摘要
随着世界人口老龄化的发展,伴有认知功能障碍的老年人群受到越来越多的关注。老年性痴呆(Dementia)被定义为一种由不同疾病引起的以进行性记忆力减退及认知功能障碍为核心症状的获得性智能损害综合征,严重影响患者的日常及社会生活,最常见的四种类型包括：阿尔茨海默病(Alzheimer's disease, AD)、血管性痴呆(Vascular dementia, VaD)、路易小体痴呆(Dementia with Lewy bodies, DLB)及额颞叶痴呆(Frontotemporal dementia, FTD)。阿尔茨海默病是最常见的一种痴呆类型,其病理学特征为神经元缺失、神经元纤维缠结和淀粉样物质沉积。目前越来越多的研究表明认知功能损害与脑内兴奋性、抑制性神经元功能异常有关。胆碱能及谷氨酸能神经元等兴奋性神经元在阿尔茨海默病病理进程中的功能异常在先前的研究中已得到证实。神经系统内主要的抑制性神经递质——γ-氨基丁酸(γ-aminobutyric acid, GABA)也被认为与认知功能有关。尸检及动物模型研究表明阿尔茨海默病的病理过程中存在GABA能系统功能异常。但是至今尚未有活体研究证实AD及VaD患者脑组织内GABA含量的变化。
磁共振波谱(magnetic resonance spectroscopy, MRS)技术应用原子核在不同化学环境下的化学位移来检测活体组织内不同代谢物的含量,使我们可以检测和量化脑内的重要代谢产物,包括天门冬氨酸(NAA),肌酸(Cr),胆碱(Cho)和肌醇(mI)等。随着波谱编辑技术的发展,尤其是MEGA-PRESS(MEscher-GArwood Point RESolved Spectroscopy)技术的应用,使得我们可以检测活体脑组织内GABA的含量。目前,MEGA-PRESS波谱序列已被成功应用于测量健康人群及一系列神经精神疾病的脑内GABA的含量。但是,迄今为止,关于活体AD患者、VaD患者脑组织内GABA含量变化的研究甚少。因此,本研究的目的是在3T磁共振上,利用MEGA-PRESS序列分别检测AD及VaD患者脑内额叶、顶叶内GABA的含量,探讨AD. VaD患者与年龄、性别相匹配的健康成人相比脑组织内GABA含量的差异。此外,AD、VaD患者脑内GABA含量与认知损害程度的相关性也是本实验的一项研究内容。
论文分三个部分,摘要如下：
第一部分MEGA-PRESS谱序列的感兴趣区重合率的研究
目的：磁共振波谱研究中感兴趣区的重合率会影响波谱数据分析结果的可靠性。本实验的目的是采用图像配准技术评价MEGA-PRESS序列扫描中志愿者两次扫描的定位重合率以及不同志愿者间感兴趣区的定位重合率以及其对感兴趣区内GABA含量的影响。
材料与方法：选取13名健康志愿者,应用3T飞利浦MRI (Achieva, TX, Best, The Netherlands)对所有志愿者行颅脑T1加权TFE序列(T1W-TFE)扫描,得到三维高分辨率图像,并在所得的三维图像上将感兴趣区(volume of interest, VOI)手动调整放置于枕叶(occipital region, OCC)及右侧中央前回感觉运动区(sensoriomotor region, SM)。其后进行MEGA-PRESS序列扫描采集GABA波谱数据。然后同一扫描者对相同志愿者用同样的扫描参数进行第二次手动定位及MEGA-PRESS序列扫描。扫描结束后对所得数据进行后处理,将每个志愿第二次扫描的感兴趣区配准到第一次扫描的脑图像上以及将所有志愿者第一次扫描的感兴趣区配准转化到标准脑图像上。图像配准转化的步骤及应用软件如下：①应用美国约翰·霍普金斯大学(Johns Hopkins University)与飞利浦公司合作研发的SvMark软件生成分别含有感兴趣区、全脑图像的蒙片PAR文件(所得蒙片即含有计算志愿者两次扫描感兴趣区重叠率的图像数据)；②将分别储存有感兴趣区、全脑蒙片数据的PAR文件运用Matlab软件转换为可供剪切软件使用的.nifti文件；③对全脑蒙片的.nifti文件应用BET (Brain Extration Tool)软件去除颅骨等非脑组织,得到只含有脑组织的模板图像；④采用FAST(FMRIB's automated segmentation tool)软件包Flirt (FMRIB's Linear Image Registration Tool)的功能将所有志愿者的感兴趣区配准、转化到标准脑模板图像上(配准后的脑图像即含有计算志愿者间感兴趣区定位重合率的数据)。