摘要
血管性认知功能障碍(vascular cognitive impairment, VCI)是指由血管因素引起的或与之伴随的认知功能损害。根据其认知障碍的严重程度和临床特点,VCI可分为血管性无痴呆型认知损害(vascular cognitive impairment no dementia, VCIND)、血管性痴呆(vascular dementia, VaD)和混合性痴呆(mixed AD/VaD)三型。对VCI患者尽早进行识别、干预,将极大改善病人预后。遗憾的是,由于缺乏统一的、令人满意的诊断标准,VCI的研究进展受到很大阻碍。研究的重点逐渐转向均质性相对较好的皮质下缺血性脑血管病(subcortical ischemic vascular disease, SIVD)。
SIVD是最常见、最具有特征的VCI亚型之一,主要病因是小血管病变(cerebral small vessel disease, SVD)。其特征性病理表现为多发性腔隙性梗死和皮质下缺血性脑白质病变(white matter lesions, WML)。尽管许多研究认为,SIVD认知功能损害的主要特征之一是执行功能障碍,但SIVD的神经心理学改变尚存在争议,一些研究仅引用简单的量表,且方法不一,对认知评估不够全面和敏感,难以得出准确而一致的结果。
脑白质病变在磁共振(magnetic resonance imaging, MRI)T2加权像和FLAIR像上表现为高信号。WML与认知功能的关系还没有明确的结论,有研究通过定量或半定量方法发现SIVD认知障碍与WML的程度、部位可能相关,但结构MRI无法反映SIVD发生、发展的动态过程,缺乏特异性。扩散张量成像(diffusion tensor imaging, DTI)利用水分子的扩散运动各向异性进行成像,通过测量部分各向异性分数(fractional anisotropy, FA)和平均扩散度(mean diffusivity, MD)可反映常规MRI不能观察到的白质纤维微细结构的改变。部分研究显示,DTI技术对SIVD患者认知损害的早期检测可能更为可靠和敏感。但是DTI参数异常的病理学基础尚不明确。氢质子磁共振波谱(1H Magnetic resonance spectroscopy,1H-MRS)可以检测活体脑内某些化学物质,提供相关代谢信息。主要测量脑区N-乙酰天门冬氨酸(NAA)、肌酸(Cr)、胆碱(Cho)及肌醇(mI)的浓度。有学者发现SVD患者中白质病变区和正常区均存在NAA和Cho代谢异常。目前有关MRS与DTI联合研究SIVD认知障碍很少见诸报道。MRS与DTI相结合有助于探讨DTI参数异常的生物化学基础,更好地反映认知状态的改变,明确SIVD病理学基础及可能的发生机制。
目前认为,SIVD发病可能是在多种机制的共同作用下引起脑小血管病变,炎性因素在其中扮演着重要的角色。一些炎性因子在脑脊液和血液中的水平变化与SIVD可能有一定的相关性。因此,检测相关炎性标志物并进一步了解其在认知损害中的作用,有助于SIVD患者的早期防治。最近研究发现,VaD、AD的神经病理学改变均与CD40/CD40L异常高表达相关的小胶质细胞活化有着密切的关联,国内尚无CD40/CD40L与SIVD认知损害的文献报道。
为此,本研究通过病例对照研究,联合应用神经心理测试、MRI、DTI、MRS及血液炎性标志物检测方法对皮质下缺血性脑血管病患者认知障碍进行观察,以便掌握其部分临床及辅助检查特征,为阐明SIVD发病机制,早期预防,早期诊断和早期治疗提供临床防治依据及思路。
第一部分:皮质下缺血性脑血管病认知障碍与脑白质病变的关系
目的:通过系列神经心理学测试分析皮质下血管性认知障碍患者的神经心理学特征,探讨SIVD患者认知功能损害与脑白质病变的关系。
方法:根据Erkinjuntti提出MRI诊断标准入选SIVD患者53例,年龄及性别相当的健康老年人25例为正常对照组。SIVD患者按照认知损害的诊断标准分为VaD组27例和VCIND组26例。由经过培训的专职医师记录受试者的年龄、性别、受教育程度,进行MMSE及多个包括记忆力、注意力、语言、视空间结构及执行功能5个认知域在内的神经心理学测试,确定VCIND患者受损的认知域。行头颅MRI扫描,应用年龄相关白质改变分级方法,对WML评分,应用相关分析和分层多元回归分析探讨认知功能与WML的关系。
结果:(1)与正常对照组比较,VaD组患者各项量表测试均严重受损,具有统计学差异(P﹤0.05);VCIND组患者MMSE、MoCA、积木测验、数字倒背评分下降,连线测验、Stroop色词测验b、Stroop色词测验c时间均延长,差异有统计学意义(P﹤0.05)。VaD组与VCIND组相比,上述各项均受损严重,差异有统计学意义(P﹤0.05)。(2)VaD组患者WML总分为(12.73±3.35)分,VCIND组WML总分为(10.44±3.23)分,均高于对照组(2.00±2.18)分,具有明显统计学差异(P﹤0.05)。二组之间没有统计学差异(P>0.05)。各区域得分其中额区、顶枕区、颞区WML较高,而基底区和幕下最低。VaD组额区、顶枕区、颞区和基底节区WML评分均较NC组明显升高,具有统计学差异(P﹤0.05);VCIND组额区、顶枕区WML评分均较NC组明显升高,具有统计学差异(P﹤0.05);VaD组较VCIND组额区、颞区评分升高(P﹤0.05)。(3)相关分析显示:WML总分与MMSE、MoCA、积木测验、画钟测验、数字流畅性测验、词语流畅性测验评分呈显著负相关(P﹤0.01);与单词回忆、单词辨认评分呈正相关(P﹤0.05);与连线测验、Stroop色词测验评分呈显著正相关(P﹤0.01);分层多元线性回归分析显示:在校正年龄、性别与受教育程度的影响后,WML总分能解释各量表评分改变的13.6-42.0%,具有统计学显著性差异(P﹤0.01)。
结论:(1)SIVD患者同时存在多个认知域损害,以执行功能、视空间结构、注意力损害较为突出,记忆、语言受累相对较轻;VCIND患者表现为执行功能、视空间结构、注意力受损,程度均低于VaD组;晚期VaD患者全面认知功能明显下降;(2) SIVD患者白质病变以额区、顶枕区较为严重;脑白质病变程度与认知总体功能密切相关;(3)WML评分可以解释不同认知域认知损害的13.6-42.0%,其中与视空间结构、执行功能的改变相对更加密切。
第二部分:磁共振扩散张量成像对皮质下缺血性脑血管病患者脑白质微结构损害的评估
目的:应用磁共振弥散张量成像技术(DTI)分析SIVD患者脑白质的超微结构变化,进一步探讨DTI参数与多种认知功能损害的相关性。
方法:对SIVD中17例VaD患者、16例VCIND患者及18例年龄及性别相当的健康老年人行常规MRI及DTI检查,分别测量胼胝体压部、额叶、顶叶、颞叶、枕叶的形似正常白质(normal-appearing white matter, NAWM);室周病变区(periventricular white matter lesions, PWML)及其周围NAWM的部分各向异性分数(FA)和平均扩散率(MD)。分析3组之间DTI参数的差别,并与多个认知域神经心理测试结果进行相关性分析。
结果:(1)与正常对照组相比,VaD患者双额叶、双颞叶、双顶叶、胼胝体压部及左侧室周的NAWM和右侧室周WML区FA值均明显下降,左顶叶NAWM、胼胝体压部、双侧室周WML区及NAWM区MD值均升高(P﹤0.05);VCIND组患者双额叶、双顶叶NAWM和右侧室周WML区FA值下降,右侧室周WML区MD值升高(P﹤0.05);VaD组患者双颞叶、胼胝体压部FA值较VCIND组下降,左顶叶、胼胝体压部及双侧室周NAWM及WML区MD值升高,有统计学差异。(2)所有被研究者参加的相关分析显示,与认知功能相关DTI指标具体包括:与总体认知相关—双顶叶、左颞叶、胼胝体压部、左室周NAWM及右室周WML区FA值,左顶叶、胼胝体压部、双侧室周NAWM及WML区MD值;与执行功能相关:双额叶、双顶叶、胼胝体压部、左室周NAWM及右室周WML区FA值,左顶叶、胼胝体压部、双侧室周NAWM及WML区MD值;与视空间结构相关:双顶叶、胼胝体压部NAWM及右室周WML区FA值,左顶叶、双侧室周NAWM及WML区MD值;与注意力相关:胼胝体压部、双侧室周NAWM及右室周WML区FA值,左顶叶、双侧室周NAWM及WML区MD值(P﹤0.05)。(3)多元逐步回归分析显示:左室周白质正常区MD值与MMSE呈负相关;右顶叶白质正常区FA值与MoCA、BDT正相关;左额叶白质正常区FA值与TMTb时间呈负相关;右室周白质正常区MD值与DST呈负相关,均有统计学差异(P﹤0.05)。
结论:(1)SIVD患者除常规MRI白质异常区外,表现正常的白质区也存在选择性微细结构损害,以额叶、顶叶、室周为主;(2)多个脑白质区FA及MD值与SIVD患者各认知域评分存在相关性,白质结构的完整性是影响SIVD患者认知障碍的重要因素;(3)DTI对于SIVD患者认知损害的早期检测可能较为可靠和敏感;(4)DTI参数可以直接量化的准确反映出白质微结构的异常表现,有利于SIVD病情监测及早期治疗。
第三部分:1H-磁共振波谱成像与磁共振扩散张量成像联合评价皮质下缺血性脑血管病患者左丘脑及左侧脑室体旁白质损害
目的:应用1H-磁共振波谱(1H-MRS)及扩散张量成像(DTI)2种磁共振新技术联合评价SIVD患者左侧脑室体旁额叶白质、左侧丘脑损害,探讨其与认知功能的关系。
方法:对SIVD中14例VaD患者、14例VCIND患者及12例年龄及性别相当的健康老年人行神经心理评估,采用PRESS序列,对左侧丘脑、左侧脑室体旁前方白质感兴趣区N-乙酰天门冬氨酸(NAA)、肌醇(mI)、含胆碱复合物(Cho)及肌酸和磷酸肌酸(Cr)浓度进行采集,并计算NAA/Cr、mI/Cr及Cho/Cr比值。同时进行常规MRI和DTI扫描,分别测定与1H-MRS所选ROI相同的双侧丘脑、双侧侧脑室体旁前方白质区的FA和MD值,并行统计学处理,进一步分析其与认知功能的关系。
结果:(1)与正常对照组比较,VaD组、VCIND组左侧丘脑和左侧脑室体旁白质区域NAA/Cr均明显降低(P﹤0.05),两组各值比较无明显差别(P﹥0.05)。(2)与正常对照组相比,VaD患者左侧脑室体旁白质FA值显著下降,双丘脑、双侧侧脑室体旁白质MD值均升高(P﹤0.05);VCIND组患者左丘脑、左侧脑室体旁MD值升高(P﹤0.05);两组无明显组间差异(P﹥0.05)。(3)相关分析显示,左丘脑、左侧脑室体旁白质的NAA/Cr、mI/Cr、Cho/Cr与同区域的FA及MD值均无明显相关关系(P﹥0.05)。(4)左丘脑Cho/Cr与TMT b呈明显正相关(P=0.008);左丘脑MD值与TMT b正相关(P<0.05);左侧脑室体旁白质NAA/Cr值与MoCA评分正相关(P=0.035);双侧脑室体旁白质MD值均与MoCA评分呈负相关,与TMT正相关(P<0.05),左侧脑室体旁白质FA值与MoCA评分呈正相关,与TMT b负相关(P<0.05)。
结论:(1)SIVD患者存在着左侧脑室体旁白质代谢异常以及室周白质超微结构损害。(2)SIVD患者早期丘脑即可能存在神经元缺失和扩散异常,1H-MRS与DTI结合能更好地检测出丘脑可能存在的隐匿性损伤。(3)左丘脑Cho/Cr与MD均与执行功能相关,左侧脑室体旁白质NAA/Cr及DTI参数变化均与总体认知功能相关。(4)双侧脑室体旁白质、丘脑MD值的改变有可能反映SIVD患者认知功能、特别是执行功能损害的严重程度。
第四部分:皮质下缺血性脑血管病患者血清炎性标志物的变化
目的:探讨SIVD患者血清中可溶性CD40配体(soluble CD40 ligand, sCD40L)、白介素-6(interleukin-6, IL-6)、高敏C反应蛋白(high sensitivity c-reactive protein, hsCRP)的水平及其与认知障碍、白质病变的相关性。
