PET分子影像在阿尔茨海默病神经炎症中的研究进展

阿尔茨海默病（AD）是最常见的神经系统退行性疾病之一,其发病机制仍不清楚。大量的研究证实神经炎症在AD的发病过程中发挥着关键作用,是AD的重要标志物之一。PET是一种先进的分子影像学检查技术,可无创、在体研究AD神经炎症发生发展过程。笔者就神经炎症在AD中的分子基础及PET分子影像在AD神经炎症方面的研究进展做简要概述。     

阿尔茨海默病等痴呆疾病的脑功能影像学研究

痴呆类疾病可分为阿尔茨海默病（AD）、皮克病、多发性梗死性痴呆（MID）等类型。它们各具不同的临床特点,神经心理学检查对痴呆的诊断及鉴别诊断起一定作用。AD等痴呆疾病的神经影像学发展越来越迅速,其中^18F-FDGPET脑功能显像技术可以早期发现AD患者大脑皮层顶,颞叶等区域葡萄糖代谢率降低,并且左,右半球不对称。^18F-FDGPET方法还可以鉴别诊断AD与其他痴呆类疾病。     

Stanford B型主动脉夹层计算机仿真研究进展

【摘要】 随着计算机技术和医学影像学发展,通过计算流体力学（CFD）方法对主动脉夹层（AD）进行仿真研究已得到越来越广泛应用。CFD仿真研究包括对AD几何模型、血管壁、血液和血流等属性模拟并获取其血流动力学参数等信息,可为临床诊治提供重要依据。该文着重介绍CFD技术在建立Stanford B型AD仿真模型及其临床应用如预测AD破裂风险、模拟AD手术治疗中血流动力学变化方面研究进展和不足,并探讨未来应用前景和发展趋势。     

分子神经影像学及其在脑科学的研究应用进展

随着科技进步和医学影像学的发展，除经典影像学（classical imaging）外，功能影像学（functional imaging）及分子影像学（molecular imaging）在临床医学及分子生物学领域已有极大的应用和开发前景。经典影像显示的是分子改变的终效应，而分子影像学可显示疾病过程中的分子异常。分子影像学是多学科综合发展的结果，目的是进行分子水平或基因水平的诊断，为治疗提供科学依据。神经功能分子显像是人类脑计划的重要组成部分，脑是最难认识和最为复杂的器官。在人类脑计划中，神经信息学是神经科学家和信息学家利用现代化信息工具，将脑的结构和功能研究结果联系起来，建立神经信息学数据库和有关神经系统所有数据系统，对不同层次脑的研究数据进行检索、比较、分析、整合、建模和仿真，绘制出脑功能、结构和神经网络图谱，达到“认识脑、保护脑和创造脑”的目标的科学。     

ApoE ε4等位基因携带者脑结构与功能的影像学纵向研究进展

载脂蛋白Eε4（ApoΕε4）等位基因是阿尔茨海默病（AD）发生的高风险基因型。随着影像学新技术的不断发展,尤其是功能磁共振成像（fMRI）的日益成熟,评估ApoEε4等位基因对脑结构和功能的影响已成为目前研究的热点,研究也大多集中在某一年龄段的横向研究。现就ApoE ε4等位基因携带者脑结构与功能的影像学纵向研究予以综述。     

应用MR影像学技术进行神经科学前沿课题的研究

近年来多层螺旋CT、MRI和核医学[主要是正电子发射计算机体层摄影（PET）、和单光子发射计算机断层摄影（SPECT）]等医学影像学技术飞速发展，神经影像学检查不仅能直接显示颅脑组织解剖和病理等形态学改变，还能观察脑组织的扩散、灌注等生理和病理生理改变，应用MR波谱（MRS）可直接显示脑代谢情况，而脑功能MR成像（fMRI）则已经成为研究心理及认知科学的最佳工具，因而神经影像学已经发生质的飞跃。     

基于体素的MRI形态分析诊断Alzheimer病的价值

目的评价基于体素的MRI形态分析（voxel-based Morphometry，VBM）法诊断Alzheimer病（AD）的价值。方法采用Siemens Sonata1．5T超导MR成像系统，对19例可能AD患者和15例年龄、性别与之相匹配的健康老年人及15例正常年轻人行全脑扫描，应用磁化准备快速梯度回波成像序列获取三维结构图像。数据分析采用以SPM99软件包为基础的全自动VBM技术进行处理。结果与健康老年对照组比较，AD患者两侧内颞叶（海马）明显萎缩（P〈0．001），右侧海马减少的体素总数为1529个，左侧海马减少的体素总数为1281个；而且AD患者右侧尾状核头和左侧内侧丘脑亦明显萎缩，减少的体素总数均为1529个；而感觉运动皮层、枕叶及小脑相对保持完好。此外，AD患者大脑皮层萎缩具有不对称性。结论VBM法操作简单，可自动化观察AD全脑萎缩情况，所得结论不仅与既往神经影像学研究结果一致，并得到了有重要价值的新发现，具有广阔的临床应用前景。     

