老年抑郁症恢复期认知损害从神经心理学测量到神经影像学研究-袁勇贵.docx

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1、东南大学 博士学位论文 老年抑郁症恢复期认知损害：从神经心理学测量到神经影像学 研究 姓名：袁勇贵 申请学位级别：博士 专业：内科学 指导教师：张志捃 20090305 中文摘要 老年抑郁症恢复期认知损害： 从神经心理学测量到神经影像学研究 东南大学临床医学院 博士研究生：袁勇贵 导师：张志瑨教授 中文摘要 背景 老年抑郁症是老年期常见的精神障碍之一，具有很高的患病率、自杀率和死亡率。 它除有情绪障碍外， 60%伴有认知损害，临床上有 “抑郁性假性痴呆 ”之称。 Portella 等对 老年抑郁症患者随访 12 个月发现，入组时患者的认知功能显著较正常对照组差， 12 月后 认知功能没有改善，

2、并且抑郁症状缓解与未缓解者之间差异也无显著性。 Devanaiicl 等对 39 例伴有认知损害的老年抑郁症患者使用舍曲林治疗 12 周，完成试验的 26 例患者 17 例有 效， 9例无效，与无效者相比，认知功能的改善仅局限在注意和执行功能方面，并且改 善程度轻微，提示老年抑郁症患者的认知损害可能是其特质性特征，经抗抑郁治疗后， 某些认知功能会有所改善，但不一定能达到正常水平，特别是记忆和执行功能，且这类 老年抑郁症患者发展成为进展性痴呆的可能增大。我们的前期研究证实，老年抑郁症患 者的轻度认知损害 （ mild cognitive impairment, MCI)发生率为 46.7% (2

3、8/60)， 2 年随访 资料显示，伴 MCI的老年抑郁症发展为痴呆的占 14.3% (4/28)，而正常对照组只有 3.1% (1/31)。 Alexopoulos等也发现， 27 例伴有认知损害的老年抑郁症 3 年内 43%发展为痴呆。 近年来，随着影像技术的发展，结构和功能影像对抑郁症病因学的贡献倍受瞩目。 越来越多的证据表明，抑郁症的发生与 大脑某些部位的结构和功能异常有关，而这些异 常主要集中在前额皮层、扣带回、尾状核、海马和小脑等脑区，并且这种异常与较差的 治疗反应、较快的复发有关。那么，恢复期老年抑郁症的大脑结构和功能是否仍存在异 常？其认知障碍是否与某些特定脑区的结构和功能异常

4、存在关联目前尚不清楚。 在本研究中，我们选择首发恢复期老年抑郁症和年龄、性别和文化程度相匹配的正 常老年人为研究对象，采用全面的神经认知量表评估两组的神经认知功能；首次使用基 于体素的形态测定法 （ voxel-based morphometry, VBM)探讨恢复期老年抑郁症 （ remitted geriatric depression, RGD)患者是否存在灰质和 /或白质体积、白质完整性异常；使用局 部一致性（ regional homogeneity, ReHo)的方法探讨静息状态下脑功能的异常，并进一 步分析其与认知损害的相关性，旨在寻找 RGD 患者认知损害的神经影像学标志，进一

5、 步揭示老年抑郁症的大脑结构和功能的异常在认知损害的病因学和病理生理学中的作 用。 第一部分老年抑郁症恢复期认知功能与正常老年人的对照研究 目的探讨恢复期老年抑郁症患者的神经认知功能特征。 方法对 40 例 RGD 患者（患者组）和 36 名健康老年人（对照组）的神经认知功能进行 全面的评定。 结果患者组在 RAVMT-延迟回忆和符号数字转换测试评分均显著低于对照组 （ P 均 100)。患者组的右侧顶下小叶灰质体积与简易精神状态量 表 （ MMSE)成绩呈显著正相关 （ r=0.340,尸 =0.032),与连线测试 A 和 B 成绩呈显著 负相关 （ 分别为户 -0.454,尸 =0.00

6、3; r=-0.404, /MJ.010)， 右侧额下回白质体积与连线 测试 A 成绩呈显著正相关（ r=0.319, 70.045)。 结论 RGD 患者存在某些部位的灰质和白质体积的异常增大，可能是该类患者执行功能 损害的神经病理基础。 关键词抑郁症；老年人；认知功能；磁共振成像；灰质；白质； 基于体素的形态分析 法 第三部分老年抑郁症恢复期认知功能与海马体积的相关性研究 目的探讨恢复期老年抑郁症患者海马体积的变化，并进一步分析其与认知损害是否相 关。 方法对 40 例恢复期老年抑郁症患者（患者组）和 36 名健康老年人（对照组）行全脑 3D 梯度回波 T1 加权序列矢状位扫描，用统计参数