方法:对SIVD中19例VaD患者、20例VCIND患者及15例年龄及性别相当的健康老年人详细查体,行神经心理评估,分别采用酶联免疫吸附法(ELISA)、动态定时散射比浊法检测受试者血清sCD40L、IL-6、hsCRP水平,并行统计学处理,进一步分析其与认知功能的关系。
结果:(1)血清sCD40L水平:SIVD两组与正常对照组相比,sCD40L浓度增高(P﹤0.05),两组之间比较差异无统计学意义(P>0.05)。(2)血清IL-6水平:与健康对照组比较,SIVD两组血清IL-6浓度升高,有统计学差异(P﹤0.05),两组之间比较差异无统计学意义(P>0.05)。(3)血清hsCRP水平:VaD组hsCRP浓度高于正常对照组,差异有统计学意义(P< 0.05)。余组间比较差异无统计学意义(P>0.05)。(4)SIVD患者sCD40L、IL-6、hsCRP水平与MMSE、MoCA、WML评分均无明显的相关性(P>0.05)。(5)sCD40L、IL-6、hsCRP两两之间呈弱正相关。
结论:(1)皮质下血管性认知障碍患者血清sCD40L、IL-6、hsCRP水平较正常老年人均明显升高,炎性因子可能参与了SIVD的发生、发展;(2)血清sCD40L、IL-6、hsCRP水平与认知功能损害、白质病变程度无明显相关;(3)血清sCD40L、IL-6、hsCRP共同促进了SIVD的病理进程。
Vascular cognitive impairment(VCI)is caused by or associated with vascular factors. It forms a spectrum that includes vascular cognitive impairment no dementia(VCIND), vascular dementia(VaD)and mixed AD/VaD. As the condition is preventable to a large extent, it is important to identify patients at early stage of cognitive impairment and to treat appropriately. However, progress in VCI research has been hindered by lack of unified and satisfactory diagnostic criteria for the condition. Research emphasis of VCI gradually turned to the relatively homogeneous subcortical ischemic vascular disease(SIVD).
SIVD is regarded as the most common subgroup of vascular cognitive impairment related to cerebral small vessel disease(SVD). It is characterised by extensive cerebral white matter lesions (WML) and lacunar infarcts in deep grey and white matter structures. SIVD is thought to be responsible for a certain pattern of cognitive impairment with predominant executive dysfunction. However, the relationship between SIVD and cognition is unclear, in part because of methodological inconsistencies across studies. In some studies, cognitive assessment has included mainly or exclusively global measures, which lack sensitivity to detect subtle cognitive changes.
WML is showed as“white matter hyperintensities (WMH)”on T2 and fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) sequence. Some studies showed that WML might result in cognitive symptoms. Although conventional MRI methods, such as quantitative and semiquantitative visual rating scales, have been widely adopted in previous SIVD studies, the cognitive relevance of these measures is still equivocal. It could not reflect the damage occurred and progression of SIVD in the high signal white matter lesions. Diffusion tensor imaging (DTI) is a non-invasive water diffusion technique and can be used for quantitatively measuring the degree and directionality of the displacement distribution of water molecules. DTI detects microstructural alterations in white matter by measuring the directionality of molecular diffusion (fractional anisotropy, FA) and the average motion of water molecules (mean diffusivity, MD). Studies in SIVD have shown that DTI is a more reliable and sensitive technique for the early detection of cognitive impairment compared with conventional MRI. However the underlying pathological basis for these DTI changes remains uncertain. 1H magnetic resonance spectroscopy (1H-MRS) is a valuable tool for the assessment of several biochemical compounds in the brain in vivo, such as N-acetylaspartate (NAA), myoinositol (mI), Choline (Cho) and Creatine (Cr). Previous studies in patients with SVD have shown reductions in NAA and choline in lesions and normal appearing white matter, compared with controls.There were few reports considering the relationship among MRS, DTI and cognitive impairment of SIVD. Combining MRS with DTI may provide valuable information about the pathophysiological changes underlying DTI abnormalities and help us to better understand the SIVD process.
It has been proposed that the pathogenesis of SIVD related to cerebral small vessel disease caused by various mechanisms. Inflammation plays an important role in the pathogenesis of SIVD. Inflammatory cytokines are elevated in the CSF and plasma of individuals with subcortical vascular dementia. The examination of inflammatory markers in relation to VaD might be benefit to early treatment. Recent work has demonstrated that VaD and AD share a common neuropathological hallmark: microglial activation associated with increased CD40/CD40L pathway signaling. There was still no report on potential relationship between CD40/CD40L and cognitive impairment in SIVD patients.
In this study we applied neuropsychological tests, conventional MRI scanning, DTI, 1H-MRS techniques and inflammatory markers to estimate neuropsychological profile and white matter characteristics of imaging in patients with SIVD. Moreover, the relationship between WML and cognitive function impairment was also investigated. It could be possible to gain reliable data which is benefit to early diagnosis and treatment of cognitive impairtment in SIVD.
Part 1: Contributions of white matter lesions to cognitive impairment in patients with subcortical ischemic vascular disease
Objectives : To describe the cognitive profile of patients with subcortical vascular cognitive impairment by using a set of cognitive measures. To investigate the nature of white matter lesions and its correlation to the cognitive function in patients with SIVD.