完成步骤①后,在Matlab上运用DOC运算(Dice overlap coefficient)(A代表OCC, B代表SM)计算两次扫描的感兴趣区配准蒙片的重叠率,得到同一志愿者两次扫描间感兴趣区的重合率。完成步骤④将所有受试者第一次扫描的感兴趣区均配准到标准脑图像上后,采用随机配对原则将13个志愿者随机配对,并应用DOC公式分别计算配对组枕叶(OCC)及中央前回感觉运动区(SM)两个感兴趣区的重叠率。最后应用美国约翰·霍普金斯大学研发的Gannet软件测量两次扫描的感兴趣区内GABA+/Cr值,比较感兴趣区两次定位间GABA+/Cr值有无统计学差异。
结果：DOC计算结果显示,同一志愿者两次扫描的0CC及SM两个感兴趣区的重合率分别为87%±5%、86%±5%。不同志愿者间OCC及SM感兴趣区的重叠率分别为75%±10%、78%±7%。Gannet测量结果显示,13名志愿者OCC及SM感兴趣区内GABA+/Cr比值在两次扫描间无明显统计学差异(OCC:t=-1.301, p=0.206; SM:t=0.260, p=0.797)。
结论：MEGA-PRESS序列感兴趣区的手动定位有较高的重合率,手动定位的差异对脑组织内GABA+/Cr值的测量无明显影响,因此应用MEGA-PRESS波谱序列测量脑组织内不同感兴趣区内GABA含量有较高的可靠性。
第二部分：阿尔茨海默病患者脑内GABA含量的研究
目的：应用MEGA-PRESS技术检测阿尔茨海默病(AD)患者及年龄、性别相匹配的健康志愿者脑内额叶、顶叶GABA的含量,比较AD患者脑GABA含量较正常志愿者有无差异,以及AD患者脑内GABA的含量与认知损害程度的相关性。
材料和方法：利用飞利浦3.0T磁共振(Philips, Achieva,TX, Best, The Netherlands),对15例临床诊断为AD的患者(AD组)和15例年龄及性别相匹配的健康志愿者(Healthy Controls, HC)(HC组)行1H-MRS扫描,并采用简易精神状态量表(MMSE)评分对所有受试者认知状态进行评价。磁共振波谱的扫描方案为：首先应用三维高分辨率磁共振T1-FFE图像作为定位像,将感兴趣区分别放置于额叶及顶叶,随后应用MEGA-PRESS序列进行磁共振波谱数据的采集。数据采集完毕后应用美国约翰·霍普金斯大学(Johns Hopkins University)研发的GABA数据分析处理工具—Gannet软件,对所得波谱数据进行后处理,测量3.02ppm处GABA+的含量(MEGA-PRESS序列所测得的3.02ppm亦含有少量高肌肽及大分子,故我们将测得的结果描述为GABA+),计算GABA+与Cr的比值(GABA+/Cr).采用独立样本t检验分别比较AD组额、顶叶GABA+/Cr与对照组GABA+/Cr水平的差异,并对AD组额、顶叶GABA+/Cr值与MMSE的相关性进行Spearman相关分析。
结果：AD组额、顶叶GABA+/Cr值(额叶：0.098±0.008；顶叶：0.086±0.016)均低于健康对照组(额叶：0.104±0.022；顶叶：0.099±0.012),但只有顶叶有统计学差异(额叶：t=-1.012,p=0.325；顶叶：t＝-2.561,p=0.016)。对于AD组GABA+/Cr值与认知损害程度的相关性分析结果显示,AD组额叶及顶叶GABA+/Cr值与MMSE评分均无明显相关性(额叶：r=-0.164,p=0.558；顶叶：r=0.025,p=0.929)。
结论：与对照组相比,AD患者脑内顶叶GABA+/Cr值显著降低。额叶GABA+/Cr值也存在降低趋势,但无统计学差异。本实验首次检测到活体组织内AD患者脑GABA含量的改变,证实了GABA能系统在AD病理过程中受累,并为AD患者的临床治疗提供了一个潜在的治疗靶点。
第三部分阿尔茨海默病与皮质下缺血性血管性痴呆患者脑内GABA含量的比较研究
目的：皮质下缺血性血管性痴呆(Subcortical ischemic vascular dementia, SIVD)是最常见的一种血管性痴呆(VaD)亚型,本实验中我们测量皮质下缺血性血管性痴呆患者脑额、顶叶感兴趣区内GABA的含量,比较SIVD及第二部分实验中AD组、健康对照组三者之间的GABA含量有无统计学差异,并评价SIVD患者不同脑组织内GABA含量与认知功能损害程度的相关性。