阿尔茨海默病Aβ斑块MR成像研究

阿尔茨海默病（AD）是老年痴呆的最常见类型，其最主要的病理特征为Aβ（β—amyloid，Aβ）斑块形成和神经原纤维缠绕。其中，Aβ沉积形成斑块可能是AD发病的中心环节。由于MRI技术具有无创性和良好的空间分辨力．故利用其对大脑内Aβ斑块进行成像成为了研究热点。就近年关于MRI技术对AD淀粉样斑块成像研究进行综述。     

阿尔茨海默病相关正电子显像剂的研究进展

阿尔茨海默病（AD）是老年人群中最常见的神经退行性疾病之一,其症状始于轻微的记忆困难,逐渐演变为认知功能障碍、复杂的日常活动功能障碍等。目前AD的早期诊断和鉴别诊断仍具有一定的挑战性,而β淀粉样蛋白（Aβ）和Tau蛋白等生物标志物在AD诊断中的作用越来越重要。笔者就AD诊断相关的正电子显像剂进行综述,以期让更多的医务工作者了解新的核医学显像技术,从而对AD进行早期诊断和治疗,延缓病情的恶化。     

Tau蛋白的异常翻译后修饰与阿尔茨海默病

阿尔茨海默病（Alzheimer’s disease，AD）是一种发生在老年期及老年前期的神经退行性疾病，其主要的病理改变包括老年斑、神经元纤维缠结和神经元脱失。由于以磷酸化和糖基化为主的Tau蛋白异常翻译后修饰与神经元纤维缠结关系密切，因此，关于Tau蛋白在AD发生发展中的作用已成为近年AD研究领域的一大热点。本文重点对目前有关Tau蛋白异常翻译后修饰与AD的关系，以及Tau蛋白在AD诊断中的作用和以其为靶标进行AD防治药物研究的现状和前景进行了综述。     

基于神经影像的复杂脑网络技术用于阿尔兹海默症的研究进展

近年来，人工智能技术被广泛地应用于阿尔兹海默症（AD）的计算机辅助诊断和疾病机理研究，基于图论的复杂网络分析技术是其中一种常见的数据挖掘方法，通过结构磁共振、功能磁共振和PET等神经成像手段获取多模态脑影像信息，结合复杂网络分析方法发现，AD患者大脑结构/功能网络存在拓扑异常改变。这一发现为AD的早期诊断和机理研究提供了新思路。笔者综述了复杂网络分析技术在AD脑结构和功能影像中的临床应用现状，并对其发展趋势进行了展望。     

Alzheimer病的海马体积测量及脑组织分割分析的初步研究

目的采用ＭＲ体积测量和组织分割分析对Ａｌｚｈｅｉｍｅｒ病（Ａｌｚｈｅｉｍｅｒｄｉｓｅａｓｅ，ＡＤ）患者和正常对照组进行研究，探讨其对ＡＤ的诊断价值。方法对临床诊断为ＡＤ患者和正常老年人各１６例作对照进行ＭＲＩ比较研究。测量两组的海马结构（ＨＦ）体积，脑灰质、脑白质、脑室外脑脊液（ＣＳＦ）和脑室ＣＳＦ体积所占颅内体积百分比，计数两组脑实质Ｔ２ＷＩ上的高信号灶并测量其最大径。结果体积测量显示ＡＤ组左、右侧ＨＦ体积均小于对照组。组织分割分析显示ＡＤ组脑灰质较对照组明显减少，脑室外ＣＳＦ和脑室ＣＳＦ体积所占颅内体积百分比较对照组增加，而脑白质两组间无显著性差异。ＡＤ组和对照组脑实质内高信号灶在大小和分布上无差异。结论ＭＲＨＦ体积测量和脑组织分割分析有助于临床了解ＡＤ的脑部形态结构改变，并能为ＡＤ的进一步诊断提供有价值的影像学评价指标。     

