晚发精神分裂症患者的神经认知和神经影像学研究
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摘要
目的：从神经心理学和神经影像学的角度,对晚发精神分裂症进行研究。
1.分析晚发精神分裂症的临床特征,探讨晚发精神分裂症患者的认知损害模式,以及认知功能与临床特征的关系。
2.探讨晚发精神分裂症患者脑部灰质体积的改变,分析灰质体积与认知变量、临床特征的相关性。
3.运用能够提示白质纤维(white matter, WM)完整性的弥散张量成像(diffusion tensor imaging, DTI)技术,探讨晚发精神分裂症患者全脑白质纤维完整性以及与认知变量和临床特征的相关性。
方法：采用多项任务的神经心理学测试,包括威斯康辛卡片分类测验(WSCT)、连续操作测验(CPT)、Stroop测验、词语流畅作业(Verbal Fluency Test)、连线测验(Trail Marking Test)、数字广度,即刻逻辑记忆测验,对来自中南大学湘雅二院精神卫生研究所的45例晚发精神分裂症住院及门诊患者与41例正常对照进行神经认知功能测试,并利用1.5T磁共振扫描仪进行全脑三维结构(3DT1)和全脑弥散张量成像(DTI)扫描。
采用优化的VBM(基于体素的形态学研究)方法对3DT1数据进行处理,分析晚发精神分裂症患者大脑灰质体积并与患者的认知变量、临床特征进行相关分析。采用基于体素的分析方法(voxel-basedanalysis, VBA)对晚发精神分裂症患者脑白质的部分各向异性(fractional anisotropy, FA)进行比较并与患者的认知变量、临床特征进行相关分析。
结果：1.晚发精神分裂症患者存在广泛的认知损害；在记忆、注意、执行功能和视觉运动等任务中的测试成绩差于正常对照组,差异有显著性(P<0.05)。
采用偏相关统计分析,以年龄、性别、受教育程度为协变量；分析各项认知变量与临床资料(包括病程、GAF评分、PANSS总分、阳性分及阴性分、抗精神病药物的剂量)的相关性；仅发现连线测验A成绩与GAF成正相关(r=0.32,p=0.041),与PANSS阴性分呈负相关(r=-0.46,p=0.013)。
2.匹配了性别、年龄和教育年限的19例晚发精神分裂症患者与17例正常对照组比较分析,结果显示晚发精神分裂症患者出现灰质密度降低的脑区包括：右侧顶叶中央后回(BA1)、右侧枕叶(BA18)、双侧额上回(BA10/11)、双侧额中回(BA8/6/10)、双侧额下回(BA6/46)、双侧颞上回(BA38)、左侧颞下回(BA20)和左侧颞中回(BA20)。
晚发精神分裂症患者双侧额叶,双侧颞叶和右侧枕叶灰质体积与病程呈负相关,而右枕中叶和左颞中回/颞下回灰质体积与药物剂量呈正相关。
晚发精神分裂症患者数字顺背成绩与右额中叶BA6、左额上回BA11和左颞中回BA20体积呈正相关。即刻逻辑记忆成绩与右额中回BA6、左额上回BA11、左额中叶BA10和左颞中回BA20体积呈正相关。Stoop的颜色阅读成绩与左额上回BA11体积呈正相关,而干扰分与右顶叶中央后回BA1、左颞中回BA20体积呈负相关；CPT操作的听觉错报数与左额下回BA46体积呈负相关。
3.匹配了性别、年龄和教育年限的20例晚发精神分裂症患者与17例正常对照组进行脑白质部分各向异性(fractional anisotropy, FA)值比较分析,发现晚发精神分裂症组多个脑区FA值降低,包括：左侧颞上回、左侧额中央前回、左额内侧回、左侧额下回、右侧核间小叶、右侧颞下回、右侧颞叶梭状回、右侧舌回右侧枕楔叶、右侧小脑蚓部、右侧小脑前叶；未见患者组白质FA值显著高于对照组的区域。
进一步计算两组被试感兴趣脑区的FA值,发现：与正常对照组比较,精神分裂症组FA值降低脑区有左侧颞上回、左侧额中央前回、右侧基底节、右侧颞下回。
研究结果未发现晚发精神分裂症患者感兴趣脑区FA值与临床变量存在相关性；而发现晚发精神分裂症感兴趣脑区FA值与认知变量存在相关性,如晚发精神分裂症左侧额下回FA值与干扰命名(r=.525,p=.031)呈正相关,左额内侧回FA值与听觉漏报(r=-.491,p=.045)呈负相关；右侧颞下回FA值与颜色命名(r=.49,P=.046)呈正相关,与视觉漏报(r=-.629,P=.009)、听觉平均反应时(r=-.549,p=.023)呈负相关,右侧核间小叶FA值与视觉平均反应时(r=-.536,p=.027)呈负相关；提示晚发精神分裂症患者左侧额回、右颞下回,右侧核间小叶区域FA值与注意操作变量呈正相关。
结论：1.晚发精神分裂症患者存在广泛的认知功能受损,且阴性症状对晚发分裂症视觉运动综合、精神灵活性有不良影响,而良好的社会功能与心理运动速度、精神灵活性有关。
2.晚发精神分裂症患者存在额叶、颞叶、枕叶和顶叶灰质体积的减少,表明晚发精神分裂症存在广泛的皮层萎缩。随病程进展,晚发精神分裂症脑区出现进行的灰质丢失；而药物治疗可以减缓灰质的丢失。晚发精神分裂症脑区灰质体积的改变可能导致了认知功能如注意和记忆的损害。
3.晚发精神分裂症患者存在额叶、颞叶、枕叶、小脑和核间叶白质纤维的完整性破坏。晚发精神分裂症患者脑区白质纤维完整性改变与认知功能损害有关。
Objective:
1. To analyse clinical characteristics and explore the patterns of cognitive impairment of late-onset schizophrenia, then to address the association between cognitive function and clinical variables.