Methods: Extensive neuropsychological tests including MMSE and covering 5 cognitive domains were performed on 53 patients with SIVD diagnosed according to the MRI criteria of Erkinjuntti and 25 normal elderly controls (NC) matched in age and gender. Global cognitive status was assessed with the Mini-Mental Status Examination (MMSE) and montreal cognitive assessment (MoCA). Memory functions were evaluated with the delayed word recall tests of MMSE and MoCA, word recall and word recornition of ADAS-cog with learning trial. Executive function was assessed with stroop colour words test (CWT) and trail making test (TMT). The visuospatial function was evaluated with block design test (BDT) and clock drawing test (CDT). Moreover, the digit span test (DST) and verbal fluency test (VFT) with animal category were used in evaluating attention and language function respectively. The patients were divided into VaD and VCIND group. Age, sex, educational level and history were recorded. Age-related white matter change rating scale, which is a visual rating scale developed by Wahlund, was used to qualitative measure and locate the WML. Finally, correlation analysis and hierarchical multiple regression analysis were used to examine the relationship between general cognitive function and WML.
Results: (1) The overall level of cognitive performance in these tests was significant inferior in VaD subjects as compared to NC subjects (P<0.05). VCIND group was worse than that of the normal elders in the tests including MMSE, MoCA, BDT, TMT, CWTb, CWTc and DST backwards (P<0.05). Between VaD and VCIND groups, significant differences were found in the same fields (P<0.05). Compared with VCIND patients, VaD subjects showed decline on the memory, executive function, visuospatial and attention function.(2)The mean WML rating scores in VaD patients and VCIND patients were(12.73±3.35)and(10.44±3.23), respectively, higher than that of NC group (P﹤0.05), which was (2.00±2.18). The study groups differed significantly from each other (P<0.05). As to each regions, the scores of frontal area, parieto-occipital area, temporal area and basal ganglia area inVaD patients were remarkedly increased than that of NC group (P<0.05), but no difference was noted at infratentorial area. Compared with controls, patients with VCIND had increased scores in frontal area and parieto-occipital area (P<0.05). A significant difference between VaD group and VCIND group was observed in frontal area and temporal area (P<0.05).(3)Correlation analysis revealed that the score of total WML was negatively correlated with MMSE, MoCA, BDT, CDT, DST and VFT scores significantly after controlling for the effects of age, gender and educational attainment (P<0.01). Positive correlations were observed between WML and word recall, word recognition (P<0.05) and TMT, CWT (P<0.01) respectively. In the hierarchical multiple regression analysis, the score of total WML explained 13.6-42.0% of the variance in each cognitive field (P<0.01).
Conclusions(:1)SIVD is related to comprehensive cognitive impairment, specifically contributed to the deterioration of executive, visuospatial and attention function. Language and memory impairment were affected slightly. The predominant impairments in patients with VCIND are executive, visuospatial and attention deficits, while in patients with VaD suffered from the progressive cognitive impairment and overall cognitive decline. (2) WML located at frontal area and parieto-occipital area was serious.The cognitive function impairment in SIVD patients could be associated with the degree of WML. (3) The score of total WML could explains 13.6-42.0% of the variance in each cognitive field independently. Extension of WML may have distinct impact on the executive and visuospatial dysfunction.
Part 2: Evaluation of microstructural white matter lesions in patients with subcortical vascular cognitive impairment using diffusion tensor imaging
Objective: To investigate the microstructural white matter lesions and its correlation with the cognitive function in patients with VaD and VCIND by using diffusion tensor imaging (DTI) technique.
Methods:17 patients with VaD, 16 patients with VCIND, and 18 normal elderly controls (NC) matched in age and gender were recruited. DTI images were acquired, and fractional anisotropy (FA), mean diffusivity (MD) of normal-appearing white matter (NAWM) in splenium of the corpus callosum, frontal, parietal, temporal, occipital lobes, periventricular area and white matter lesions in periventricular area were determined. These diffusion measurements were compared across the 3 groups, and significant differences were further performed for correlation with tests of comprehensive cognitive function.
Results:(1) Compared with controls, patients with VaD had reduced FA in the bilaterial frontal lobes, bilaterial temporal lobes, bilaterial parietal lobes, splenium of the corpus callosum, left periventricular area and right periventricular WML (P﹤0.05). Additional areas showing increased MD were the left parietal lobe, splenium of the corpus callosum, bilaterial periventricular areas and bilaterial periventricular WML(P﹤0.05). Compared with NC group, VCIND patients demonstrated decreased FA value in the bilaterial frontal lobes,bilaterial parietal lobes, right periventricular WML(P﹤0.05)and increased MD in right periventricular WML(P﹤0.05). Patients with VaD had higher MD in the bilateral periventricular NAWM and WML and lower FA in bilateral temporal lobes, splenium of the corpus callosum than VCIND patients(P﹤0.05). (2) After adjusting for age, gender and education, a correlation analysis of the MD and FA of each ROI with cognitive impairment in five fields was performed in all subjects. FA values in bilateral parietal lobes, left temporal lobe, splenium of the corpus callosum, left periventricular NAWM, right periventricular WML and MD values in the left parietal lobe, splenium of the corpus callosum, bilateral periventricular NAWM and WML correlated with global cognitive function (MoCA score) (P<0.05). FA values in bilateral frontal lobes, bilateral parietal lobes, splenium of the corpus callosum, left periventricular NAWM, right periventricular WML and MD values in the left parietal lobe, splenium of the corpus callosum, bilateral periventricular NAWM and WML were found to be statistically correlated with executive measures (P<0.05). FA values in bilateral parietal lobe, splenium of the corpus callosum, right periventricular WML and MD values in the right parietal lobe, splenium of the corpus callosum, bilateral periventricular NAWM and WML correlated with visuospatial function (P<0.05). FA values in splenium of the corpus callosum, bilateral periventricular NAWM and right periventricular WML and MD values in the left parietal lobe, bilateral periventricular NAWM and WML were found to be statistically correlated with attention tes(tP﹤0.05). (3) Multiple linear regression analysis of NAWM with cognition was done for the five neuropsychological measures with significant univariate correlations. MMSE score correlated with diffusivity in left periventricular normal-appearing white matter (P=0.023). FA value in right parietal lobe NAWM positive correlated with MoCA and BDT(P﹤0.05). FA value in left frontal lobe positive correlated with TMT(P=0.014). DST score negative correlated with diffusivity in right periventricular NAWM(P=0.012).
Conclusions:(1) The select microstructural white matter lesions in NAWM of SIVD patients could be showed by DTI. These lesions are major presented in the frontal lobe, parietal lobe and periventricular regions. (2) FA and MD values changes in normal appearing white matter correlated significantly with cognitive performance. Microstructural white matter impairment might be important to comprehensive cognitive decline in SIVD patients. (3) DTI is a more reliable and sensitive technique for the early detection of cognitive impairment in SIVD patients. (4)DTI measures may be useful for monitoring disease progression and may serve as surrogate markers for intervention trials in SIVD.
Part 3: Evaluation of the lesions in left thalamus and left paraventricular white matter region in patients with subcortical vascular congnitive impairment using 1H magnetic resonance spectroscopy and diffusion tensor imaging
Objective : To investigate the lesions of left thalamus and left paraventricular white matter region and the correlation with cognition in patients with SIVD compared with healthy controls by using 1H magnetic resonance spectroscopy (1H-MRS) and diffusion tensor imaging (DTI). Methods: 14 patients with VaD, 14 patients with VCIND, and 12 gender and age matched normal controls (NC) were recruited. All subjects underwent clinical examination, neuropsychological assessment. The quantitative analysis of N-acetylaspartate (NAA), myoinositol (mI), Choline (Cho) and Creatine (Cr) resonance signals in region of interests (ROI) located in the left thalamus and left paraventricular white matter region were measured. Ratios of NAA/ Cr, mI/ Cr and Cho/ Cr were calculated in three groups. At the same time, conventional MRI and DTI scanning were received, fractional anisotropy (FA) and mean diffusivity (MD) values of white matter in the same bilateral regions were measured respectively. In addition, the relationship was described between the MRS, DTI ratios and cognitive impairment reflected in MMSE, MoCA and TMT of all subjects.
Results:(1) The NAA/Cr ratio showed a gradual decrease in the SIVD patients in the left thalamus and left paraventricular white matter region compared with control(sP﹤0.05). No significant difference between VaD and VCIND groups was observed in NAA/ Cr ratio(P﹥0.05). There was no statistically differences in the other ratios among three groups(P﹥0.05). (2) Compared with controls, patients with VaD had significantly reduced FA in the left paraventricular white matter region and increased MD in the bilateral thalamus and paraventricular area(P﹤0.05). VCIND patients demonstrated increased MD value in the left thalamus and left paraventricular white matter compared with NC group(P﹤0.05). No significant difference between VaD and VCIND patients was observed (P﹥0.05). (3) After controlling for age-related, no correlation was found between NAA/Cr, mI/Cr, Cho/Cr value and DTI parameters in the ROI(P﹥0.05). (4) A significant positive correlation was observed between TMTb time and Cho/Cr(P=0.001)and also MD value in the left thalamus (P<0.05). A statistically positive correlation was found between NAA/Cr and MoCA score in the left paraventricular region(P=0.019). MD values in bilateral paraventricular white matter areas were negatively correlated with MoCA score and positively correlated with TMT(P<0.05). FA value in the left paraventricular white matter area was positively correlated with MoCA score and negatively correlated with TMTb time(P<0.05).