阿尔茨海默病患者脑葡萄糖代谢变化PET/CT研究

目的 探讨阿尔茨海默病(AD)患者脑区葡萄糖代谢变化特征及意义.方法 依据临床诊断标准纳入AD患者17例(AD组),同时选择基本特征匹配的15例健康志愿者做对照(HC组),2组患者均行18 F-FDG PET脑显像,计算机处理获得三维重建图像.采用视觉分析、感兴趣区(ROI)技术与脑功能分析软件对2组PET图像进行统计分析.结果 ①AD患者葡萄糖代谢减低主要累及顶叶、颞叶、额叶皮质、后扣带回和海马,不累及枕叶、基底核、丘脑和小脑,不影响躯体感觉和运动功能.②与轻度AD比较,中重度AD顶叶、颞叶、额叶、后扣带回和海马区葡萄糖代谢减低程度更为显著,范围也有所扩大,部分患者可累及视觉与语言中枢.③系统自带脑代谢分析软件较视觉评价和ROI分析技术更加客观,精细度更高,能够精确反映脑区葡萄糖代谢变化,适合推广应用.结论 AD患者大脑皮层葡萄糖代谢减低区分布具有一定特点和规律,18 F-FDG PET显像对于AD的诊断、鉴别诊断与疗效评价有一定意义.     

Impact of amyloid imaging on drug development in Alzheimer's disease

Imaging agents capable of assessing amyloid-beta (Abeta) content in vivo in the brains of Alzheimer's disease (AD) subjects likely will be important as diagnostic agents to detect Abeta plaques in the brain as well as to help test the amyloid cascade hypothesis of AD and as an aid to assess the efficacy of anti-amyloid therapeutics currently under development and in clinical trials. Positron emission tomography (PET) imaging studies of amyloid deposition in human subjects with several Abeta imaging agents are currently underway. We reported the first PET studies of the carbon 11-labeled thioflavin-T derivative Pittsburgh Compound B in 2004, and this work has subsequently been extended to include a variety of subject groups, including AD patients, mild cognitive impairment patients and healthy controls. The ability to quantify regional Abeta plaque load in the brains of living human subjects has provided a means to begin to apply this technology as a diagnostic agent to detect regional concentrations of Abeta plaques and as a surrogate marker of therapeutic efficacy in anti-amyloid drug trials.     

18F-labeled styrylpyridines as PET agents for amyloid plaque imaging

Positron emission tomography (PET) imaging of beta-amyloid (Abeta) plaques in the brain is a potentially valuable tool for studying the pathophysiology of Alzheimer's disease (AD). It may also be applicable for measuring the effectiveness of therapeutic drugs aimed at lowering Abeta plaques in the brain. We have successfully reported a series of 18F-labeled fluoropegylated stilbenes for PET imaging studies. Encouraging results clearly demonstrated the usefulness of 18F-labeled stilbenes as potential Abeta plaque-imaging agents. In the present study, we applied a similar approach to a styrylpyridine backbone structure. Among all derivatives examined, (E)-2-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-5-(4-dimethylaminostyryl)-pyridine (2) displayed high binding affinity in postmortem AD brain homogenates (Ki=2.5+/-0.4 nM, with [125I]IMPY as radioligand). No-carrier-added [18F]2 was successfully prepared by [18F]fluoride displacement of the corresponding tosylate precursor with a high labeling yield (30-40%) and a high radiochemical purity (>99%). Specific activity at the end of synthesis was determined to be 1500-2000 Ci/mmol. The tracer [18F]2 showed adequate lipophilicity (log P=3.22). In vivo biodistribution of [18F]2 in normal mice exhibited excellent initial brain penetration and rapid washout (7.77% and 1.03% dose/g in the brain at 2 and 30 min after intravenous injection, respectively)--properties that are highly desirable for Abeta-plaque-specific brain imaging agents. Autoradiography of AD brain sections and homogenate binding with postmortem AD brain tissues confirmed the high binding signal of [18F]2 due to the presence of Abeta plaques. These preliminary results suggest that novel PET tracers may be potentially useful for the imaging of Abeta plaques in the living human brain.     

Alzheimer disease: new concepts on its neurobiology and the clinical role imaging will play

Alzheimer disease (AD) is one of, if not the most, feared diseases associated with aging. The prevalence of AD increases exponentially with age after 60 years. Increasing life expectancy coupled with the absence of any approved disease-modifying therapies at present position AD as a dominant public health problem. Major advances have occurred in the development of disease biomarkers for AD in the past 2 decades. At present, the most well-developed AD biomarkers are the cerebrospinal fluid analytes amyloid-β 42 and tau and the brain imaging measures amyloid positron emission tomography (PET), fluorodeoxyglucose PET, and magnetic resonance imaging. CSF and imaging biomarkers are incorporated into revised diagnostic guidelines for AD, which have recently been updated for the first time since their original formulation in 1984. Results of recent studies suggest the possibility of an ordered evolution of AD biomarker abnormalities that can be used to stage the typical 20-30-year course of the disease. When compared with biomarkers in other areas of medicine, however, the absence of standardized quantitative metrics for AD imaging biomarkers constitutes a major deficiency. Failure to move toward a standardized system of quantitative metrics has substantially limited potential diagnostic usefulness of imaging in AD. This presents an important opportunity that, if widely embraced, could greatly expand the application of imaging to improve clinical diagnosis and the quality and efficiency of clinical trials.     

