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类型 其它 预答辩日期 2017-10-09
开始(开题)日期 2016-01-19 论文结束日期 2017-04-10
地点 中大医院2号楼10楼示教室 论文选题来源 973、863项目     论文字数 5 (万字)
题目 早发型和晚发型抑郁症患者神经认知与基于静息态功能磁共振的神经影像学研究
主题词 早发型抑郁症,晚发型抑郁症,认知功能,神经影像学
摘要 研究背景 抑郁症是一种高度一致性的精神障碍疾病,在老年期(≥60岁)这一特定人群的抑郁症通常称为老年抑郁症(late life depression, LLD)。目前,随着社会老龄化进程的加快,老年抑郁症已经成为严重的社会公共健康问题。既往有研究根据抑郁症首次发病年龄的不同,将抑郁症分为早发型抑郁症(early onset depression, EOD)和晚发型抑郁症(late onset depression, LOD)。其后研究发现,相较于LOD患者,EOD患者嗜睡、焦虑、自杀意念和自杀行为等表现更为明显,并且其与家族遗传史关系更为密切。而LOD患者则更多的表现为快感缺失,且血管性病理改变更为显著。此外,LOD患者神经认知损害更为严重,大脑异常改变也更为突出,甚至今后发展为痴呆的风险也更高。 在神经认知方面,近年来的研究表明,老年抑郁症常伴随有多领域认知损害,且随着抑郁症状的缓解,这些认知损害并未恢复到正常水平。在急性期老年抑郁症患者中,信息处理速度被认为是其核心认知损害,可以介导其他临床症状对其余认知领域的影响,而执行功能则是仅次于信息处理速度的核心认知损害。但是有研究发现抑郁症状恢复后,老年抑郁症患者的信息处理速度恢复到正常水平,因此恢复期老年抑郁症信息处理速度不再处于核心地位。既往研究发现,LOD患者在记忆功能、信息处理速度和执行功能方面损害更为严重,那么在恢复期的LOD患者中,信息处理速度是否已经恢复到正常水平仍不明确,并且信息处理速度是否仍然处于核心地位也不清楚。 近些年来,影像学技术已成为大脑神经科学和精神病学研究领域中的重要工具之一。其中,抑郁症的“脑神经网络功能调节障碍”假说已经成为抑郁症神经认知科学研究最受关注的热点之一。然而,目前关于抑郁症异常脑区的致病机制仍未明确,并且没有较为一致的研究结果,这可能是抑郁症异质性的一个表现。目前关于EOD和LOD的研究中,结构影像学表明LOD在海马等脑区体积减小更为严重,但是并未发现有关于功能影像学方面的直接比较研究。既往年轻抑郁症与老年抑郁症的比较中可以发现,两个抑郁亚型的大脑功能存在一定的差异性,但是这两者年龄存在显著性差异,这可能对功能影像的结果造成一定的影像。因此,十分有必要直接比较老年期的EOD和LOD患者的大脑功能情况。血氧水平依赖性信号(Blood Oxygenation Level-Dependent, BOLD)和动脉自旋标记信号(arterial spin labeling, ASL)是目前使用较多的用于研究大脑功能的磁共振技术。其中,采用BOLD序列进行功能连接分析可以探讨大脑功能的整合情况,分析脑区与脑区之间网络的异常改变。而采用ASL序列可以计算大脑局部脑血流量(cerebral blood flow, CBF),可以反映大脑的局部功能情况。 在本研究中,我们通过选取恢复期的EOD和LOD患者以及年龄匹配的健康受试者,采用多维度认知神经心理学量表评估认知功能,并利用静息态功能磁共振(Functional Magnetic Resonance Imaging, fMRI)探讨大脑功能状况:(1)探讨探讨恢复期EOD和LOD患者认知损害严重程度及其核心认知领域与临床变量之间关联性;(2)利用BOLD序列探讨恢复期晚发型和早发型抑郁症患者在默认网络、执行控制网络和突显网络中功能连接的特点;(3)采用ASL技术分析恢复期早发型和晚发型抑郁症患者脑血流量的异常改变以及这些改变与认知功能的关系。最终,希望通过以上三部分研究加深我们对EOD和LOD神经认知损害的神经功能机制的了解,为今后深入探讨两者认知损害进展方向和机制提供有价值的信息。 第一部分 恢复期早发型和晚发型抑郁症患者认知损害特征研究 目的:探讨恢复期EOD和LOD患者认知损害严重程度及其核心认知领域与临床变量之间关联性。 方法:入组36名恢复期EOD,38名恢复期LOD患者和65名年龄匹配的健康受试者。对所有受试者进行一整套神经心理学评估和磁共振扫描,神经心理学评估包括执行功能、记忆功能、信息处理速度、注意功能和视空间技能。采用方差分析、轮廓分析和逐步回归分析进行统计分析。 结果:恢复期EOD患者记忆功能显著差于健康受试者;而恢复期LOD患者执行功能、记忆功能和信息处理速度均显著差于健康受试者;两患者组比较各个认知功能无显著差异。轮廓分析显示恢复期EOD和LOD患者认知领域表现无显著差异,而各个神经心理学测试表现差异主要来源与执行功能和记忆功能。逐步回归分析显示,恢复期EOD患者中,执行功能为核心认知领域,能介导年龄对记忆功能的影响,但不能介导教育程度对注意功能的影响;而在恢复期LOD患者中,执行功能是最核心认知领域,其次为信息处理速度,其中执行功能能介导灰质体积对记忆功能的影响,而信息处理速度能介导年龄对注意功能的影响。 结论:恢复期LOD患者认知损害比恢复期EOD患者更为广泛。恢复期EOD患者核心认知领域是执行功能,而恢复期LOD患者核心认知领域是执行功能和信息处理速度。 关键词:早发型抑郁症,晚发型抑郁症,核心认知功能,执行功能,信息处理速度 第二部分 恢复期早发型和晚发型抑郁症患者静息态功能连接特征研究 目的:本研究主要探讨恢复期晚发型和早发型抑郁症患者在默认网络、执行控制网络和突显网络中功能连接的特点。 方法:本研究选取64名恢复期老年抑郁症患者(33名恢复期晚发型抑郁症患者和31名恢复期早发型抑郁症患者)和43名健康受试者。所有受试者均完成一整套完整的神经心理学评估和静息态磁共振扫描。静息态功能磁共振数据预处理后,选取5个感兴趣区作为种子点进行功能连接分析。然后,基于体素水平采用协方差分析来检查恢复期LOD、EOD患者和健康受试者功能连接的差异性。最后,提取显著组间差异脑区的功能连接值与神经认知功能z分进行偏相关分析。 结果:在默认网络中,三组受试者间功能连接差异性脑区主要集中在额叶皮层、颞叶皮层、扣带回和左侧角回。同理,在执行控制网络中,三组受试者间功能连接差异性脑区主要位于额叶皮层、颞叶皮层和扣带回;而在突显网络中,三组受试者间差异性脑区则主要位于双侧额叶-脑岛-纹状体区域、额叶皮层和中扣带回/补充运动区。与恢复期LOD患者相比,恢复期EOD患者在默认网络、执行控制网络和突显网络的功能连接下降更明显。恢复期LOD患者中记忆功能减退与执行控制网络功能连接下降显著相关。 