2. To assess volumetric abnormalities of grey matter throughout the entire brain in individuals with late-onset schizophrenia, and to address the association between cognitive functions, clinical variables and grey matter of brain structure in patient groups.
3. To assess white matter integrity throughout the entire brain in individuals with late-onset schizophrenia, and to address the association between cognitive function, clinical variables and white matter alterations in patient group.
Methods:
Using comprehensive neuropsychological tasks including Wisconsin card sorting test, verbal fluency test, digit span test, trial marking test, Stroop color word conflict test, instantly logical memory and Continuous Performance Test. We compared neuropsychological functions in patients with late-onset schizophrenia(n=45) and normal controls(n=41).
3D T1Weighted images were acquired by magnetic resonance imaging from19patients with late-onset schizophrenia and17healthy volunteers. Regional deviation in grey matter volume was assessed using optimized volumetric voxel-based morphometry.
1.5T diffusion weighted images were acquired by magnetic resonance imaging from20patients with late-onset schizophrenia and17healthy volunteers. DTI was used to assess white matter integrity in patients and healthy controls. Differences in fractional anisotropy (FA) were measured using voxel-based morphometry.
Results:
1. All of patients with late-onset schizophrenia demonstrated a broad range of cognitive impairments. The patients manifest significant differences in memory, attention and performance function and visual motor tasks compared to healthy controls. In patients with late-onset schizophrenia, trial marking test part A performance was positively related to GAF (r=32, P=.041), but inversely to negative scale scores of PANSS (r=-0.46, P=013).
2. Patients with late-onset schizophrenia showed decreased gray matter volume in right parietal postcentral gyrus BA1, right middle occipital gyrus BA18, bilateral superior frontal gyrus BA10/11, bilateral middle frontal gyrus BA8/6/10, bilateral superior frontal gyrus BA6/46, bilateral superior temporal gyrus BA38, left inferior temporal gyrus BA20and left middle temporal gyrus BA20. Within the patient group, volume of grey matter in bilateral frontal gyrus, bilateral temporal gyrus and right middle occipital gyrus was negatively related to duration of illness, whereas grey matter volume in right middle occipital gyrus and left temporal gyrus positively related to dosage of antipsychotics.