Quantitative NMR measurements of hippocampal atrophy in Alzheimer's disease

Nuclear magnetic resonance (NMR) imaging was employed to study 10 patients with Alzheimer's disease (AD) and seven healthy elderly control subjects. Coronal sections were used to make volumetric measurements of the hippocampus, ventricles, subarachnoid space, and brain parenchyma. The hippocampal volume (normalized relative to the size of the lenticular nucleus) was reduced by 40% in the AD group compared to the controls, with no overlap between the two groups. Overall measures of brain atrophy and ventricular and sulcal enlargement also showed significantly different group means, although with overlap between the two groups. Hippocampal atrophy did not correlate with either overall brain atrophy or dementia severity, although the degree of brain atrophy was correlated with dementia severity. These results show that NMR is capable of providing in vivo quantification of diminished hippocampal size in AD which is not correlated with overall brain atrophy and which may differentiate AD from normal aging.     

Validation of an 18F-labeled biphenylalkyne as a positron emission tomography imaging agent for β-amyloid plaques

AimRecently, the feasibility of detecting amyloid plaques in the living brain by positron emission tomography (PET) imaging has been successfully demonstrated. As such, imaging β-amyloid (Aβ) plaques in the brain may further advance the differential diagnosis of the disease and allow clinicians to measure the effectiveness of therapeutic drugs aimed at lowering plaques in the brain. We report herein the preclinical validation of a potential ¹⁸F-labeled biphenylalkyne, AV-138, as a preliminary step toward developing the imaging agent for patients suspected of having Alzheimer's disease.MethodsIn vitro binding was carried out in the homogenates prepared from postmortem AD brains with [¹²⁵I]IMPY as the radioligand. [¹⁸F]AV-138 was successfully prepared using a tosylate precursor and Sumitomo modules for radiosynthesis. Similarly, specific binding of [¹⁸F]AV-138 (0.02–0.05 nM) to homogenates, prepared from gray and white matters of pooled AD patients and control subjects, was performed. Specific binding to Aβ plaques was measured by autoradiography in AD brain sections (n=11), and the same brain sections were fluorescently stained with thioflavin-S (TF-S). Images of both radiolabeling and fluorescent staining of plaques obtained by a phosphor imager were used for correlation image analysis.ResultsAs expected, AV-138 displayed a high binding affinity (K_i=2.4±0.7 nM) in AD gray matter homogenates (due to its high level of Aβ plaque accumulation). Specific binding can be clearly measured in the AD gray matter homogenates, but not in the AD white matters. Control brain homogenates, due to a lack of Aβ plaques, also showed no specific binding. Furthermore, in vitro autoradiography of postmortem AD brain sections showed that the high binding signal of [¹⁸F]AV-138 was specifically due to Aβ plaques. Fluorescent staining of plaques with TF-S correlated well with the radiolabeling of [¹⁸F]AV-138 in AD brain sections (r>0.90).ConclusionTaken together, these preliminary results strongly suggest that [¹⁸F]AV-138 is potentially useful for imaging Aβ plaques in the living human brain.     

Changes in brain morphology in Alzheimer disease and normal aging: is Alzheimer disease an exaggerated aging process?

BACKGROUND AND PURPOSE: Whether Alzheimer disease (AD) represents exaggerated aging rather than a disease is controversial. Data about the effects of normal aging on the human brain are essential for clarifying this issue; however, whether coherent common patterns of regional morphologic brain changes emerge in the normal aged brain is unclear. Clarification of regional morphologic changes in the brain associated with normal aging and AD was sought using MR imaging. METHODS: Ninety-two healthy volunteers and 26 mildly to moderately impaired patients with AD participated. Images were anatomically normalized, and voxel-by-voxel analyses were done. RESULTS: In healthy volunteers, an age-related decline in the volume of the prefrontal cortex, insula, anterior cingulate gyrus, superior temporal gyrus, inferior parietal lobule, and precuneus was found. These decreases might contribute to the cognitive changes during normal aging. In patients with AD, a significant reduction of gray matter volume in the hippocampal formation and entorhinal cortex bilaterally was noted. CONCLUSION: Morphologic changes associated with normal aging are clearly different from those seen with AD.