结论:恢复期EOD和LOD患者在默认网络、执行控制网络和突显网络中功能连接均显著下降,且恢复期EOD患者下降更为明显。此外,恢复期LOD患者执行控制网络功能连接损害能直接影响记忆功能的改变。 关键词:早发型抑郁症(EOD),晚发型抑郁症(LOD),默认网络(DMN),执行控制网络(ECN),突显网络(SN) 第三部分 恢复期早发型和晚发型抑郁症患者脑血流量分布特点 目的:分析恢复期早发型和晚发型抑郁症患者脑血流量的异常改变以及这些改变与认知功能的关系。 方法:本研究入组32名恢复期EOD,32名恢复期LOD和43名年龄匹配的健康受试者。对所有受试者进行一整套神经心理学评估和pASL序列磁共振扫描。采用基于体素的统计分析方法分析pASL数据。 结果:恢复期LOD患者低灌注脑区主要位于双侧楔前叶、楔叶、右侧额叶-扣带回-纹状体区域、右侧颞叶皮层、枕叶皮层和顶叶皮层,而高灌注脑区主要位于左侧额叶皮层、颞叶皮层和扣带回。恢复期EOD患者低灌注脑区主要位于左侧小脑和右侧距状回/舌头/梭状回区域,而高灌注脑区主要位于右侧角回。恢复期LOD患者脑血流量异常改变比恢复期EOD患者更为严重。恢复期LOD患者异常脑血流量与认知功能呈显著相关性,而恢复期EOD患者无此相关关系。 结论:脑血流量在大脑半球分布不对称性可能是恢复期LOD患者的特征性改变。恢复期LOD患者脑血流量的异常改变可能是影响认知损害的因素之一。 关键词:早发型抑郁症(EOD),晚发型抑郁症(LOD),脑血流量(CBF)
英文题目 Neurocognitive and neuroimaging research in early and late onset depression: based on resting-state fMRI
英文主题词 early onset depression, late onset depression, cognitive function, neuroimaging
英文摘要 Background Depression is a highly heterogeneous psychiatric disorder, and it is considered as late life depression (LLD) when depressive episode in elderly (age ≥ 60 years). Currently, with the coming of aging society, LLD has become a public health problem. According to the age of first depressive episode, LL could be divided into early onset depression (EOD) and late onset depression (LOD). Compared with LOD patients, EOD patients show more symptoms including somnolence, anxiety, suicidal ideation and suicidal behavior, and more family history of depression. In addition, LOD patients are more likely to have anhedonia and vascular pathology. Furthermore, LOD patients exhibit greater cognitive function impairments, aberrant changes of brain and risk of dementia. LLD patients always have multiple cognitive impairments, and these cognitive functions do not improve to normal level even after the depressive symptom has remitted. Information processing speed is the core cognitive impairment followed by executive function in the acute phase of LLD, meaning that it could mediate the influences of clinical variables on other cognitive domains. However, prior studies reported that information processing speed had improved to normal level after the depressive symptom remitted, and it became non-core cognitive function. LOD patients show greater memory, processing speed, executive function impairments than EOD patients. It is not clear whether information processing speed has returned to normal level and whether it is still the core cognitive function in remitted LOD. In recent years, imaging technology has become important tool in neuroscience and psychiatry research. The hypothesis of “dysfunction of brain neural network” is associated with a close attention in depression research. However, there is no consistent result of abnormal brain changes to explain the depression pathogenesis, which may be due to heterogeneity of depression. Prior study has reported greater hippocampal atrophy in LOD patients relative to EOD