Within the schizophrenia group, the performance of digit span test and instantly logical memory was positively related to volume of grey matter in bilateral frontal gyrus and left middle temporal gyrus. The score of Stoop test (color reading) was positively related to volume of grey matter in left superior frontal gyrus, whereas interference score was negatively related to that of right parietal postcentral gyrus and left middle temporal gyrus. Decreased volume of gray matter in left inferior frontal gyrus was correlated with poorer performance on the auditory error of CPT.
3. Schizophrenic patients showed lower fractional anisotropy of white matter in left frontal precentral gyrus, left superior temporal gyrus, left medial frontal gyrus, left frontal sub-gyrus, right sub-lobar extra-nuclear, right temporal sub-gyrus, right temporal fusiform gyrus, right lingual gyrus, right occipital cuneus, and right cerebellar vermis, right cerebellum anterior lobe culmen.
No significant correlation was found between duration of illness, antipsychotic medication dosages, PANSS scores and FA value of any of the clusters.
An positive relationship of DTI fractional anisotropy (FA) values in left frontal gyrus, sub-lobar extra-nuclear, right temporal sub-gyrus and right sub-lobar extra-nuclear with attention performance was observed.
Conclusion:
1. Patients groups performed worse than normal control and showed a profile of cognitive impairment. Some cognitive indexes were associated with several clinical variables in patient groups.
2. There was a significant decrease in gray matter volume in patients with late-onset schizophrenia in bilateral frontal gyrus, bilateral temporal gyrus, right parietal gyrus and right occipital gyruss. Among patients, longer duration of illness has also been associated with reduced volume of grey matter in brain regions which may be relieved by dosage of antipsychotic medication. Grey matter volume decrease in brain regions would be associated most strongly with poorer cognitive performance on memory and attention tests.
3. The results are consistent with evidence that patients with late-onset schizophrenia exhibit abnormalities of neuron membrane disturbance. The white matter integrity is disconnection in left frontal lobe, bilateral temporal lobe, right occipital, right occipital and right cerebellum in patient groups. White matter impairment in left frontal lobe, right sub-lobar extra-nuclear and right temporal sub-gyrus was related to attention dysfunction in late-onset schizophrenic patients.
1.分析晚发精神分裂症的临床特征,探讨晚发精神分裂症患者的认知损害模式,以及认知功能与临床特征的关系。
2.探讨晚发精神分裂症患者脑部灰质体积的改变,分析灰质体积与认知变量、临床特征的相关性。
