Wolfson Molecular Imaging Centre, School of Cancer and Enabling Sciences, University of Manchester, Manchester, UK.
Lancet Neurol. 2011 Jul;10(7):667-70. doi: 10.1016/S1474-4422(11)70123-5.
The hypothesis that amyloid deposition is the leading cause of Alzheimer's disease (AD) is supported by findings in transgenic animal models and forms the basis of clinical trials of anti-amyloid agents. According to this theory, amyloid deposition causes severe damage to neurons many years before onset of dementia via a cascade of several downstream effects. This hypothesis has, however, not yet been directly tested in human beings because of the very limited possibility of diagnosing amyloid deposition in vivo, which until recently required either brain biopsy or PET imaging with an on-site cyclotron and radiochemistry laboratory. Moreover, a clinical diagnosis of AD requires that patients have dementia, at which stage any effective treatment aimed at reducing amyloid deposition will probably be too late.
The amyloid imaging tracers flutemetamol, florbetapir, and florbetaben labelled with (18)F have been developed for PET; they can be produced commercially at central cyclotron sites and subsequently delivered to clinical PET scanning facilities. These tracers are currently undergoing formal clinical trials to establish whether they can be used to accurately image fibrillary amyloid and to distinguish patients with AD from normal controls and those with other diseases that cause dementia. They might also be used as biomarkers to predict development of AD before onset of dementia and to assess the effect of anti-amyloid therapy. Negative amyloid scans indicate absence of AD with a high level of accuracy, but healthy elderly volunteers might have positive amyloid scans, so their predictive value in isolation is less clear. Close association of in-vivo amyloid imaging results with post-mortem histopathological findings was shown with florbetapir in a phase 3 study. WHERE NEXT?: Therapeutic studies of anti-amyloid agents that include amyloid tracers as biomarkers are expected to be useful for drug development and to clarify the relation between amyloid removal and clinical effects. Once the (18)F tracers become available for diagnostic use, large-scale longitudinal studies will be needed to clarify their prognostic and diagnostic power in relation to age, risk factors, and AD subtypes. Ultimately, these tracers will hopefully clarify the pathophysiological role of amyloid in AD and contribute to development of new treatments.
淀粉样蛋白沉积是阿尔茨海默病（AD）的主要病因，这一假说得到了转基因动物模型研究结果的支持，并为抗淀粉样蛋白药物的临床试验提供了基础。根据这一理论，淀粉样蛋白沉积通过一系列下游效应，在痴呆症发作前多年对神经元造成严重损害。然而，由于体内诊断淀粉样蛋白沉积的可能性非常有限，这一假说尚未在人类身上得到直接验证。直到最近，这一检测要么需要进行脑活检，要么需要使用现场回旋加速器和放射化学实验室的正电子发射断层扫描（PET）成像。此外，AD 的临床诊断要求患者出现痴呆，而在这一阶段，任何旨在减少淀粉样蛋白沉积的有效治疗可能都为时过晚。
已开发出带有（18）F 的淀粉样蛋白成像示踪剂 flutemetamol、florbetapir 和 florbetaben 用于 PET；它们可以在中央回旋加速器站点商业化生产，随后运送到临床 PET 扫描设施。这些示踪剂目前正在进行正式的临床试验，以确定它们是否可用于准确成像纤维状淀粉样蛋白，并将 AD 患者与正常对照者和那些患有导致痴呆的其他疾病的患者区分开来。它们也可以作为生物标志物，用于在痴呆症发作前预测 AD 的发生，并评估抗淀粉样蛋白治疗的效果。阴性淀粉样蛋白扫描可高度准确地表明不存在 AD，但健康的老年志愿者可能会出现阳性淀粉样蛋白扫描，因此其单独的预测价值尚不明确。一项 3 期研究显示，florbetapir 的体内淀粉样蛋白成像结果与死后组织病理学发现密切相关。
下一步是什么？：包含淀粉样蛋白示踪剂作为生物标志物的抗淀粉样蛋白药物的治疗研究有望对药物开发有用，并阐明淀粉样蛋白清除与临床效果之间的关系。一旦（18）F 示踪剂可用于诊断，就需要进行大规模的纵向研究，以阐明它们在年龄、危险因素和 AD 亚型方面的预后和诊断能力。最终，这些示踪剂有望阐明淀粉样蛋白在 AD 中的病理生理学作用，并为新疗法的开发做出贡献。
