable from high-risk individuals. During an on average of one-year follow-up, approximately 25% individuals developed full-blown BP. ..There has been little knowledge about the mechanism by which individuals at UHR stage of BP display abnormal changes in the brain structure (e.g. increased gray matter volumes in the right superior frontal cortex). Body responds to stress caused by adverse physical and psychosocial conditions through hormonal mediators, which are glucocorticoids and catecholamines. On one hand, they are essential for adaptation, maintenance of homeostasis and survival in short run. On the other, if the stress is prolonged, these hormones will exert detrimental effects on the body. Such cost to the body is considered as allostatic load. BP has been hypothesized as a disease of allostatic load, which helps to explain some characteristics and impairments in multiple systems seen in BP, including cognitive impairment, increased inflammatory reactions, high comorbidity with physical conditions such as cardiovascular disease and diabetes. Thus, we hypothesize that allostatic load may underlie the abnormal brain structural changes in the UHR individuals. . .We will prospectively follow up 100 individuals at the UHR stage of BP using our previous validated UHR criteria for BP for 2.0-2.5 years. A comparison group of 50 health controls will be recruited. T1-weighted images and Diffusion Tensor Images (DTI) are used to assess the gray matter volumes and white matter integrity both at baseline and the follow-up time. The longitudinal changes in gray matter volume and white matter integrity from baseline to the follow-up time will be compared between the UHR group and the healthy controls and between BP-onset group and BP-non-onset group confirmed by the follow-up. The relations between the longitudinal changes of gray mater volumes, white mater integrity and clinical characteristics will be assessed. To assess the impact of allostatic load on the changes in brain structure, we will first measure a collection of biomarkers for allostatc load in the UHR individuals, including IL-6, IL-10, TNF-alpha, and glucocorticoid, then their relations with longitudinal changes in gray matter volumes will be assessed. Finally, in applying a biopsychosocial medical model, we will test both risk factors and protective factors for the development of BP and the interactions of environmental factors with biological factors...This study is a prospective longitudinal design.By studying the association between longitudinal changes in the brain structure and the clinical outcome of UHR individuals for BP, it opens the opportunity for putting into practice early intervention for BP. Furthermore, although UHR individuals fall short of the criteria for bipolar disorder, some, if not many, are already suffering from varying symptoms. This study sheds light on the clinical need of UHR individuals, with attempts to provide evidence for justifying early intervention.

双相障碍临床超高危人群（即双相障碍患者一级亲属并且临床表现为亚临床综合征）进一步发展为双相障碍的风险很高。我们前期研究报道，双相障碍临床超高危人群的脑结构异常，表现为前额叶等脑区灰质体积增多；平均1年的临床随访发现，双相障碍转化率为25%。目前，疾病转化的神经结构基础及其机制不明。因此，本研究拟对100例双相障碍临床超高危人群进行前瞻性随访研究（2.0-2.5年），结合多模态神经影像学、分子生物学和认知行为学等手段探讨：双相障碍临床超高危人群脑结构（皮层灰质和白质纤维）的进行性改变与临床转归的关系；非稳态负荷机制（包括皮质醇增高、过度代偿反应和慢性炎症反应等）与脑结构改变的关系；多层次探索不同因素（如生活事件、情感气质和HPA轴调节异常）及其相互作用对该人群临床转归和功能的影响。本研究不局限于目前只关注发作期的诊断模式，重视疾病早期阶段，有利于双相障碍病理机制的探讨和为早期干预提供靶标。

双相障碍是一种常见的精神障碍，临床表现为既有抑郁发作又有躁狂或 轻躁狂发作。一旦发病，许多患者需要终身服药，且双相障碍具有反复发作和慢性化的特点。双相障碍的预防和早期发现是一个重要的科学问题。双相障碍临床超高危人群，我们定义为既有双相障碍父母家族史并且已经出现亚临床（阈下）综合征，该人群进一步发生发展为双相障碍的风险较高。在此背景下，此项目拟计划对100例双相障碍临床超高危人群进行横断面和纵向跟踪随访研究，以期发现双相障碍发病前（临床超高危期）的病理生理特征（包括脑结构、认知功能和炎症反应等）和预测双相障碍发病的生物学标记物。 主要研究内容为： ①探索双相障碍发病前的高危期和临床超高危期的特征和机制，包括脑结构和脑功能、认知功能和炎症反应等角度； ②确定可预测双相障碍临床超高危人群发生双相障碍的生物学标记物。. 项目顺利完成，共收集105名双相临床超高危和65名正常对照组，收集的数据资料详实，随访时程中位数约1.5年。此项目研究资料已完成数据分析和论文撰写，共发表10篇SCI收录论文，主要结果数据和发现介绍如下： （1）在双相障碍临床超高危人群中，近20%的被试在随访期（中位数约1.5年）发生双相障碍，大脑白质钩状束（UA）微结构（FA值）可预测双相障碍是否发病，敏感性88.9%，特异性77.3% （ Li et al., Translational Psychiatry, 2021）（2）双相障碍临床超高危人群（有阈下症状的双相障碍患者子女）的炎症反应水平指标（IL-6）较无症状的双相障碍患者子女明显升高，可能与代偿反应和非稳态反应有关。大脑前扣带回缘部的灰质体积与IL-6水平成正相关，并且前扣带回缘部的灰质体积部分介导了IL-6对双相障碍高危人群认知功能的影响（Lin K., et al., Brain Behav Immun.2020;83:192-199）。（3）双相障碍临床超高危期与正常对照组比较，出现工作记忆、时空间记忆和认知计划能力的损害。（4）双相障碍疾病生物标记物包括双侧颞叶-纹状体环路和小脑部分区域的灰质体积减少；双相障碍内表型包括双侧小脑灰质体积减少（Lin et al., J Affect Disord. 2018）