7、图 2 (statistic parameter mapping 2, SPM2)软件处理图像，采用感兴趣区 （ region of interest, ROI)方法比较两组间海马体 积的差异。 结果患者组的左右侧海马绝对体积和相对体积与对照组差异均无显著性（片 0.05)。 患者组的连线测试 B 评分与左侧海马绝对体积呈显著负相关 （ A-0.333, 0.036)，画钟 测试评分与左侧海马绝对体积和相对体积均成显著负相关 （ 分别为 A=-0.338, 产 -0.330,卢 0.038)。 结论恢复期老年抑郁症患者的海马体积正常，并且海马体积可能与执行功能、视空间 结构功能存在关联。 关键

8、词抑郁症；老年人；磁共振成像；海马；感兴趣区 第四部分老年抑郁症恢复期认知损害与白质纤维完整性改变的相关性研究 目的探讨恢复期老年抑郁症患者全脑白质纤维完整性是否受损，并进一步分析其与认 知损害是否相关。 方法对 37 例恢复期老年抑郁症患者（患者组）和 33 名健康老年人（对照组）行全脑弥 散张量成像 （ diffiision tensor imaging, DTI)扫描，用 SPM2 软件处理图像，采用基于体 素的分析方法 （ voxel-basedapproach， VBA)组间比较分数各向异性值 （ fractional anisotropy, FA) 结果患者组 FA 值较对照组显著

9、降低的脑区主要包括：右侧额上回、左侧额下回、左侧 楔前叶、右侧枕中回、左侧楔叶（未校正， P0.001)。 患者组的左侧楔前叶 FA 值与 CFT- 中文摘要 延迟回忆成绩呈显著正相关（；一 0.334,卢 0.043),右侧额上回叶 FA 值与数字广度测试 成绩呈显著负相关 （ r=-0.372, PKJ.023)。 结论恢复期老年抑郁症患者多部位脑白质纤维的完整性受损，可能是该类患者视觉情 节记忆和短时注意功能异常的神经病理基础。 关键词抑郁症；老年人；磁共振成像；弥散；分数各向异性 第五部分老年抑郁症恢复期认知损害与静息态脑功能异常的相关性研究 目的探讨恢复期老年抑郁症患者静息状态下脑功

10、能特点，并进一步分析其与认知损害 是否关联。 方法采用功能磁共振成像 (functional magnetic resonance imaging, fMR 丨 )技术，检测静息 状态下 38 例恢复期老年抑郁症患者 (患者组 )和性别、年龄、受教育程度均与患者相匹配 的32 名正常人 (对照组 )的脑功能活动，并对两组进行比较。利用 ReHo 方法分析 fMRI 数据， 用SPM2 软件进行双样本凇验 (P0.001,未校正 )。 结果患者组的 ReHo 值显著高于对照组的脑区有右侧顶下小叶和右侧中央前回，未见 患者组的 ReHo 值显著低于对照组的脑区。患者组的右侧顶下小叶 ReHo 值与

11、 CFT-延迟 回忆成绩呈显著负相关（ -0.343,卢 0.035)。 结论恢复期老年抑郁症患者在静息状态下存在某些脑区的活动异常，这可能是该类患 者视觉情节记忆的神经病理基础。 关键词抑郁症；老年人；磁共振成像；静息状态；局部一致性 第六部分老年抑郁症恢复期多模态影像学结果之间的相关性研究 目的探讨恢复期老年抑郁症患者不同模态影像学结果的相关性。 方法同时完成 3D、 DTI 和静息态 fMRI 的 35 例 RGD 患者和 30 例对照组受试者的各模态影 像学结果作相关性分析。 结果 RGD患者右侧顶下小叶灰质体积与其 Reho值并无显著相关性 (rK).156， /M).371)， 而

12、右侧额下回白质体积却与右侧顶下小叶、右侧中央前回 Reho 值呈显著正相关（分别 为A-0.386, 70.022; /-0.579, /MJ.000);患者组的左侧楔前叶 FA 值与右侧顶下小叶 Reho 值呈显著负相关 （ r=-0.400, /MJ.017)。 结论恢复期老年抑郁症患者存在多个脑区的异常，而且异常脑区之间存在着关联。 关键词抑郁症；老年人；磁共振成像；多模态影像；相关性 . HI 英文摘要 Cognitive impairment in remitted geriatric depression: evidences from neuropsychological tes

13、t to neuroimaging studies. Clinical Medical College of Southeast University Doctoral Candidate YUAN Yong-gui Advisor ZHANG Zhi-jun Abstract Background Depressed elderly often exhibit cognitive impairments that are substantial, prevalent, and disabling. Follow-up studies showed that 45% patients with

14、 geriatric depression had persistence of cognitive impairment or deterioration after the remission of depressive symptoms. The patient of geriatric depression with cognitive impairment has increased risk of conversion to dementia， and it might be a preclinical stage of dementia. Despite increasing e