材料与方法：对13例临床诊断为SVID的患者行'H-MRS扫描(采用MEGA-PRESS序列),扫描方法同第二部分,首先应用高分辨率T1-TFE图像进行定位,将感兴趣区分别手动放置于前额叶及顶叶进行MEGA-PRESS扫描,此外,SVID组患者也进行MMSE评分以评价其认知水平。所得波谱数据采用美国霍普金斯大学(Johns Hopkins University)开发的Gannet软件进行后处理,测量GABA+值并计算GABA+/Cr比值。将SVID组及第二部分实验中所得AD组、健康对照组的额、顶叶GABA+/Cr值采用单因素方差分析进行组内及组间比较。SVID患者GABA+/Cr值与MMSE评分之间的相关性也采用Spearman相关系数进行分析。
结果：SVID患者组额叶及顶叶GABA+/Cr值(额叶：0.086±0.010；顶叶：0.086±0.014)均低于正常对照组(额叶：0.104±0.022；顶叶：0.099±0.012)。SIVD组、AD组及对照组三组之间单因素方差分析结果显示,顶叶GABA+/Cr有统计学差异(F=4.954,p=0.012),额叶无明显统计学差异(F=0.932,p=0.402)。三组顶叶数据两两比较结果显示SIVD组GABA+/Cr值较健康与AD组GABA+/Cr值无明显统计学差异(p=0.979),而SIVD组及AD组顶叶GABA+/Cr值均较健康对照组显著降低(SIVD:p=0.012, AD:p=0.008)。此外,Spearman相关分析结果表明,SVID组额、顶叶GABA+/Cr值与MMSE均无明显相关性(额叶：r=-0.301,p=0.318；顶叶：r=0.205,p=0.502)。
结论：皮质下缺血性血管性痴呆患者(SIVD)的顶叶GABA+/Cr较正常对照组均显著降低,但SIVD与AD组脑内额、顶叶的GABA+/Cr值无明显统计学差异。这一发现证实了SIVD患者脑内存在GABA能神经系统功能异常,有利于我们进一步了解皮质下缺血性血管性痴呆的病理过程。在今后的研究中我们将进一步进行大样本研究以及其他脑区域的研究进一步探讨阿尔茨海默病及血管性痴呆患者脑内GABA含量的差异。
With the development of aging, dementia gets worldwide concern. Dementia is defined as a collection of symptoms ranging from memory impairment, a loss of communication skills and a gradual deterioration in the person's ability to carry out daily tasks and activities of living, which causes significant impairment in social and occupational functioning of the dementia people. There are several forms of dementia, Alzheimer's disease (AD), vascular dementia (VaD), Dementia with Lewy bodies (DLB), frontotemporal dementia (FTD) et al. AD is considered to be the most common dementia, characterizing by three hallmark pathological Lesions (amyloid plaques, neurofibrillary tangles and synaptic loss). VaD is the second most common form dementia, which is described as the memory and cognitive loss symptoms due to vascular diseases within the brain.