patients. However, we did not found the functional imaging research in both EOD and LOD patients. There are different alterations of brain function between young depression and late life depression, the differences of age may be contributed to these brain differences. Therefore, it is necessary to investigate the brain function between EOD and LOD in elderly. Blood oxygenation level-dependent (BOLD) and arterial spin labeling (ASL) are magnetic resonance techniques to investigate the brain function. The BOLD could explore the functional integration of brain by functional connectivity, and determine the network alterations between brain regions. ASL could be used to calculate the regional cerebral blood flow (CBF) values, which reflect the regional function of brain. This study recruited remitted EOD, LOD patients and age-match health controls. For all participants, we assessed their cognitive function using multi-domain neurocognitive tests and analysis brain function using resting-state functional magnetic resonance imaging data. The present study yielded three main research directions: (1) To investigate the severity and characteristic of cognitive impairments in remitted EOD and LOD patients and their relationship with clinical variables. (2) We aimed to elaborate the neurobiological markers of remitted LOD and EOD in the default mode network (DMN), executive control network (ECN) and salience network (SN) by using BOLD data. (3) We sought to investigate the CBF alterations and their relations with cognitive deficits in remitted EOD and LOD by using ASL data. Finally, this study is expected to advance the current understanding of neurobiological mechanism underlying the cognitive dysfunction in EOD and LOD patients, and shed lights on exploring the direction and mechanism of cognitive progressive degeneration in the future. Part1. The characteristic of cognitive dysfunction in remitted early onset and late onset depression Objective: To investigate the severity and characteristic of cognitive impairments in remitted EOD and LOD patients and their relationship with clinical variables. Methods: Remitted EOD (n=36), LOD (n=38) and age-matched controls (n=65) were canned with fMRI and evaluated with a battery of neuropsychological tests grouped into executive function, memory, information processing speed, attention and visuospatial domains. A series of statistical analyses were used including analysis of variance (ANOVA), profile analysis and multiple linear stepwise regression analysis. Results: Remitted EOD patients performed memory impairment and remitted LOD patients showed poor performances on executive function, memory and information processing speed relative to controls. There was no significantly different cognitive function between remitted EOD and LOD patients. Profile analysis found no significantly different patterns of cognitive