The Centre for Mental Health, Imperial College London, UK.
Department of Psychiatry, School of Clinical Medicine, Addenbrooke's Hospital, University of Cambridge, UK.
Ageing Res Rev. 2017 Jul;36:88-104. doi: 10.1016/j.arr.2017.03.004. Epub 2017 Mar 22.
It is well established that the neurodegenerative process of Alzheimer's disease (AD) begins many years before symptom onset. This preclinical phase provides a crucial time-window for therapeutic intervention, though this requires biomarkers that could evaluate the efficacy of future disease-modification treatments in asymptomatic individuals. The last decade has witnessed a proliferation of studies characterizing the temporal sequence of the earliest functional and structural brain imaging changes in AD. These efforts have focused on studying individuals who are highly vulnerable to develop AD, such as those with familial genetic mutations, susceptibility genes (i.e. apolipoprotein epsilon-4 allele), and/or a positive family history of AD. In this paper, we review the rapidly growing literature of functional imaging changes in cognitively intact individuals who are middle-aged: positron emission tomography (PET) studies of amyloid deposition, glucose metabolism, as well as arterial spin labeling (ASL), task-dependent, resting-state functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS) studies. The prevailing evidence points to early brain functional changes in the relative absence of cognitive impairment and structural atrophy, although there is marked variability in the directionality of the changes, which could, in turn, be related to antagonistic pleiotropy early in life. A common theme across studies relates to the spatial extent of these changes, most of which overlap with brain regions that are implicated in established AD. Notwithstanding several methodological caveats, functional imaging techniques could be preferentially sensitive to the earliest events of AD pathology prior to macroscopic grey matter loss and clinical manifestations of AD. We conclude that while these techniques have great potential to serve as biomarkers to identify at-risk individuals, more longitudinal studies with greater sample size and robust correction for multiple comparisons are still warranted to establish their utility.
众所周知，阿尔茨海默病（AD）的神经退行性过程在症状出现前多年就已经开始。这个临床前阶段为治疗干预提供了一个关键的时间窗口，但这需要生物标志物来评估未来对无症状个体的疾病修饰治疗的疗效。在过去的十年中，大量研究描述了 AD 最早的功能和结构脑成像变化的时间顺序。这些研究集中在研究那些极易患上 AD 的个体，如携带家族基因突变、易感基因（即载脂蛋白 Epsilon-4 等位基因）和/或 AD 阳性家族史的个体。在本文中，我们回顾了认知正常的中年个体中功能成像变化的快速增长文献：正电子发射断层扫描（PET）研究淀粉样蛋白沉积、葡萄糖代谢以及动脉自旋标记（ASL）、任务相关的静息状态功能磁共振成像（fMRI）和磁共振波谱（MRS）研究。目前的证据表明，在没有认知障碍和结构萎缩的情况下，大脑功能会出现早期变化，尽管变化的方向存在显著的可变性，这可能与生命早期的拮抗多效性有关。研究中的一个共同主题是这些变化的空间范围，其中大部分与已经确定的 AD 相关的脑区重叠。尽管存在一些方法学上的限制，但功能成像技术可能更敏感于 AD 病理的最早事件，而不是宏观灰质丢失和 AD 的临床表现。我们的结论是，虽然这些技术具有作为生物标志物识别高危个体的巨大潜力，但仍需要更多的纵向研究，具有更大的样本量和对多重比较的稳健校正，以确定它们的效用。