3.运用能够提示白质纤维(white matter, WM)完整性的弥散张量成像(diffusion tensor imaging, DTI)技术,探讨晚发精神分裂症患者全脑白质纤维完整性以及与认知变量和临床特征的相关性。
方法：采用多项任务的神经心理学测试,包括威斯康辛卡片分类测验(WSCT)、连续操作测验(CPT)、Stroop测验、词语流畅作业(Verbal Fluency Test)、连线测验(Trail Marking Test)、数字广度,即刻逻辑记忆测验,对来自中南大学湘雅二院精神卫生研究所的45例晚发精神分裂症住院及门诊患者与41例正常对照进行神经认知功能测试,并利用1.5T磁共振扫描仪进行全脑三维结构(3DT1)和全脑弥散张量成像(DTI)扫描。
采用优化的VBM(基于体素的形态学研究)方法对3DT1数据进行处理,分析晚发精神分裂症患者大脑灰质体积并与患者的认知变量、临床特征进行相关分析。采用基于体素的分析方法(voxel-basedanalysis, VBA)对晚发精神分裂症患者脑白质的部分各向异性(fractional anisotropy, FA)进行比较并与患者的认知变量、临床特征进行相关分析。
结果：1.晚发精神分裂症患者存在广泛的认知损害；在记忆、注意、执行功能和视觉运动等任务中的测试成绩差于正常对照组,差异有显著性(P<0.05)。
采用偏相关统计分析,以年龄、性别、受教育程度为协变量；分析各项认知变量与临床资料(包括病程、GAF评分、PANSS总分、阳性分及阴性分、抗精神病药物的剂量)的相关性；仅发现连线测验A成绩与GAF成正相关(r=0.32,p=0.041),与PANSS阴性分呈负相关(r=-0.46,p=0.013)。
2.匹配了性别、年龄和教育年限的19例晚发精神分裂症患者与17例正常对照组比较分析,结果显示晚发精神分裂症患者出现灰质密度降低的脑区包括：右侧顶叶中央后回(BA1)、右侧枕叶(BA18)、双侧额上回(BA10/11)、双侧额中回(BA8/6/10)、双侧额下回(BA6/46)、双侧颞上回(BA38)、左侧颞下回(BA20)和左侧颞中回(BA20)。
晚发精神分裂症患者双侧额叶,双侧颞叶和右侧枕叶灰质体积与病程呈负相关,而右枕中叶和左颞中回/颞下回灰质体积与药物剂量呈正相关。
晚发精神分裂症患者数字顺背成绩与右额中叶BA6、左额上回BA11和左颞中回BA20体积呈正相关。即刻逻辑记忆成绩与右额中回BA6、左额上回BA11、左额中叶BA10和左颞中回BA20体积呈正相关。Stoop的颜色阅读成绩与左额上回BA11体积呈正相关,而干扰分与右顶叶中央后回BA1、左颞中回BA20体积呈负相关；CPT操作的听觉错报数与左额下回BA46体积呈负相关。
3.匹配了性别、年龄和教育年限的20例晚发精神分裂症患者与17例正常对照组进行脑白质部分各向异性(fractional anisotropy, FA)值比较分析,发现晚发精神分裂症组多个脑区FA值降低,包括：左侧颞上回、左侧额中央前回、左额内侧回、左侧额下回、右侧核间小叶、右侧颞下回、右侧颞叶梭状回、右侧舌回右侧枕楔叶、右侧小脑蚓部、右侧小脑前叶；未见患者组白质FA值显著高于对照组的区域。
进一步计算两组被试感兴趣脑区的FA值,发现：与正常对照组比较,精神分裂症组FA值降低脑区有左侧颞上回、左侧额中央前回、右侧基底节、右侧颞下回。
研究结果未发现晚发精神分裂症患者感兴趣脑区FA值与临床变量存在相关性；而发现晚发精神分裂症感兴趣脑区FA值与认知变量存在相关性,如晚发精神分裂症左侧额下回FA值与干扰命名(r=.525,p=.031)呈正相关,左额内侧回FA值与听觉漏报(r=-.491,p=.045)呈负相关；右侧颞下回FA值与颜色命名(r=.49,P=.046)呈正相关,与视觉漏报(r=-.629,P=.009)、听觉平均反应时(r=-.549,p=.023)呈负相关,右侧核间小叶FA值与视觉平均反应时(r=-.536,p=.027)呈负相关；提示晚发精神分裂症患者左侧额回、右颞下回,右侧核间小叶区域FA值与注意操作变量呈正相关。
结论：1.晚发精神分裂症患者存在广泛的认知功能受损,且阴性症状对晚发分裂症视觉运动综合、精神灵活性有不良影响,而良好的社会功能与心理运动速度、精神灵活性有关。
2.晚发精神分裂症患者存在额叶、颞叶、枕叶和顶叶灰质体积的减少,表明晚发精神分裂症存在广泛的皮层萎缩。随病程进展,晚发精神分裂症脑区出现进行的灰质丢失；而药物治疗可以减缓灰质的丢失。晚发精神分裂症脑区灰质体积的改变可能导致了认知功能如注意和记忆的损害。
3.晚发精神分裂症患者存在额叶、颞叶、枕叶、小脑和核间叶白质纤维的完整性破坏。晚发精神分裂症患者脑区白质纤维完整性改变与认知功能损害有关。
Objective:
1. To analyse clinical characteristics and explore the patterns of cognitive impairment of late-onset schizophrenia, then to address the association between cognitive function and clinical variables.
2. To assess volumetric abnormalities of grey matter throughout the entire brain in individuals with late-onset schizophrenia, and to address the association between cognitive functions, clinical variables and grey matter of brain structure in patient groups.
3. To assess white matter integrity throughout the entire brain in individuals with late-onset schizophrenia, and to address the association between cognitive function, clinical variables and white matter alterations in patient group.
