Quantitative Neuroimaging Assessment of White Matter Integrity in the Context of Aging and AD

项目总结 尽管患阿尔茨海默病(AD)的最重要的危险因素是年龄，但 从正常衰老到阿尔茨海默病的神经生物学过程还不是很清楚。损失 已知白质(WM)完整性在正常衰老中发生，并假设加速丧失 WM的完整性是从正常衰老向AD过渡的一种机制。事实上，与年龄相关的损失 额叶和颞叶晚髓鞘关联区的WM完整性是相同的新皮质 最易受AD病理发展影响的地区。 直接回应PAR-15-357宣布：在以下背景下了解阿尔茨海默病 大脑老化，我们建议调查大脑WM完整性变化是关键机制的假说 通过它，正常衰老的大脑可以过渡到阿尔茨海默病。我们团队最近开发了基于核磁共振的生物标记物 它们对WM完整性的细微变化很敏感。这些生物标志物由定量的白质纤维束完整性组成 (WMTI)表征特定组织属性的指标，如轴突密度和髓鞘完整性。vbl.使用 这些WMTI指标，我们区分了正常对照组和MCI患者，表明WM 变化发生在AD疾病过程的早期。我们还演示了这些WMTI指标可能是 在这个过程的早期，通过区分有和没有海马体的正常对照组是有用的 萎缩。因此，这个项目的总体假设是，WM完整性的加速丧失在 从正常衰老过渡到AD，并通过结合WMTI、Aβ积聚程度、 神经退行性变(即海马和皮质萎缩)和认知功能，我们将能够分层 认知功能正常的老年人转换为MCI/AD的风险。

PROJECT SUMMARY Although the single most significant risk factor for developing Alzheimer's disease (AD) is age, the neurobiological processes underlying the transition from normal aging to AD are not well understood. The loss of white matter (WM) integrity is known to occur in normal aging and it is hypothesized that an accelerated loss of WM integrity is one mechanism for the transition from normal aging to AD. Indeed, the age-related loss of WM integrity in late-myelinating association regions in the frontal and temporal lobes are the same neocortical regions most vulnerable to the development of AD pathology. In direct response to announcement PAR-15-357: Understanding Alzheimer's Disease in the Context of Brain Aging, we propose to investigate the hypothesis that changes in brain WM integrity are key mechanisms by which a normal aging brain can transition to AD. Our group has recently developed MRI-based biomarkers that are sensitive to subtle changes in WM integrity. These biomarkers consist of quantitative WM tract integrity (WMTI) metrics that characterize specific tissue properties such as axonal density and myelin integrity. Using these WMTI metrics, we have differentiated normal controls from patients with MCI, indicating that WM changes occur early in the AD disease process. We have also demonstrated that these WMTI metrics may be useful even earlier in the process by differentiating between normal controls with and without hippocampal atrophy. Thus, the overall hypothesis of this project is that an accelerated loss of WM integrity is evident in the transition from normal aging to AD, and by combining biomarkers of WMTI, degree of Aβ accumulation, neurodegeneration (i.e. hippocampal and cortical atrophy), and cognitive function, we will be able to stratify cognitively intact older adults for risk of conversion to MCI/AD.