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

本提案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（风险标记）。这种敏感的阿尔茨海默病标志物在识别高危人群、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活动。我们和其他人在受试者休息时观察到BOLD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，即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，海马体的形成是阿尔茨海默病发病过程的初始位点。此外，神经退行性变化的进展在个体之间非常一致，是可预测的，并且在患者之间几乎没有变化。在AD中，病变最终导致海马严重损伤（称为“底效应”）和痴呆的临床表现。我们的初步结果表明，COSLOF指数能够区分可能/可能的AD患者和认知健康对照。基于以上结果，我们提出了一项前瞻性和纵向研究，以验证海马体结构COSLOF指数可以预测轻度认知障碍（MCI）受试者AD痴呆发病的假设。我们选择MCI受试者是因为他们的AD发病率高（每年10- 12%）。在5年的时间结束时，我们可以回顾性地确定COSLOF指数在预测AD临床前发病进展方面的敏感性，以及区分那些注定会发展为AD的MCI受试者和那些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.