Conclusions:(1) It is suggested that axonal loss or dysfunction in the left paraventricular white matter and microstructural white matter lesions were important process in SIVD patients. (2) The characteristic axonal loss or dysfunction and diffusion abnormalities in thalamus could be found in early SIVD patients. Combining 1H-MRS with DTI alterations could provide the valuable informations about potential lesions of thalamus in patients with SIVD. (3) The change of Cho/Cr value in the left thalamus was correlated with executive function and NAA/Cr value in the left paraventricular white matter might be important to global cognitive function. (4) The MD values in the paraventricular white matter and thalamus were correlated with cognitive impairment, especially executive dysfunction in patients with SIVD.
Part 4: Clinical significance of serum inflammatory markers in patients with subcortical ischemic vascular disease
Objective:To evaluate the levels of soluble CD40 ligand (sCD40L), interleukin-6 (IL-6)and high sensitivity c-reactive protein (hsCRP)in the serum of Patients with SIVD and the correlation with cognition and white matter lesions (WML).
Methods:19 patients with VaD, 20 patients with VCIND and 15 gender and age matched normal controls (NC) were recruited. All subjects were underwent clinical examination, neuropsychological assessment and conventional MRI. The serum levels of sCD40L, IL-6, hsCRP were detected by enzyme linked immunosorbent assay (ELISA) and fixedtime nephelometry methods in all subjects, respectively. In addition, the relationship was described among these inflammatory factors and WML, cognitive impairment in patients with SIVD.
Results:(1) A statistically increase of sCD40L serum level of SIVD patients versus healthy controls was detected ( P<0.05). No significant difference between VaD and VCIND groups was observed (P﹥0.05). (2) Compared with controls, patients with SIVD had elevated IL-6 serum levels ( P<0.05). There was no statistically difference in the VaD and VCIND patients (P﹥0.05). (3) The serum hsCRP expression was increased in VaD patients compared with the other groups(P<0.05). (4) There was no statistically correlation between the serum levels of sCD40L, IL-6, hsCRP and MMSE, MoCA, WML scores. (5) Slight positive correlation among sCD40L, IL-6, hsCRP was observed (P<0.01).
Conclusions:(1) Increased serum levels of sCD40L, IL-6, hsCRP in patients with SIVD might indicate that inflammatory processes may be activated in SIVD. (2) Enhanced serum levels of sCD40L, IL-6, hsCRP could not imply the association with the severity of cognitive impairment and WML in SIVD patients. (3) The inflammatory markers including sCD40L, IL-6, hsCRP maybe promote the pathological changes of SIVD in common.
引文
1 Jokinen H, Kalska H, Mantyla R, et al. Cognitive profile of subcortical ischaemic vascular disease. J Neurol Neurosurg Psychiatry, 2006, 77(1):28-33
2徐群,曹雯炜,潘元美,等.皮质下缺血性血管病的神经心理特征.中国卒中杂志,2009, 4(3):189-193
3 Jokinen H, Kalska H, Ylikoski R, et al. MRI-defined subcortical ischemic vascular disease: baseline clinical and neuropsychological findings. The LADIS Study, Cerebrovasc Dis, 2009, 27(4): 336-344
4 Reed BR, Mungas DM, Kramer JH, et al. Profiles of neuropsy chological impairment in autopsy-defined Alzheimer's disease and cerebrovascular disease. Brain, 2007, 130(pt 3):731-739
5 Ingles JL, Boulton DC, Fisk JD, et al. Preclinical vascular cognitive impairment and Alzheimer disease: neuropsychological test performance 5 years before diagnosis. Stroke, 2007, 38(4):1148-1153
6 Baillon S, Muhonunad S, Marudkar M, et al. Neuropsychological performance in Alzheimer's disease and vascular dementia: comparisons in a memory clinic population. Int J Geriatr Psyehiatry, 2001, 18(7): 602-608
7 Stephens S, Kenny RA, Rowan E, et al. Neuropsychological characteristics of mild vascular cognitive impairment and dementia after stroke. Int J Geriatr Psychiatry, 2004, 19(11):1053-1057
8 Erkinjuntti T, Inzitari D, Panton I, et al. Limitations of clinical criteria for the diagnosis of vascular dementia in clinical trials. Is a focus on subcortical vascular dementia a solution? Ann NY Acad Sci, 2000, 903:262-272
9 Inzitari D, Carlucci G, Pantoni L. White matter changes: the clinical consequences in the aging population. J Neural Transm Suppl, 2000, 59: 1-8
10 Garde E, Mortensen EL, Rostrup E, et al. Decline in intelligence is associated with progression in white matter hyperintensity volume. JNeurol Neurosurg Psychiatry, 2005, 76(9):1289-1291
11 Wright CB, Festa JR, Paik MC, et al. White matter hyperintensities and subclinical infarction: associations with psychomotor speed and cognitive flexibility. Stroke, 2008, 39(3):800-805
12 Geerlings MI, Appelman AP, Vincken KL, et al. Association of white matter lesions and lacunar infarcts with executive functioning: the SMART-MR study, 2009, 170(9):1147-1155
13 Tullberg M, Fletcher E, Decarli C, et a1.White matter lesions impair frontal lobe function regardless of their location.Neurology, 2004, 63(2): 246-253
14赵仁亮,谭纪萍,秦海强,等编译. 2006年NINDS/CSN关于血管性认知功能障碍统一标准的建议.中国卒中杂志, 2007, 2(6): 513-521
15 Wahlund LO, Barkhof F, Fazekas F, et al. A new rating scale for age- related white matter changes applicable to MRI and CT. Stroke, 2001, 32(6): 1318-1322
16血管性认识功能损害专家共识组.血管性认识功能损害的专家共识.中华内科杂志, 2007, 46:1052-1055
17 Roman GC, Tetemichi TK, Erkinjuntti T, et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology, 1993, 43(2):250-260
18 Wentzel C, Darvesh S, Macknight C, et al. Inter-rater reliability of the diagnosis of vascular cognitive impairment at a memory clinic. Neuroepidemiology, 2000, 19(4):186-193
19张明园,瞿光业,金华,等.几种痴呆测试工具的比较.中华神经精神科杂志,1991,24:194-196
20 Roman GC, Sachdev P, Royall DR, et al. Vascular cognitive disorder: a new diagnostic category updating vascular cognitive impairment and vascular dementia. J Neurol Sci, 2004, 226 (1-2): 81-87
21 Nasreddine ZS, Phillips NA, Bedirian V. The montreal cognitive assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc, 2005, 53(4): 695-699
22 Roman GC. Defining dementia: clinical criteria for the diagnosis of vascular dementia. Acta Neurol Scand Suppl, 2002, 178: 6-9
23 Phjasvaara T, Mantyla R, Ylikoski R, et al. Clinical features of MRI-defined subcortical vascular disease. Alzheimer Dis Assoc Disord, 2003, 17(4): 236-242
24 Mok VC, Wong A, Lam WW, et al. Cognitive impairment and functional outcome after stroke associated with small vessel disease. J Neurol Neurosurg Psychiatry, 2004, 75(4):560-566
25 Graham NL, Emery T, Hodgesl R, et al. Distinctive cognitive profiles in Alzheimer's disease and subcortical vascular dementia. Neurol Nearosurg Psychiatry, 2004, 75(1):61-71
26 Alves GS, Alves CE, Lanna ME, et al. Clinical characteristics in subcortical ischemic white matter disease. Arq Neuropsiquiatr, 2009, 67(2A):173-178
27 Moorhouse P, Song X, Rockwood K, et al. Executive dysfunction in vascular cognitive impairment in the consortium to investigate vascular impairment of cognition study. J Neurol Sci, 2010, 288(1-2):142-146
28 Tekin S, Cummings JL. Frontal-subcortical neuronal circuits and clinical neuropsychiatry: un update.J Psychosom Res, 2002, 53(2):647-654
29 Jokinen H, Kalska H, M?ntyl? R, et al. White matter hyperintensities as a predictor of neuropsychological deficits post-stroke. J Neurol Neurosurg Psychiatry, 2005, 76(9):1229-1233
30 Fein G, Di Sclafani V, Tabane J, et al. Hippocampal and cortical atrophy predict dementia in subcortical ischemic vascular disease. Neurology, 2000, 55(11):1626-1635
31 Kramer JH, Mung D, Reed BR, et al. Forgetting in dementia with and without subcortical lacunes. Clin Neuropsychol, 2004, 18(1):32-40
32 Scheltens P, Barkhof F, Valk J, et al. White matter lesions on magnetic resonance imaging in clinically diagnosed Alzheimer’s disease. Evidence for heterogeneity. Brain, 1992, 115(pt3):735-748
33 Au R, Massaro JM, Wolf PA, et al. Association of white matterhyperintensity volume with decreased cognitive functioning: The Framingham Heart Study. Arch Neurol, 2006, 63(2): 246-250
34 Bocti C, Swartz RH, Gao FQ, et a1.A new visual rating scale to assess strategic white matter hyperintensities within cholinergic pathways in dementia.Stroke, 2005, 36(10): 2126-2131
35 Swartz RH, Stuss DT, Gao F, et al. Independent cognitive effects of atrophy and diffuse subcortical and thalamico-cortical cerebrovascular disease in dementia. Stroke, 2008, 39(3): 822-830
1 Au R, Massaro JM, Wolf PA, et al. Association of white matter hyperintensity volume with decreased cognitive functioning: The Framingham Heart Study. Arch Neurol, 2006, 63(2):246-250
2 Yoshita M, Fletcher E, Harvey D, et al. Extent and distribution of white matter hyperintensities in normal aging, MCI, and AD. Neurology, 2006, 67(2):2192-2198
3 Tullberg M, Fletcher E, DeCarli C, et al. White matter lesions impair frontal lobe function regardless of their location.Neurology, 2004, 63(2): 246-253
4 Gold G, Kovari E, Herrmann FR, et al. Cognitive consequences of thalamic, basal ganglia, and deep white matter lacunes in brain aging and dementia. Stroke, 2005, 36(6):1184-1188
