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

该提案的目标是开发和验证一种早期的，非侵入性的，定量的阿尔茨海默病（风险标志物）的临床前阶段的功能性磁共振成像（fMRI）。 这种AD的敏感标记物在识别风险人群、促进早期评估和提供有效的疾病管理方面具有显着优势。 功能磁共振成像技术的最新发展使我们能够以高的空间和时间分辨率间接观察神经元的活动。 我们和其他人已经观察到自发低频（SLF）波动的BOLD对比加权神经生理信号在受试者在休息。 我们已经开发了一个指数，COSLOF指数，以量化SLF信号的变化。许多已发表的神经病理学研究结果表明，海马结构是AD疾病过程的起始位点。 此外，神经退行性变化的进展在个体之间是非常均匀的，是可预测的，并且显示出很小的患者间差异。 在AD中，病变最终导致海马的严重损伤（称为“地板效应”）和痴呆的临床表现。 我们的初步结果表明，COSLOF指数有能力区分可能/可能的AD患者和认知健康的对照。 基于所有这些结果，我们提出了一个前瞻性和纵向研究，以测试的假设，即在海马结构中的COSLOF指数可以预测轻度认知功能障碍（MCI）的受试者AD痴呆的发病。 我们选择研究MCI受试者，因为他们的AD发病率很高（每年10- 12%）。 在五年期结束时，我们可以回顾性地确定COSLOF指数的敏感性，以预测AD进展的临床前发作，并区分那些注定发展为AD的MCI受试者与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.