domains between remitted EOD and LOD patients. While the significantly different patterns of neuropsychological tests between two patient groups mainly due to their differences in executive function and memory. Multiple linear stepwise regression analysis revealed that executive function was the core cognitive domain which mediated the influence of age on memory, but not the influence of education on attention in remitted EOD patients. Similarly, remitted LOD patients showed that executive function was the core cognitive domain followed by information processing speed. The executive function mediated the influence of grey matter volume on memory, and the information processing speed mediated the influence of age on attention. Conclusion: Remitted LOD patients have more widely cognitive impairments than remitted EOD patients. Executive function is the core cognitive function in remitted EOD patients, while executive function and information processing speed are the core cognitive functions in remitted LOD patients. Key words: early onset depression, late onset depression, core cognitive function, executive function, information processing speed. Part2. Aberrant resting-state functional connectivity between early and late onset depression Objective: This research aimed to elaborate the neurobiological markers of remitted LOD and EOD in the default mode network (DMN), executive control network (ECN) and salience network (SN). Methods: A total of 33 remitted LOD, 31 remitted EOD and 43 matched healthy controls (HC) underwent a battery of neuropsychological tests and scanned by fMRI. The three networks were explored using a seed based ROI approach. After functional image preprocessing, selected five ROIs as seeds to analysis the functional connectivity. The analysis of covariance was used to explore the differences of the seed functional connectivity in remitted EOD, LOD and HC groups. The partial correlation analysis was used to investigate the relationship between aberrant functional connectivity and cognitive domains. Results: Significantly different resting-state functional connectivity of frontal, temporal cortex, cingulate cortex and left angular within the DMN were found among the 3 groups. Similarly, there was significantly different connectivity of frontal, temporal cortex and cingulate cortex within the ECN and different connectivity of bilateral fronto-insula-striatum (FIS), frontal cortex and middle cingulate cortex/supplementary motor area (MCC/SMA) within the SN among 3 groups. The significantly low connectivity was found in DMN, ECN and SN in the remitted EOD patients compared with the remitted LOD patients. The impaired memory was significantly correlated with the decreased connectivity of ECN in remitted LOD patients. Conclusion: Both remitted EOD and LOD patients have significantly decreased functional connectivity of DMN, ECN