5 Bombois S, Debette S, Bruandet A, et al. Vascular subcortical hyperintensities predict conversion to vascular and mixed dementia in MCI patients. Stroke, 2008, 39(7):2046-2051
6 Huang J, Friedland RP, Auchus AP. Diffusion tensor imaging of normal-appearing white matter in mild cognitive impairment and early Alzheimer disease: preliminary evidence of axonal degeneration in the temporal lobe. AJNR Am J Neuroradiol, 2007, 28 (10):1943-1948
7 Mukherjee P. Diffusion tensor imaging and fiber tractography in acute stroke. Neuroimaging Clin N Am, 2005, 15(3):655-665
8 Kealey SM, Kim Y, Whiting WL, et al. Determination of multiple sclerosis plaque size with diffusion tensor MR imaging: comparison study with healthy volunteers. Radiology, 2005, 236(2): 615-620
9 Masutani Y, Aoki S, Abe O, et al. MR diffusion tensor imaging recent advance and new technique for diffusion tensor visualization. Eur J Radiol, 2003, 46(1):53-66
10 Bammer R, Augustin M, Strasser-Fuchs S, et a1. Magnetic resonance diffusion tensor imaging for characterizing diffuse and focal white matterabnormalities in multiple sclerosis. Magn Reaon Med, 2000, 44(4):583-591
11 MolkoN, Pappata S, Mangin JF, et al. Monitoring disease progression in CADASIL with diffusion magnetic resonance imaging: A study with whole brain histogram analysis. Stroke, 2002, 33(12):2902-2908
12 Zhou Y, Lin FC, Zhu J, et al. Whole brain diffusion tensor imaging histogram analysis in vascular cognitive impairment. Neurologic Sci, 2008, 268 (1-2): 60-64
13 Head D, Buekner R, Lshimony JS, et al. Differential vulnerability of anterior white matter in nondemented aging with minimal acceleration in dementia of the Alzheimer type: evidence from diffusion tensor imaging. Cerebral cortex, 2004, 14(4):410-423
14 Scazynski JS, Sigurdsson S, Jonsdottir MK, et al. Cerebral infarcts and cognitive performance of location and number of infarcts. Stroke, 2009, 40(3):677-682
15 Pantoni L, Gareia JH, et al. Pathogenesis of leukoaraiosis: a review. Stroke, 1997,28(3):652-659
16 Miyao S, Takano A, Teramoto J, et al. Leukoaraiosis in relation prognosis for patients with lacunar infarction. Stroke, 1992, 23(10):1434-1438
17贺燕,郭洪志.脑白质疏松症与Binswanger病认知功能障碍的对比研究.卒中与神经疾病,2004, 11(2):56-59
18 Shenkin SD, Bastin ME, Macgillivray TJ, et al. Cognitive correlates of cerebral white matter lesions and water diffusion tensor parameters in community dwelling older people. Cerebrovasc Dis, 2005, 20(5):310-318
19 Reed BR, Eberling JL, MungasD, et al. Effects of white matter lesions and lacunes on cortical function. Arch Neurol, 2004, 6(10):1545-1550
20 Tekin S, Cummings JL. Frontal-subcortical neuronal circuits and clinical neuropsychiatry: un update. J Psychosom Res, 2002, 53(2):647-654
21 Swartz RH, Stuss DT, Gao F, et al. Independent cognitive effects of atrophy and diffuse subcortical and thalamico-cortical cerebrovascular disease in dementia. Stroke, 2008, 39(3): 822-830
1 Spencer DC, Zitzelberger T, Roe AW, et al. MRS in relation to hippocampal volume in the oldest old. Neurology, 2003, 60(7):1194-1196
2 Schuff N, Amend D, Ezekiel F, et al. Different patterns of N- acetylaspartate loss in subcortical ischemic vascular dementia and AD. Neurology, 2003, 61(3):358-364
3 Hemfinghans S, Frolich L, Gerriz C, et al. Brain metabolism in Alzheimer Disease and vascular dementia assessed by in vivo proton magnetic resonace spect roscopy. Psychiatry Res, 2003, 123(3):183-190
4 Capizzano AA, Schuff N, Amend DL, et al. Subcortical ischemic vascular dementia: assessment with quantitative MR imaging and 1H MR spectroscopy. AJNR Am J Neuroradiol, 2000, 21(4): 621-630
5 Tullberg M, Fletcher E, DeCarli C,et a1. White matter lesions impair frontal lobe function regardless of their location. Neurology, 2004, 63(2): 246-253
6 Sullivan MO, Morris RG, Markus HS. Brief cognitive assessment for patients with cerebral small vessel disease. J Neurol Neurosurg Psychiatry, 2005, 76(8): 1140-1145
7 Loewenstein DA, Acevedo A, Agron J, et a1. Cognitive profiles in Alzheimer’s disease and in mild cognitive impairment of different etiologies. Dement Geriatr Cogn Disord, 2006, 21(5-6): 309-315
8 Yoshita M, Fletcher E, Harvey D, et al. Extent and distribution of white matter hyperintensities in normal aging, MCI, and AD. Neurology, 2006,67(2): 2192-2198
9 Nitkunan A, Rebecca A, Charlton, RA, et al. Reduced N-acetylaspartate is consistent with axonal dysfunction in cerebral small vessel disease. NMR Biomed, 2009, 22(3):285-291
10 Kantarci K, Petersen RC, Boeve BF, et al. 1H MR spectroscopy in common dementias. Neurology, 2004, 63 (8):1393-1398
11 Nishio S, Morioka T, Mihara F. Cerebral ganglioglioma with epilepsy:neuroimaging features and treatment. Neurosurg Rev, 2001, 24(1):14-19
12 Matasumoto K, Tamiya T, Ono Y. Cerebral gangliogliomas: clinical characteristics, CT and MRI. Acta Neurochir(Wien), 1999, 141(2):134-141
13 Cianfoni A, Niku S, Imbesi SG. Metabolite findings in tumefactive demyelinating lesions utilizing short echo time proton magnetic resonance spectroscopy. AJNR Am J Neuroradiol, 2007, 28(2): 272-277
14 Den Heijer T, Sijens PE, Prins ND, et al. MR spectroscopy of brain white matter in the prediction of dementia. Neurology, 2006, 66(4):540-544
15 Constans JM, Meyerhoff DJ, Gerson J, et al. 1H-MR spectroscopic imaging of white matter signal hyperintensities: Alzheimer’s disease and ischemic vascular dementia. Radiology, 1995, 197(2):517-523 610-616
17 Molko N, Pappata S, Mangin JF, et al. Monitoring disease progression in CADASIL with diffusion magnetic resonance imaging: A study with whole brain histogram analysis. Stroke, 2002, 33(12):2902-2908
18 O′Sullivan M, Singhal S, Charlton R, et al. Diffusion tensor imaging of thalamus correlates with cognition in CADASIL without dementia. Neurology, 2004, 62(5):702-707
19邓敏,李文彬,李梅,等.血管性痴呆左侧额叶的磁共振波谱研究. J Chin Med Imaging, 2008, 19(9):609-611
20 Carey CL, Kramer JH, Josephson SA, et al. Subcortical lacunes are associated with executive dysfunction in cognitively normal elderly. Stroke, 2008, 39(2):397-402
21 Tekin S, Cummings JL. Frontal-subcortical neuronal circuits and clinical neuropsychiatry: an update. J Psychosom Res, 2002, 53(2):647-654
22 Pugh KG, Lipsitz LA. The microvascular frontal-subcortical syndrome of aging. Neurobiol Aging, 2002, 23(3):421-431
1 Zuliani G, Ran zini M, Guer ra G, et al. Plasma cytokine profile in older subjects with late onset Alzheimer's disease or vascular dementia. J Psychiatr Res, 2007, 41(8): 686-693
2 Duan W, Gui L, Zhou Z, et al. Adenosine A(2A) receptor deficiency exacerbates white matter lesions and cognitive deficits induced by chronic cerebral hypoperfusion in mice. Neurol Sci, 2009, 285(1): 39-45
3 Schonbeck U, Libby P. The CD40/CD40L receptor/ligand dyad. Cell Mol Life Sci, 2001, 58 (1):4-43
4 Andre P, Prasad KS, Denis CV, et al. CD40L stabilizes arterial thrombi by a beta 3 integrin-dependent mechansm. Nat Med, 2002, 8(3):247-252
5 Giunta B, Figueroa KP, Town T, et al. Soluble CD40 ligand in dementia. Drugs Future. 2009, 34(4):333-340
6 Deng Y, Lu J, Sivakumar V, et al. Amoeboid microglia in the periventricular white matter induce oligodendrocyte damage through expression of proinflammatory cytokines via MAP kinase signaling pathway in hypoxic neonatal rats. Brain Pathol, 2008, 18(3):387-400
7 Chui HC. Subcortical ischemic vascular dementia. Neurol Clin, 2007, 25(3):717-740
8 Mocali A, Cedrola S, Della Malva N, et al. Increased plasma levels of soluble CD40, together with the decrease of TGF beta1, as possible differential markers of Alzheimer disease. Exp Gerontol, 2004, 39(10): 1555-1561
9 Kotowicz K, Dixon GL, Klein NJ, et al. Biological function of CD40 on human endothelial cells: costimulation with CD40 ligand and interleukin-4 selectively induces expression of vascular cell adhesion molecule-1 and P-selectin resulting in preferential adhesion of lymphocytes. Immunology, 2000, 100(4):441-448
10 Shibuya H, Nagai T, Ishii A, et al. Differential regulation of Th1 responses and CD154 expression in human CD4+T cells by IFN-alpha. Clin ExpImmunol, 2003, 132(2):216-224
11 Reinders ME, Sho M, Robertson SW, et al. Proangiogenic function of CD40 ligand-CD40 interactions. J Immunol, 2003, 171(3):1534-1541
12 Kuwabara Y, Ichiya Y, Sasaki M, et al. Time dependency of the acetazolamide effect on cerebral hemodynamics in patients with chronic occlusive cerebral arteries: early steal phenomenon demonstrated by 15O-H2O positron emission tomography. Stroke, 1995, 26(10): 825-1829
13 Ishikawa M, Vowinkel T, Karen Y, et al. CD40/CD40 ligand signaling in mouse cerebral microvasculature after focal ischemia/reperfusion. Circulation, 2005, 111(13):1690-1696
14 Bauer J, Ganter U, Strauss S, et al. The participation of interleukin-6 in the pathogenesis of Alzheimer's disease. Bes Immunol, 1992, 143(6):650-657
15 Zuliani G, Guerra G, Ranzini M, et al. High interleukin-6 plasm levels are associated with functional impairment in older patients with vascular dementia. Int J Geriatr Psychiatry, 2007, 22(4): 305-311
16 Wada-Isoe K, Wakutani Y, Urakami K, et al. Elevated interleukin-6 levels in cerebrospinal fluid of vascular dementia patients. Acta Neuro Scand, 2004, 110(2): 124-127.
