An FMRI Index as a Risk Marker for Alzheimer's Disease

这项建议的目标是利用功能磁共振成像(FMRI)开发和验证阿尔茨海默病临床前阶段的早期、非侵入性、定量标记物(风险标记物)。这样一个敏感的AD标志物将在识别高危人群、促进早期评估和提供有效的疾病管理方面具有显著优势。功能磁共振成像技术的最新发展使我们能够以高空间和时间分辨率间接观察神经元的活动。我们和其他人观察到受试者在休息时大胆的对比加权神经生理信号的自发低频(SLF)波动。我们开发了一个指数，COSLOF指数，来量化SLF信号的变化。大量已发表的神经病理学研究结果表明，在AD的发病过程中，海马结构是最初的部位。此外，神经退行性改变的进展在个体之间是显著一致的，是可预测的，并且患者之间几乎没有变化。在阿尔茨海默病中，这种损害最终会导致海马体的严重损害(称为“地板效应”)和痴呆的临床表现。我们的初步结果表明，COSLOF指数具有区分可能/可能的AD患者和认知健康对照的能力。基于所有这些结果，我们提出了一项前瞻性和纵向研究，以检验海马区COSLOF指数可以预测轻度认知障碍(MCI)受试者阿尔茨海默病(AD)的发病。我们选择研究MCI受试者，因为他们AD的发病率很高(每年10%-12%)。在五年期结束时，我们可以回顾确定COSLOF指数预测AD进展的临床前发病的敏感性，并区分那些注定要发展为AD的MCI受试者和那些正在经历正常衰老过程的受试者。

The goal of this proposal is to develop and validate an early, non-invasive, quantitative marker for the pre-clinical stage of Alzheimer's disease (risk marker) using functional magnetic resonance imaging (fMRI). Such a sensitive marker for AD will have significant advantages in identifying people at risk, facilitating early assessment and providing effective disease management. Recent developments in fMRI technology allow us to indirectly observe neuronal activity with high spatial and temporal resolution. We and others have observed spontaneous low frequency (SLF) fluctuations in the BOLD contrast-weighted neurophysiological signal in subjects at rest. We have developed an index, the COSLOF index, to quantify changes of SLF signal. The results of numerous published neuropathological studies suggest that the hippocampal formation is the initial locus in the disease processes of AD. In addition, the progression of neurodegenerative changes is remarkably uniform across individuals, is predictable, and shows little inter-patient variation. In AD, the lesions eventually lead to severe damage to the hippocampus (referred to as the "floor effect") and clinical expression of dementia. Our preliminary results demonstrate that the COSLOF index has the ability to distinguish between probable/possible AD patients and cognitively healthy controls. Based on all these results, we propose a prospective and longitudinal study to test the hypothesis that the COSLOF index in the hippocampal formation can predict the onset of AD dementia in subjects with mild cognitive impairment (MCI). We chose to study MCI subjects because of their high incidence (yearly 10-12 percent) of AD development. At the end of the five-year period, we can determine retrospectively the sensitivity of the COSLOF index to predict the pre-clinical onset of AD progression and to distinguish those MCI subjects who are destined to develop AD from those who are undergoing normal aging processes.