Although the exact biochemical processes of synaptic failure in dementia remain poorly understand, it is likely to include a gross dysfunction of neurotransmitter systems, including the excitatory pathways and inhibitory pathways. The disruption of excitatory pathways has been broadly accepted. γ-aminobutyric acid (GABA), the predominant inhibitory neurotransmitter in human brain, is also considered to be associated with cognitive function.
Magnetic resonance spectroscopy (MRS) enables the non-invasive in vivo measurement of major neurometabolite levels and has been successfully used to evaluate brain regional N-acetylaspartate (NAA), creatine (Cr), choline (Cho) and myo-inositol (mI). Recent developments involving1H-MRS editing PRESS-based techniques, such as MEGA-Point Resolved Spectroscopy (PRESS), offers the noninvasive technique to evaluate GABA levels in the human brain, and has been successfully applied to measure GABA levels in normal brain and a number of neurologic, psychiatric diseases. While, paucity MRS study has assessed the brain level of GABA in AD patients.
In this study, the edited MRS technique, MEGA-PRESS, was used to explore in vivo whether brain GABA levels change in AD and VaD patients by comparing to those of age-and gender-matched healthy control subjects. The assessment of relationship between GABA levels and the cognitive impairments in AD, VaD patients were also performed.
This study contains three parts:
Part1.Volume of Interest placement study for edited magnetic resonance spectroscopy
Objective:MEGA-PRESS sequence is aneditedmagnetic resonance spectroscopy (MRS) technique, and has been successfullyused to evaluate the brain regional GABA levels.The accuracy of volume of interest (VOI) placementmay affect the reliability of GABA levels quantification. In this part of study we use registration tools to evaluate the MRS voxels overlapping rate within and between subjects.
Material and Methods:13healthy subjects were recurited in this experiment. For each participant,T1-weighted3D TFE images were acquired for localization and GABA edited MRS data were acquired using MEGA-PRESS sequence. VOIs were firstly placed in the right sensorimotor region (SM) and in the occipital region (OCC). The second placement was done with the same protocol to log voxel location parameters, following with the MEGA-PRESS sequence to get the GABA data again.The voxel data of subjects acquired from the two scans were then registered to their Tl-TFE images of the first scan, and all the voxels from the first scan were regsitrated to the standard space. Theregistration process went as follows:Ⅰ.The voxels (both OCC and SM voxels) of each subject from the two scans were registered to their T1W-images of the first scans using Svmask tool, generating the voxel mask images, which were used forvoxel overlapping rate calculationwithin subjcect; Ⅱ. The voxels and whole brain.PAR files were converted to Nifti format with the use of Matlab toolkit; Ⅲ. In order to exclude the effect of non-brain tissue, the3D Nifti format brain images were extracted using Brain Extraction Tool (BET) from FSL software package;Ⅳ. All the voxels and extracted brain images from the first scanwere registered to the reference standard space using FMRIB's Linear Image Registration Tool (Flirt) from FSL software package, and the registrated images were used to calculate thevoxel overlapping rate between subjects. After images registration, the Dice overlap coefficient (DOC) was used to calculate the MRS voxels overlap within and betweensubjects. Finally, the GABA levels (GABA+/Cr) of all subjects were calculated using Gannet tool in Matlab.
Results:The DOC results show that the overlapping rates of occipital and sensorimotor voxels withinsubject were87%±5%and86%±5%,respectively. The MRS voxels overlapping rates betweensubjects were75%±10%in OCC voxel and78%±7%in SM voxel. No statistical differences of GABA+/Cr ratios were found between the two scans (OCC:t=-1.301, p=0.206;SM:t＝0.260, p=0.797).