17 Schmidt R, Schmidt H, Curb JD, et al. Early inflanunatlon and dementia: a
25-Year follow up of the Honolulu-Asia Aging Study. Ann Neurol, 2002, 52(2):168-174
18 van Oijen M, Witteman JC, Hofman A, et al. Fibrinogen is Associated with an increased risk of Alzheimer disease and vascular demntia. Stroke, 2005, 36(12): 2637-2641
19 Li G, Cui G, Tzeng NS, et al. Femtomolar concentrations of dextromethorphan protect mesencephalic dopaminergic neurons from inflammatory damage. Faseb J, 2005, 19(6): 489-496
20朱幼丽,周红,孙姬,等.血管性痴呆患者外周血白介素IL-2、IL-6及IL-8的表达特征.中国全科医学, 2005, 8(15):1246-1247
21 Tarkowski E, Liljeroth AM, Minthon L, et al. Cerebral Pattern of Pro-and anti-inflanunatory eytokines in dementias. Brain Res Bull, 2003,61(3): 255-260
22 Schmidt WP, Roesler A, Kretzschmar K, et al. Functional and cognitive consequences of silent stroke discovered using brain magnetic resonance imaging in an elderly population. J Am Geriatr Soc, 2004, 52(7):1045- 1050
1 Erkinjuntti T, Inzitari D, Panton I, et al. Limitations of clinical criteria for the diagnosis of vascular dementia in clinical trials. Is a focus on subcortical vascular dementia a solution? Ann NY Acad Sci, 2000, 903:262-272
2 Schmidtke K, Hull M.Cerebral small vessel disease:how does it progress? J Neurol sci, 2005, 229-230:13-20
3 Reed BR, Mungas DM, Kramer JH, et al. Profiles of neuropsy chological impairment in autopsy-defined Alzheimer's disease and cerebrovascular disease. Brain, 2007, 130(pt 3):731-739
4 Sharp SI, Aarsland D, Day S, et al. Hypertension is a potential risk factor for vascular dementia: systematic review. Int J Geriatr Psychiatry. 2011, 26(7):661-669
5 Shimomura T, Anan F, Umeno Y, et a1.Hyperhomocysteinaemia is a significant risk factor for white matter lesions in Japanese type 2 diabetic patients.Eur J Neurol, 2008, 15(3):289-294
6 Gouw AA, van der Flier WM, Fazekas F, et a1.Progression of white matter hyperintensities and incidence of new lacunes over a 3-year period: the leukoaraiosis and disability study. Stroke, 2008, 39(5): 1414-1420
7王贺波,齐亚超,吕佩源,等.皮质下缺血性脑血管病的临床特征及其认知损害的危险因素。中国全科医学, 2010, 13(28): 485-489
8 Forti P, Olivelli V, Rietti E,et al. Serum Thyroid-Stimulating Hormone as a Predictor of Cognitive Impairment in an Elderly Cohort. Gerontoloqy, 2011 Mar 23, [Epub ahead of print]
9 Lanfranconi S, Markus HS. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. Stroke, 2010, 41(8): e513-518
10 Hong YJ, Yoon B, Shim YS, et al. APOEε4 Allele Status in Korean Dementia Patients with Severe White Matter Hyperintensities. J Alzheimers Dis. 2011, [Epub ahead of print]
11 Cummings JL. Frontal-subcortical circuits and human behavior. Arch Neurol, 1993, 50(8):873-880
12 Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci, 1986, 9: 357-381
13 Chui HC. Subcortical ischemic vascular dementia. Neurol Clin, 2007 Aug, 25(3): 717-740
14 Tullberg M, Fletcher E, DeCarli C, et al. White matter lesions impair frontal lobe function regardless of their location. Neurology, 2004, 63(2): 246-253
15 Gold G, Kovari E, Herrmann FR, et al. Cognitive consequences of thalamic, basal ganglia, and deep white matter lacunes in brain aging and dementia. Stroke, 2005, 36(6): 1184-1188
16 Grau-Olivares M, Arboix A. Mild cognitive impairment in stroke patients with ischemic cerebral small-vessel disease: a forerunner of vascular dementia? Expert Rev Neurother, 2009, 9(8):1201-1217
17 Roman GC. Defining dementia: clinical criteria for the diagnosis of vascular dementia. Acta Neurol Scand Suppl, 2002, 178:6-9
18 Phjasvaara T, Mantyla R, Ylikoski R, et al. Clinical features of MRI-defined subcortical vascular disease. Alzheimer Dis Assoc Disord, 2003, 17(4): 236-242
19 Mok VC, Wong A, Lam WW, et al. Cognitive impairment and functional outcome after stroke associated with small vessel disease. J Neurol Neurosurg Psychiatry, 2004, 75(4): 560-566
20 Jokinen H, Kalska H, Mantyla R, et al. Cognitive profile of subcortical ischaemic vascular disease. J Neurol Neurosurg Psychiatry, 2006, 77(1): 28-33
21 de Mendonca A, Ribeiro F, Gueiro M, et al. Clinical significance of subcortical vascular disease in patients with mild cognitive impairment. Eur J Neurol, 2005, 12(2): 125-130
22徐群,曹雯炜,潘元美,等。皮质下缺血性血管病的神经心理特征。中国卒中杂志, 2009, 4(3): 189-193
23 Jokinen H, Kalska H, Ylikoski R et al. MRI-defined subcortical ischemic vascular disease: baseline clinical and neuropsychological findings. The LADIS Study, Cerebrovasc Dis, 2009, 27(4): 336-344
24 Graham NL, Emery T, Hodgesl R. Distinctive cognitive profiles in Alzheimer's disease and subcortical vascular dementia. J Neurol Neurosurg Psychiatry, 2004, 75(1): 61-71
25 Jokinen H, Kalska H, M?ntyl? R, et al. White matter hyperintensities as a predictor of neuropsychological deficits post-stroke. J Neurol Neurosurg Psychiatry, 2005, 76(9): 1229-1233
26 Fein G, Di Sclafani V, Tabane J, et al. Hippocampal and cortical atrophy predict dementia in subcortical ischemic vascular disease. Neurology, 2000, 55(11): 1626-1635
27 Kandiah N, Narasimhalu K, Lee J, et al. Differences exist in the cognitive profile of mild Alzheimer's disease and subcortical ischemic vascular dementia. Dement Geriatr Cogn Disord, 2009, 27(5): 399-403
28 Mega MS, Cummings JL. Frontal-subcortical circuits and neuropsychiatric disorders. J Neuropsychiatry Clin Neurosci, 1994, 6(4): 358-370
29 Carey CL, Kramer JH, Josephson SA, et al. Subcortical lacunes are associated with executive dysfunction in cognitively normal elderly. Stroke, 2008, 39(2): 397-402
30 Tekin S, Cummings JL. Frontal-subcortical neuronal circuits and clinical neuropsychiatry: an update.J Psychosom Res, 2002, 53(2): 647-654
31 Ingles JL, Boulton DC, Fisk JD, et al. Preclinical vascular cognitive impairment and Alzheimer disease: neuropsychological test performance 5 years before diagnosis. Stroke, 2007, 38(4): 1148-1153
32 Baillon S, Muhonunad S, Marudkar M, et al. Neuropsychological performance in Alzheimer's disease and vascular dementia: comparisons in a memory clinic population. Int J Geriatr Psychiatry, 2003, 18(7): 602-608
33 Stephens S, Kenny RA, Rowan E, et al. Neuropsychological characteristics of mild vascular cognitive impairment and dementia afterstroke. Int J Geriatr Psychiatry, 2004, 19(11): 1053-1057
34 Hill EL. Executive dysfunction in autism. Trends Cogn Sci, 2004, 8(1): 26-32
35 Kramer JH, Mung D, Reed BR, et al. Forgetting in dementia with and without subcortical lacunes. Clin Neuropsychol, 2004, 18(1): 32-40
36 Vataja R, Pohjasvaara T, Mantyla R, et al. Depression-executive dysfunction syndrome in stroke patients. Am J Geriatr Psychiatry, 2005, 13(2): 99-107
37 Alexopoulos GS. Vascular disease, depression, and dementia. J Am Geriatr Sic, 2003, 51(8):1178-1180
38 Billino J, Luerssen J, von Renteln-Kruse W, et al. Effects of Subcortical Vascular Ischemic Dementia and Aging on Negative and Neutral Word List Learning. Dement Geriatr Cogn Disord, 2011, 31(3): 188-194
39 Bella R, Pennisi G, Cantone M, et al. Clinical presentation and outcome of geriatric depression in subcortical ischemic vascular disease. Gerontology, 2010, 56(3):298-302
40 Folstein MF, Folstein SE, McHugh PR. "Mini-Mental State": a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res, 1975, 12(3):189-198
41 Crum RM, Anthony JC, Bassett SS, et al. Population-based norms for the Mini-Mental State Examination by age and educational level. JAMA, 1993, 269(18):86-91
42张振馨,王新德,洪霞,等。北京城乡55岁或以上居民简易智能状态检查测试结果的分布特征。中华神经科杂志, 1999, 32 (3):149-153
43 Jacova C, Kerteszb A, Blair M, et al. Neuropsychological testing and assessment for dementia. Alzheimers Dement. 2007, 3(4): 299-317.
