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阿尔茨海默病(Alzheimer disease,AD)是一种以进行性认知功能障碍和行为异常为特征的中枢神经系统退行性疾病,是老年人最常见的痴呆类型,其病死率居老年人病死率的第5位。目前,全球大约有4 400万AD患者,由于人口的迅速老龄化,预计到2050年,AD患者数可能会翻倍。AD不仅给患者带来巨大的痛苦,也给其家庭和社会带来了沉重的精神压力和医疗负担。家族性或早发性AD与遗传因素有关,最常见的是淀粉样前体蛋白(APP)基因、早老素1(PS1)以及早老素2(PS2)基因突变[1];而对于散发性或晚发性AD,载脂蛋白E(APOE)基因在许多水平上改变人体的衰老过程,从而促进AD的发生。即使遗传因素与AD的相关性得到了研究者的广泛支持,但近几年的研究结果更趋向于AD是由多种复杂病因(如肠道菌群失调[2]、糖尿病、吸烟、衰老和DNA损伤[3]等)共同作用导致的。AD的大体病理学改变为脑组织萎缩(特别是颞叶和海马区)。组织病理学上有两大典型的改变,即难溶性β淀粉样蛋白(amyloid beta-peptides,Aβ)在神经元外沉积形成的神经炎性斑块(neuritic plaques,NP)以及Tau蛋白过度磷酸化在神经元内聚集形成的神经原纤维缠结(neurofibrillary tangles,NFT)。Aβ的生成与清除失衡被认为是导致神经细胞变性的起始事件。Tau蛋白是体内含量最高的微管相关蛋白,正常脑中Tau蛋白的功能是与微管蛋白结合,促进其聚合形成微管及与形成的微管结合来维持微管的稳定性。Tau蛋白的过度磷酸化使微管结构受损,从而促进Tau蛋白聚集形成NFT,最终导致突触间连接丧失和神经元死亡[4]。过去,AD的确诊主要依据尸检病理学分析,近十年来,随着活体脑成像的蓬勃发展,AD的诊断和疾病管理也发生了巨大变化。CT和MRI可以显示双侧颞叶和海马区的萎缩,SPECT灌注显像和18F-FDG PET可见顶叶、额叶和颞叶,尤其是海马区血流灌注的降低和代谢异常,但这些显像方法均缺乏特异性。近年来,针对Aβ和Tau蛋白的显像研究为AD的诊断提供了更多的病理生理学信息。应用Aβ特异性PET显像剂可以实现NP的定性和定量分析[5],Tau蛋白PET显像剂近几年也飞速发展。由于分子水平上的改变在大多数情况下先于脑萎缩等组织病理学改变,且发生在认知症状出现之前, 因此分子影像学检查是临床上诊断AD的更有前景的方法。此外,分子影像探针可以特异性地结合Aβ和Tau蛋白,有利于AD与其他认知功能障碍的疾病(血管性痴呆、额颞叶痴呆以及路易体痴呆)相鉴别,在临床上具有重要作用。当前对AD的治疗主要是以综合治疗为主,但改善认知功能减退仍十分困难。针对AD发病机制的靶点药物也在开发试验阶段[6],运动疗法、脑干细胞移植等有望成为治疗AD的新契机。
阿尔茨海默病分子影像探针的研究进展
Research advances on molecular imaging probes for Alzheimer disease
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摘要: 阿尔茨海默病(AD)是一种进行性神经退行性疾病。β淀粉样蛋白(Aβ)沉积和过度磷酸化的Tau蛋白形成的神经原纤维缠结(NFT)是该病的病理学特征。在过去的20年中,分子影像探针在AD的诊疗中取得了很大进展,其作用已经超越了传统的脑灌注和葡萄糖代谢显像。与Aβ或NFT特异性结合的分子影像探针可成为准确和早期诊断AD的有价值工具,且其已被提出作为最近修订的临床诊断标准中的生物标志物。笔者主要对Aβ和NFT分子影像探针的研究进展进行综述。Abstract: Alzheimer disease (AD) is a progressive neurodegenerative disease. Amyloid beta-peptides (Aβ) deposition and neurofibrillary tangles (NFT) formed by hyperphosphorylated Tau protein are the pathological features of the disease. In the past two decades, molecular imaging probes have made great progress in the diagnosis and treatment of AD, and have perfomred the important role beyond traditional cerebral perfusion and glucose metabolism imaging. Molecular imaging probes which specifically bind to Aβ or NFT can become valuable tools for accurate and early diagnosis of AD, and have been proposed as biomarkers in the recently revised clinical diagnostic criteria. In this paper, the research status and advances of Aβ and NFT molecular imaging probes are reviewed.
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Key words:
- Alzheimer disease /
- Molecular probes /
- Amyloid beta-peptides /
- Tau proteins
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