and SN. Remitted EOD patients show greater disruptions of connectivity than remitted LOD patients. The aberrant functional connectivity of ECN is associated with memory deficit in remitted LOD patients. Key words: early onset depression, late onset depression, default mode network, executive control network, salience network. Part3. Characteristic of CBF changes in remitted early and late onset depression Objective: This research aimed to investigate the CBF alterations and their relations with cognitive deficits in remitted EOD and LOD. Methods: This study included 32 remitted EOD, 32 remitted LOD patients and 43 age-matched healthy controls (HC). All the participants underwent 3-T MRI with pulsed arterial spin labeling (pASL). The pASL data were processed by voxel-by-voxel statistical analysis. Results: There were significant hypoperfusion in bilateral precuneus, cuneus, right fronto-cingulate- striatal areas, right temporal, occipital and parietal lobes, and hyperperfusion in left frontal, temporal cortex and cingulate gyrus in LOD patients relative to healthy controls. In patients with EOD, a significant hypoperfusion was observed in left cerebellum and right calcarine/lingual/fusiform gyrus, and hyperperfusion in right angular gyrus. LOD patients demonstrated more serious CBF changes than EOD patients. Significant correlations between CBF and cognitive function were detected in LOD patients, but not EOD patients. Conclusion: These results suggest that hemispheric asymmetry of CBF may be a unique characteristic in remitted LOD patients. These alterations of CBF are likely to provide a biomarker for cognitive impairments in LOD patients. Key words: early onset depression, late onset depression, cerebral blood flow.
学术讨论
主办单位时间地点报告人报告主题
中大医院神经内科 2015-03-10 神经内科教研室 岳莹莹 抑郁症疗效预测的基因影像研究
中大医院神经内科 2014-05-20 神经内科教研室 廖文象 老年抑郁与认知损害
中大医院神经内科 2014-06-24 神经内科教研室 廖文象 老年抑郁症抗抑郁药治疗与认知功能的关系
中大医院神经内科 2014-11-04 神经内科教研室 廖文象 量表总结
东南大学医学院14级博士研究生 2014-06-04 基一楼会议室 廖文象 恢复期老年抑郁症和遗忘型轻度认知功能障碍神经影像学研究
中大医院神经内科 2015-04-14 神经内科教研室 岳春贤 记忆,再认
中大医院神经内科 2015-04-21 神经内科教研室 陈颖 DTI在老年抑郁白质异常中的应用
中大医院神经内科 2015-05-10 神经内科教研室 Gavin Reynolds Antipsychotic drug treatment – clinical effects and mechanisms
     
学术会议
会议名称时间地点本人报告本人报告题目
24th European Congress of Psychiatry 2016-03-12 西班牙马德里
遗传性神经肌肉病诊治新进展高级学习班暨2017神经肌肉病全国巡讲 2017-04-08 中大医院2号楼5楼会议中心
首届中大论坛:关注心脑及外周血管健康 2016-10-28 中大医院2号楼5楼会议中心
中华医学会第十八次全国神经病学学术会议 2015-09-18 成都 早发型和晚发型老年抑郁症静息态脑网络功能连接研究
第 3 届中国抑郁障碍研究者学术会议 2015-08-29 成都市新华宾馆 老年抑郁症和遗忘型轻度认知障碍默认网络功能连接研究
     
代表作
论文名称
The characteristic of cognitive dysfunction in remitted late life depression and amnestic MCI
Cerebral blood flow changes in remitted early- and late-onset depression patients
 
答辩委员会组成信息
姓名职称导师类别工作单位是否主席备注
闫福岭 正高 主任医师,教授 博导 东南大学
袁勇贵 正高 主任医师,教授 博导 东南大学
柯晓燕 正高 主任医师,教授 博导 南京医科大学
张向荣 正高 主任医师 博导 南京医科大学
谢春明 正高 研究员 博导 东南大学
      
答辩秘书信息
姓名职称工作单位备注
李晓莉 其他 助理研究员,讲师 东南大学