44郭起浩,洪震,吕传真。阿尔茨海默病的常用神经心理评定量表评介。中华神经科杂志, 2003, 36(4):310-312
45肖世富。神经心理测验和评定量表在阿尔茨海默病的应用及价值。中国现代神经疾病杂志, 2005, 5(3): 137-140
46赵仁亮,谭纪萍,秦海强,等编译。2006年NINDS/CSN关于血管性认知功能障碍统一标准的建议。中国卒中杂志, 2007, 2(6): 513-521
47李焰生,俞羚,高枚春,等译。美国国立神经疾病和卒中研究所-加拿大卒中网血管性认知障碍统一标准。国际脑血管疾病杂志, 2007, 15(1): 4-24
48 Bowler JV. Modern concept of vascular cognitive impairment. Br Med Bull, 2007, 83: 291-305
49 O′Sullivan M, MorrisR G, MarkusH S. Brief cognitive assessment for Patients with cerebral small vessel disease. J Neurol Neurosurg Psychiatry, 2005, 76(8):1140-1145
50 Au R, Massaro JM, Wolf PA, et al. Association of white matter hyperintensity volume with decreased cognitive functioning: the framingham heart study. Arch Neurol, 2006, 63(2): 246-250
51 Yoshita M, Fletcher E, Harvey D, et al. Extent and distribution of white matter hyperintensities in normal aging, MCI, and AD. Neurology, 2006, 67(12):2192-2198
52 Wright CB, Festa JR, Paik MC, et al. White matter hyperintensities and subclinical infarction: associations with psychomotor speed and cognitive flexibility. Stroke, 2008, 39(3):800-805
53 Du AT, Schuff N, Laakso MP, et al. Effects of subcortical ischemic vascular dementia and AD on entorhinal cortex and hippocampus. Neurology, 2002, 58(11):1635-1641
54 Geerlings MI, Appelman AP, Vincken KL, et al. Association of white matter lesions and lacunar infarcts with executive functioning: the SMART-MR study. Am J Epidemiol, 2009, 170(9): 1147-1155
55 Molko N, Pappata S, Mangin JF, et al. Monitoring disease progression in CADASIL with diffusion magnetic resonance imaging: A study with whole brain histogram analysis. Stroke, 2002, 33(12):2902-2908
56 Xu Q, Zhou Y, Li YS, et al. Diffusion tensor imaging changes correlate with cognition better than conventional MRI findings in patients with subcortical ischemic vascular disease. Dement Geriatr Cogn Disord, 2010, 30(4):317-326
57 Zhou Y, Lin FC, Zhu J, et al. Whole brain diffusion tensor imaging histogram analysis in vascular cognitive impairment. J Neurologic Sci, 2008, 268 (1-2): 60-64
58 Chuff N, Capizzano AA, Du AT, et al. Different patterns of N- acetylaspartate loss in subcortical ischemic vascular dementia and AD. Neurology, 2003, 61(3): 358-364
59 Nitkunan A, McIntyre DJO, Barrick TR, et al. Correlations between MRS and DTI in cerebral small vessel disease. NMR Biomed, 2006, 19(5): 610-616
60 Shim Y, Yang D, Kim B, et al. Comparison of regional cerebral blood flow in two subsets of subcortical ischemic vascular dementia: Statistical parametric mapping analysis of SPECT. J Neurol Sci, 2006, 250(1-2):85-91
61 Kato H, Yoshikawa T, Oku N, et al. Statistical parametric analysis of cerebral blood flow in vascular dementia with small-vessel disease using Tc-HMPAO SPECT. Cerebrovasc Dis, 2008, 26(5):556-562
62 Reed BR, Eberling JL, MungasD. Effects of white matter lesions and lacunes on cortical function. Arch Neurol, 2004, 61(10): 1545-1550
63 Schuff N, Matsumoto S, Kmiecik J, et al. Cerebral blood flow in ischemic vascular dementia and Alzheimer's disease, measured by arterial spin-labeling magnetic resonance imaging. Alzheimers Dement, 2009, 5(6): 454-462
64 Wardlaw JM, Sandercock PA, Dennis MS, et al. Is breakdown of the blood-brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia? Stroke, 2003, 34(3): 806-812
65 Blermo, WallinA, EkmenR, et al. Neuron specific enolase in cerebrospinal fluid: a biochemical marker for neuronal degeneration in dementia disorders? J Neural Transm Park Dis Dement Sect, 1994, 8(3):183-191
66 Wallin A, Sjogren M. Cerebrospinal fluid cytoskeleton proteins in patients with subcortical white-matter dementia. Mech Ageing Dev, 2001, 122(16): 1937-1949
67 Formichi P, Parnetti L, Radi E, et al. CSF levels of beta-amyloid 1-42, tau and phosphorylated tau protein in CADASIL. Eur J Neurol, 2008, 15(11): 1252-1255
68 Zuliani G, Ranzini M, Guerra G, et al. Plasma cytokine profile in older subjects with late onset Alzheimer's disease or vascular dementia. J Psychiatr Res, 2007, 41(8): 686-693
1 Hachinski V, Iadecola C, Petersen RC, et al. National Institute of Neurological Disorder and Stroke-Canadian Stroke Network Vascular cognitive impairment harmonization standards. Stroke, 2006, 37(9): 2220- 2241
2 Rockwood K, Black SE, Song X, et al. Clinical and radiographic subtype of vascular cognitive impairment in a clinic-based cohort study. J Neurol Sci , 2006, 240(12): 7-14
3 Moorhouse P, Roekwood K. Vascular cognitive impairment: current conced clinical developments. Laneet Neurol, 2008, 7(3): 246-55
4李祖贵.轻度认知障碍的功能性神经影像学研究进展.国际放射医学核医学分册,2006,30(2): 76-79
5 Knopman D, Cummings J, Dekosky S, et al. Practice parameters: diagnosis of dementia (an evidence-based review). Neurology, 2001, 56(9): 1143-1158
6赵仁亮,谭纪萍,秦海强,等编译. 2006年NINDS/CSN关于血管性认知功能障碍统一标准的建议.中国卒中杂志,2007,2(6): 513-521
7 Corbett A, Bennett H, Kos S. Cognitive dysfunction following subcortical infarction. Arch Neurol, 1994, 51(10): 999-1001
8 Bowler JV. The concept of vascular cognitive impairment. Neurol sci, 2002, 203-204: 11-15
9 Pohjasvaara T, Mantyla R, Aronen HJ, et al. Clinical and radiological determinants of pre-stroke cognitive decline in a stroke cohort. J Neurol Neurosurg psychiatry, 1999, 67(6): 742-748
10 Swartz RH, Black SE, Sela G, et al. Cognitive impairment in dementia: correlations with atrophy and cerebrovascular disease quantified by magnetic resonance imaging. Brain Cogn, 2002, 49(2): 228-232
11 Mok V, Chang C, WongA, et al. Neuroimaging determinants of cognitive performances in stroke associated with small vessel disease. J Neuroimaging, 2005, 15(2): 129-137
12 Loeb C, Gandolfo C, Bino G. Intellectual impairment and cerebral lesions in multiple cerebral infarcts. A clinical computed tomography study. Stroke, 1988, 19(5): 560-565
13 Desmond DW, Moroney JT,Paik MC,et al. Frequency and clinical determinants of dementia after ischemic stroke. Neurology, 2000, 54 (5): 1124-1131
14 Moser DJ, Cohen RA, Paul RH, et al. Executive function and magnetic resonance imaging subcortical hyperintensities in vascular dementia. Neuropsychiatry Neuropsychol Behav Neurol, 2001, 14(2): 89-92
15 Rockwood K, Moorhouse PK, Song X, et al. Disease progression in vascular cognitive impairment:cognitive, functional and behavioural outcomes in the Consortium to investigate vascular impairment of cognition (CIVIC) cohort study. J Neurol sci, 2007, 252(2):106-112
16 Kalvach P, Gregova D. Cerebral microangiopathy in the mosaic of new discoveries. J Neurol Sci, 2005, 229-230: 7-12
17 Scazynski JS,Sigurdsson S,Jonsdottir MK,et al. Cerebral infarcts and cognitive performance of location and number of infarcts. Stroke,2009,40(3): 677-682