Methods:
Using comprehensive neuropsychological tasks including Wisconsin card sorting test, verbal fluency test, digit span test, trial marking test, Stroop color word conflict test, instantly logical memory and Continuous Performance Test. We compared neuropsychological functions in patients with late-onset schizophrenia(n=45) and normal controls(n=41).
3D T1Weighted images were acquired by magnetic resonance imaging from19patients with late-onset schizophrenia and17healthy volunteers. Regional deviation in grey matter volume was assessed using optimized volumetric voxel-based morphometry.
1.5T diffusion weighted images were acquired by magnetic resonance imaging from20patients with late-onset schizophrenia and17healthy volunteers. DTI was used to assess white matter integrity in patients and healthy controls. Differences in fractional anisotropy (FA) were measured using voxel-based morphometry.
Results:
1. All of patients with late-onset schizophrenia demonstrated a broad range of cognitive impairments. The patients manifest significant differences in memory, attention and performance function and visual motor tasks compared to healthy controls. In patients with late-onset schizophrenia, trial marking test part A performance was positively related to GAF (r=32, P=.041), but inversely to negative scale scores of PANSS (r=-0.46, P=013).
2. Patients with late-onset schizophrenia showed decreased gray matter volume in right parietal postcentral gyrus BA1, right middle occipital gyrus BA18, bilateral superior frontal gyrus BA10/11, bilateral middle frontal gyrus BA8/6/10, bilateral superior frontal gyrus BA6/46, bilateral superior temporal gyrus BA38, left inferior temporal gyrus BA20and left middle temporal gyrus BA20. Within the patient group, volume of grey matter in bilateral frontal gyrus, bilateral temporal gyrus and right middle occipital gyrus was negatively related to duration of illness, whereas grey matter volume in right middle occipital gyrus and left temporal gyrus positively related to dosage of antipsychotics.
Within the schizophrenia group, the performance of digit span test and instantly logical memory was positively related to volume of grey matter in bilateral frontal gyrus and left middle temporal gyrus. The score of Stoop test (color reading) was positively related to volume of grey matter in left superior frontal gyrus, whereas interference score was negatively related to that of right parietal postcentral gyrus and left middle temporal gyrus. Decreased volume of gray matter in left inferior frontal gyrus was correlated with poorer performance on the auditory error of CPT.
3. Schizophrenic patients showed lower fractional anisotropy of white matter in left frontal precentral gyrus, left superior temporal gyrus, left medial frontal gyrus, left frontal sub-gyrus, right sub-lobar extra-nuclear, right temporal sub-gyrus, right temporal fusiform gyrus, right lingual gyrus, right occipital cuneus, and right cerebellar vermis, right cerebellum anterior lobe culmen.
No significant correlation was found between duration of illness, antipsychotic medication dosages, PANSS scores and FA value of any of the clusters.
An positive relationship of DTI fractional anisotropy (FA) values in left frontal gyrus, sub-lobar extra-nuclear, right temporal sub-gyrus and right sub-lobar extra-nuclear with attention performance was observed.
Conclusion:
1. Patients groups performed worse than normal control and showed a profile of cognitive impairment. Some cognitive indexes were associated with several clinical variables in patient groups.
2. There was a significant decrease in gray matter volume in patients with late-onset schizophrenia in bilateral frontal gyrus, bilateral temporal gyrus, right parietal gyrus and right occipital gyruss. Among patients, longer duration of illness has also been associated with reduced volume of grey matter in brain regions which may be relieved by dosage of antipsychotic medication. Grey matter volume decrease in brain regions would be associated most strongly with poorer cognitive performance on memory and attention tests.
3. The results are consistent with evidence that patients with late-onset schizophrenia exhibit abnormalities of neuron membrane disturbance. The white matter integrity is disconnection in left frontal lobe, bilateral temporal lobe, right occipital, right occipital and right cerebellum in patient groups. White matter impairment in left frontal lobe, right sub-lobar extra-nuclear and right temporal sub-gyrus was related to attention dysfunction in late-onset schizophrenic patients.
引文
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