15、vidence for roles of structural and functional brain impairments in the etiology of geriatric depression, the relationship between selective regional brain volume differences and cognitive deficits remains unclear. Previous morphometric magnetic resonance imaging (MRI) studies using region-of intere

16、st (ROI) analyses have revealed that elderly patients with major depressive disorder showed volume reduction in the prefrontal cortex, anterior cingulate cortex, hippocampus and head of the caudate nucleus. A lot of evidence also showed that the abnormalities of microstructural white matter were ass

17、ociated with geriatric depression. Alexopoulos et al. found that lower fractional anisotropy (FA) in distributed cerebral networks was associated with poor antidepressant response of geriatric dqjression. Some studies also rqjorted that white matter hyperintensities of geriatric depression were rela

18、ted to cognitive decline in various domains, particularly executive skills, attention and mental speed* Several studies in remitted depression have also demonstrated abnormalities of focal metabolism, specifically increased metabolism in anterior cingulate, orbitofrontal cortex, and medial thalamus

19、during tryptophan depletion and reduced metabolism in the pregenual anterior cingulate during induced sadness. These studies suggested that metabolic activity of several regions may serve as signatures, not merely of a depressivestate， but of a depressive trait In this study, we investigated the abn

20、ormalities of some brain regions detected by optimized voxel-based morphometry (VBM), diffusion tensor imaging (DTI)- functional MRI (fMRI) and resting-state fMRI were correlated with remitted geriatric depression(RGD), and the abnormalities might be one of neuroimaging markers of cognitive deficits

21、 in the RGD patients. Part One: Comparision of neurocognitive function between remitted geriatic depression and healthy controls. IV 英文摘要 Objective To investigate the features of neurocognitive fiinction in first-episode RGD. Methods Forty subjects with first-episode RGD and 36 well-matched healthy

22、controls were recruited for this study and a battery of neuropsychological tests were conducted on the subjects. Results RGD patients had significantly lower scores in Auditory Verbal Learning Test (AVLT) delayed recall and Symbol Digit Modalities Test than healthy control subjects. RGD patients had

23、 significantly higher scores in Trail Making test A and B than healthy control subjects. Conclusion These results reveal that RGD is associated with the abnormalities of episodic memory, execution function and persistence of attention. Key words Remitted geriatric depression, Cognitive function Part

24、 Two: Regional gray and white matter changes are associated with cognitive deficits in remitted geriatric depression: an optimized voxel-based morphometry study. Objective To investigate structural abnormalities in first-episode RGD using optimized VBM in closely matched patients and healthy control

25、s, and to examine the relationship of performances on neuropsychological tests with regional gray and white matter volumes. Methods Forty subjects with first-episode RGD and 36 well-matched healthy controls were recruited for this study and neuropsychological tests and MRI were conducted on the subj

26、ects. The differences in regional gray and white matter volume were determined between these two groups by optimized VBM. Results RGD patients had significantly larger gray matter volumes of right inferior parietal lobule and right medial frontal gyrus compared with healthy control subjects. The whi

27、te matter volumes of left inferior parietal lobule and right inferior frontal gyrus were significantly larger in patients with RGD relative to healthy controls. There was a significant positive correlation between right inferior parietal lobule gray volume and Mini-Mental State Examination (MMSE) (r

28、=0.340, P=0.032), and a significant negative correlation between right inferior parietal lobule gray volume and Trail Making Test A and B (respectively, r=-0.454, P=0.003; r=-0.404, P=0.010) in patients with RGD. There was a significant positive correlation between white matter volume of right infer

29、ior frontal gyrus and Trail Making Test A (A*=0.3 19, i=0.045) in patients with RGD. Conclusion These results reveal that RGD is associated with larger white matter volumes of left inferior parietal lobule and right inferior frontal gyrus, and the right inferior frontal gyrus may thus be involved in

30、 the pathophysiology of executive fiinction in RGD. Key words Remitted geriatric depression, Cognitive function, Gray matter, White matter, Voxel-based morphometry, Magnetic resonance imaging Part Three: Hippocampus volume changes are associated with cognitive deficits in remitted geriatric depressi

31、on. Objective To investigate hippocampus volume changes in first-episode RGD using region of interest (ROI) in closely matched patients and healthy controls, and examining the relationship of performances on neuropsychological tests with hippocampus volume. Methods Forty subjects with first-episode

32、RGD and 36 well-matched healthy controls were recruited for this study and neuropsychological tests and MRI were conducted on the subjects. The differences in hippocampus volume were determined between these two groups by ROI. v 英文摘要 _ Results There were significant differences in bilateral absolute