Conclusion:The overlapping rate of voxel placement withinsubject and betweensubjects in this study show over75%, with no significant differences of GABA+/Cr ratios between the two scans, suggesting thatVOI placement of MEGA-PRESS sequence has high repeatability andMEGA-PRESS sequence can be used in the study on the measurement of brain regional GABA levels in vivo.
Part2. Evaluation of GABA levels in patients with Alzheimer's disease
Objectives:To determine whether there are in vivo differences of y-aminobutyric acid (GABA) levels in frontal and parietal regions of Alzheimer's disease (AD) patients, compared with matched healthy controls using proton magnetic resonance spectroscopy (1H-MRS), and whether brain GABA levels correlate with cognitive impairment.
Material and Methods:Fifteen AD patients and fifteen age-and gender-matched healthy controls underwent1H-MRS of the frontal and parietal lobes using the 'MEGA-Point Resolved Spectroscopy Sequence'(MEGA-PRESS) technique, and cognitive levels of all subjects were evaluated using Mini-Mental State Examination (MMSE) tests. MRS data were processed using the Gannet program, which includes contributions from GABA, macromolecules and homocarnosine (and therefor the signal detected is defined as GABA+). Differences of GABA+to creatine (GABA+/Cr) ratios between AD patients and controls were tested using a two-tailed t-test, and Spearman correlation analysis was used to evaluate the relationship between GABA+/Cr and MMSE scores.
Results:Significant lower GABA+/Cr ratios were found in the parietal region of AD patients compared to controls (t=-2.561, p=0.016). Although the mean GABA+/Cr ratios in the frontal region of AD (0.098±0.008) were lower than those of healthy controls (0.104±0.022), this finding was not statistically significant (t=-1.012, p=0.325). In the AD patients, no significant correlations between GABA+/Cr and MMSE scores were found in either the frontal (r=-0.164, p=0.558) or parietal regions (r=0.025, p=0.929).
Conclusion:Decreased GABA+/Cr levels were present in the parietal region of patients with AD in vivo, suggesting that abnormalities of the GABAergic system may be present in the pathogenesis of AD.
Part3.The evaluation of GABA levels in patients with subcortical ischemic vascular dementia and Alzheimer's disease
Objective:In this part, we use edited MRS technique to evaluate the brain GABA levels of frontal, parietal regions in patients with Subcortical ischemic vascular dementia (SVID) and to assess whether there are brain GABA levels differences among SVID, AD patients and age-, gender-matched healthy controls.
Material and Methods:13clinically diagnosed SVID patients underwent T1-FFE sequence and edited MRS scan (using MEGE-PRESS sequence), and MMSE test were performed to evaluate the cognitive impairment of the SVID patients. The MRI and MRS data of the15patients with AD and age-gender-matched healthy controls collected in part-two study were also recruited this study. The MRS data were processed using Gannet tool just as part one study and the GABA levels were described as GABA+/Cr ratios. The differences of GABA+/Cr levels among SVID, AD patients and healthy controls were analyzed using one way ANOVA. The relationship between GABA+/Cr levels and MMSE scores were also performed using spearman correlation analysis.
Results:Decreased mean GABA+/Cr levels were detected in both frontal (0.086±0.010) and parietal regions (0.086±0.014) of patients with SVID, compared with age-and gender-matched healthy controls (frontal:0.104±0.022; parietal:0.099±0.012). However, only in parietal region, significant lower GABA+/Cr levels were found in this study (F=4.954, p=0.012). With regard to the GABA+/Cr levels differences between SVID and AD patients, no significant differences were found in parietal regions (p=0.979). In additionally, no significant correlation between GABA+/Cr levels and MMSE scores were detected in either frontal (r=-0.301, p=0.318) or parietal regions (r=0.205, p=0.502).
Conclusion:Decreased GABA+/Cr levels were found in parietal region of patients with SVID, which offered evidence that GAB Anergic system involves in the process of SVID. But no GABA+/Cr levels differences were found between SVID and AD patients, GABA+/Cr could notyet be a biomarkerto differentiate SVID from AD.
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