18 Barber R,Scheltens P, Gholkar A,et a1.White matter lesions on magnetic resonance imaging in dementia with Lewy bodies. Alzheimer’s disease,vascular dementia and normal aglng.J Neurol Neurosurg Psychiatry,1999, 67(1): 66-72
19 Schmidt R. Comparison of magnetic resonance imaging in Alzheimer's disease, vascular dementia and normal aging.Eur Neurol,1999,32(2):164-169
20何国军,陈俊抛,温志波,等.阿尔茨海默病与血管性痴呆患者白质疏松的MRI定量研究。中国临床康复,2004, 8(28): 6066-6067
21 Price CC,Jefferon AL,Merino JG,et a1.Subcortical vascular dementia intergrating neuropsychological and neuroradiologic data.Neurology,2005, 65(3): 376-382
22 Au R, Massaro JM, Wolf PA, et al. Association of white matterhyperintensity volume with decreased cognitive functioning: The Framingham Heart Study. Arch Neurol, 2006, 63(2): 246-250
23 Yoshita M, Fletcher E, Harvey D, et al. Extent and distribution of white matter hyperintensities in normal aging, MCI, and AD. Neurology, 2006, 67(2): 2192-2198
24 Wright CB,Festa JR,Paik MC,et al. White matter hyperintensities and subclinical infarction: associations with psychomotor speed and cognitive flexibility. Stroke, 2008, 39(3): 800-805
25 Geerlings MI, Appelman AP, Vincken KL, et al. Association of white matter lesions and lacunar infarcts with executive functioning: the SMART-MR study. Am J Epidemiol , 2009, 170(9): 1147-1155
26 Tullberg M,Fletcher E,DeCarli C,et a1.White matter lesions impair frontal lobe function regardless of their location.Neurology,2004,63(2): 246-253
27 Saehdev PS,Bordaty H,Valenzuela MJ,et al. The neuropsychological profile of vascular cognitive impairment in storke and TIA Patients. Neurology, 2004, 62(6): 912-919
28 Gold G, Kovari E,Herrmann FR,et al. Cognitive consequences of thalamic, basal ganglia, and deep white matter lacunes in brain aging and dementia. Stroke, 2005, 36(6):1184-1188
29 O'Brien JT,Paling S,Barber R,et al. Progressive brain atrophy on serial MRI in dementia with Lewy bodies, AD , and vascular dementia. Neurology,2001,56(10): 1386-1388
30 Fein G, Di Sclafani V, Tanabe J, et al. Hippocampal andcortical atrophy predict dementia in subcortical ischemic vascular disease. Neurology, 2000, 55(11): 1626-1635
31 O'Sullivan M, Ngo E, Viswanathan A, et al. Hippocampal volume is an independent predictor of cognitive performance in CADASIL. Neurobiol Aging, 2009 , 30(6):890-897.
32 Du AT, Schuff N, Laakso MP, et al. Effects of subcortical ischemic vascular dementia and AD on entorhinal cortex and hippocampus.Neurology, 2002, 58(11): 1635-1641
33 Staekenborg SS, van Straaten EC, vander Flier WM, et al. Small vessel versus large vessel vascular dementia: risk factors and MRI findings. J Neurol, 2008, 255(11): 1644-1651
34 Sung YH, Park KH, Lee YB, et al. Midbrain atrophy in subcortical ischemic vascular dementia. J Neurol, 2009, 256(12): 1997-2002
35 Seo SW, Ahn J, Yoon U, et al. Cortical thinning in vascular mild cognitive impairment and vascular dementia of subcortical type. J Neuroimaging, 2010, 20(1): 37-45
36 Chen Y, Chen X, Xiao W, et al. Frontal lobe atrophy is associated with small vessel disease in ischemic stroke patients. Clin Neurol Neurosurg, 2009, 111(10): 852-857
37 Sderlund H, Nilsson LG, Berger K, et al. Cerebral changes on MRI and cognitive function: the CASCADE study. Neurobiol Aging, 2006, 27(1): 16-23
38 Masutani Y,Aoki S,Abe O,et a1. MR diffusion tensor imaging recent advance and new technique for diffusion tensor visualization.Eur J Radiol,2003,46(1): 53-66
39 Bammer R,Augustin M,Strasser-Fuchs S,et a1.Magnetic resonance diffusion tensor imaging for characterizing diffuse and focal white matter abnormalities in multiple sclerosis.Magn Reaon Med,2000,44(4):583-591
40 Molko N, Pappata S, Mangin JF, et al. Monitoring disease progression in CADASIL with diffusion magnetic resonance imaging: A study with whole brain histogram analysis. Stroke, 2002, 33(12): 2902-2908
41 Jones DK, Lythgoe D, Horsfield MA, et al. Characterization of white matter damage in ischemic leukoaraiosis with diffusion tensor MRI. Stroke, 1999, 30 (2): 393-397
42 Zhou Y, Lin FC, Zhu J, et al. Whole brain diffusion tensor imaging histogram analysis in vascular cognitive impairment. Neurologic Sci, 2008, 268 (1-2): 60-64
43 O'Sullivan M, Morris RQ, Huckstep B, et al. Diffusion tensor MRI correlates with executive dysfunction in patients with ischaemic leukoaraiosis. J Neurol Neurosurg Psychiatry, 2004, 75(3): 441-447
44 Xu Q, Zhou Y, Li YS, et al. Diffusion tensor imaging changes correlate with cognition better than conventional MRI findings in patients with subcortical ischemic vascular disease. Dement Geriatr Cogn Disord, 2010, 30(4):317-326
45 Ranganathan LN, Govindarajan S. Proton magnetic resonance (1H MR) spectroscopy in common dementias. Natl Med J India, 2005, 18(2):85-86
46 Capizzano AA, Schuff N, Amend DL, et al. Subcortical ischemic vascular dementia: assessment with quantitative MR imaging and 1H MR spectroscopy. AJNR Am J Neuroradiol, 2000, 21(4): 621-630
47 Nitkunan A, Mclntyre DJ, Barrick TR, et al. Correlations between MRS and DTI in cerebral small vessel disease. NMR Biomed, 2006, 19(5): 610-616
48 Shim YS, Yang DW, Kim BS, et al. Comparison of regional cerebral blood flow in two subsets of subcortical ischemic vascular dementia: Statistical parametric mapping analysis of SPECT. J Neurological Sciences, 2006, 250 (1-2): 85-91
49 Kato H, Yoshikawa T, Oku N, et al. Statistical parametric analysis of cerebral blood flow in vascular dementia with small-vessel disease using 99mTc-HMPAO SPECT. Cerebrovasc Dis, 2008, 26(5): 556-562
50 Waragai M, Mizumura S, Yamada T, et al. Differentiation of early-stage Alzheimer's disease from other types of dementia using brain perfusion single photon emission computed tomography with easy Z-score imaging system analysis. Dement Geriatr Cogn Disord, 2008, 26(6): 547-555
51 Kimura M, Shimoda K, Mizumura S, et al. Regional cerebral blood flow in vascular depression assessed by 123I-IMP SPECT. J Nippon Med Sch, 2003, 70(4): 321-326
52 Tatsch K, Koch W, Linke R, et al. Cortical hypometabolism and crossed cerebellar diaschisis suggest subcortically induced disconnection inCADASIL: an18F-FDG PET study. J Nucl Med, 2003, 44(6): 862-869
53 Reed BR, Eberling JL, Mungas D, et al. Effects of white matter lesions and lacunes on cortical function. Arch Neurol, 2004, 6(10): 1545-1550
54 Kerrouche N, Herholz K, Mielke R, et al. 18FDG PET in vascular dementia: differentiation from Alzheimer's disease using voxel-based multivariate analysis. J Cereb Blood Flow Metab, 2006, 26(9): 1213-1221