33、 volumes and relative volumes of hippocampus between two groups. There was a significant negative correlation between left hippocampus absolute volume and Trail Making Test B (r=-0.333, F=0.036), and negative significant correlations between clock drawing test and left absolute volume and relative v

34、olume of hippocampus (respectively, =-0.338, P=0.033; r=-0.330, P=0.038) in patients with RGD. Conclusion RGD patients have nomoral volumes of hippocampus, it may thus be involved in the pathophysiology of cognitive function in RGD. Key words Remitted geriatric depression, Cognitive function, Hippoc

35、ampus, Region of interest, Magnetic resonance imaging Part Four: White matter integrity of the whole brain is associated with cognitive deficits in remitted geriatric depression. Objective To investigate whether abnormalities are presented in the whole white matter in patients with first-q)isode RGD

36、 by diffusion tensor imaging which could demonstrate the white matter integrity. And to explore the relationship between white matter integrity and cognitive impairment. Methods 37 remitted geriatric depression patients and 33 well-matched healthy controls underwent diffusion tensor imaging scans of

37、 MRI, which were analyzed by a rigorous voxel-based approach. The RGD patients and healthy controls received a cognitive battery using standardized administration. Results These results showed that fractional anisotropy in white matter of the patients was lower than that in the controls at the right

38、 superior frontal gyrus, left inferior frontal gyrus, left precuneus, right middle occipital gyrus and left cuneus. There were significant positive correlation between mean fractional anisotropy (FA) values of left precuneus and Rey-Osterrieth Complex Figure Test (CFT) delayed recall score (r=0.334,

39、 P=0.043), and a significant negative correlation between mean FA values of right superior frontal gyrus and Digit Span Test (r=-0.372, P=0.023) in patients with RGD. Conclusion These results suggest that white matter integrity of the whole brain is disrupted in first-episode remitted geriatric depr

40、ession, and these abnormalities are perhaps involved in the psychopathology and pathophysiology of cognitive impairment in remitted geriatric depression. Key words Remitted geriatric depression, Magnetic resonance imaging, Diffusion, Fractional Anisotropy Part Five: Abnormal neural activity is assoc

41、iated with cognitive deficits in the patients with remitted geriatric depression: A resting-state functional magnetic resonance imaging study. Objective To investigate regional activity abnormalities of first-episode RGD using a resting-state MRI in closely matched patients and healthy controls, and

42、 to examine the relationship between performances on neuropsychological tests and regional activity abnormalities. Method A newly reported regional homogeneity approach was used to analyze blood oxygen level-dependent fMRI data on resting state in 38 patients with remitted geriatric depression and 3

43、2 well-matched healthy controls. All subjects were measured by neuropsychological tests. VI 英文摘要 Results: Increased regional homogeneity (ReHo) in remitted geriatric depression was found mainly in the right inferior parietal lobule and right precentral gyrus. And there were significant negative corr

44、elations between ReHo values of right inferior parietal lobule and Rey-Osterrieth Complex Figure Test (CFT) delayed recall score (r=-0.343, F=0.035) in the patients with RGD,一 Conclusion Our study reveals that RGD is associated with abnormal activity of certain brain regions, which are believed to b

45、e involved in the psychopathology and pathophysiology of cognitive function in remitted geriatric depression. Key words Remitted geriatric depression, Functional magnetic resonance imaging (fMRI), Resting state, Regional homogeneity Part Six: The relationships of multi-modal magnetic resonance imagi

46、ng data in remitted geriatric depression. Objective To investigate the relationships of multi-modal MRI data in RGD. Methods 35 subjects with first-episode RGD and 30 well-matched healthy controls were recruited for this study and multi-modal magnetic resonance imaging (MRI) were conducted on the su

47、bjects. Results There were no significant differences between gray matter volume and Reho value of right inferior parietal lobule in RGD patients (r=0.156, P=0.31). There was significant postive correlations between white matter volume of right inferior frontal gyrus and Reho value of right inferior

48、 parietal lobule and precentral gyrus (respectively， 尸 6.386,尸 =0.022; r=0.579, XX000), and a negative significant correlation between FA value of left precuneus and Reho value of right inferior parietal lobule (r=-0.40 , P=0.017) in patients with RGD. Conclusion RGD patients have the abnormality of

49、 several brain regions, and significant correlations of several brain regions. Key words Remitted geriatric depression, Magnetic resonance imaging, Multi-modal, Correlation VII 主要缩略语 本文所用主要缩略语 (Abbreviations) ACC anterior cingulated cortex 一 前扣带回 AD Alzheimers disease 阿尔茨海默病 ADL activity of daily living 曰常生活活动能力量表 AVMT audio verbal memory test 听觉词语记忆测验 BDNF brain-derived neurotrophic factor 脑源性神经生长因子 BA Brodmann area Brodmann 分区 BOLD blood oxygenation level depe