Aberrant cortical entrainment in biomarker-confirmed Alzheimer's disease and mild cognitive impairment

摘要/项目摘要 美国人口正变得日益老龄化和阿尔茨海默病（AD）的流行 其共同的前兆轻度认知障碍（MCI）预计在未来几年将急剧上升。 因此，有一个直接的国家需要进一步了解这些神经的神经生理学基础， 退化性疾病最近的研究表明，干扰的γ-波段神经振荡活动的动物 AD模型此外，伽马频率下的视觉刺激已经显示出增加了 淀粉样蛋白-β（A β）和过度磷酸化的tau蛋白，同时改善认知能力。尽管 尽管有这些突破性的发现，但对AD患者伽马振荡活动的研究仍然很少。 与此相关，视觉空间注意过程是最早和最严重的影响认知功能之一 MCI和AD。这一区域的功能障碍也被证明对识别阿尔茨海默氏症更有特异性。 型痴呆相对于其他形式（例如，额颞叶痴呆）与其他 认知域（例如，内存）。尽管神经心理学测试显示视觉空间功能明显缺陷， 注意在MCI和AD患者，很少有人知道的神经振荡活动，这些基础 赤字目前的研究旨在通过利用空间精度和 精确的时间分辨率（即，脑磁图（MEG）成像。简而言之， AD、MCI和人口统计学匹配的对照组将在MEG记录期间完成两项认知任务： 研究多光谱视觉诱导活动和另一个研究视觉空间注意处理。 所得到的MEG数据将被转换到时间-频率域，并使用波束形成成像 approach.电神经活动的输出动态功能图将用于检查基线和 任务相关的夹带和振荡活动之间的区域服务的视觉和视觉空间处理。在 特别是，我们将确定MCI和AD患者的统计学异常神经振荡，然后 将这些神经数据与局部A β沉积和整体表现联系起来（例如，通用和特定领域 认知、功能等）。我们的目的是：（1）量化视觉夹带过程中的皮层动力学 在特定频率（即，20、35、40和45 Hz），并判定与MCI或轻度AD患者之间的关系。 局部γ活动和定量A β沉积之间的关系，以及（2）识别参与跟踪的缺陷 MCI和轻度AD患者的视觉刺激，并确定这与认知表现的关系。本 最后，我们将利用最新的脑磁图和源重建技术，神经振荡分析方法， 定量A β PET成像和神经心理学评估，以描述神经生理学基础 MCI和AD患者的认知障碍。这项研究将有助于阐明 MCI和AD患者的潜在认知功能障碍，主要目标是科学发现， 发展申请人的研究和临床技能，以培养成功的医生科学家。

Abstract/Project Summary The United States population is becoming increasingly older and the prevalence of Alzheimer’s disease (AD) and its common precursor, mild cognitive impairment (MCI), is expected to dramatically rise in the coming years. As such, there is an immediate national need to further understand the neurophysiological basis of these neuro- degenerative diseases. Recent studies have shown disruption of gamma-band neural oscillatory activity in animal models of AD. Further, visual stimulation at gamma frequencies has been shown to increase the clearance of amyloid-β (Aβ) and hyperphosphorylated tau in mouse models, while improving cognitive performance. Despite these groundbreaking findings, research into gamma oscillatory activity in humans with AD remains scarce. Relatedly, visuospatial attention processes are among the earliest and most severely affected cognitive functions in MCI and AD. Dysfunction in this domain has also been shown to be more specific for identifying Alzheimer’s type dementia relative to other forms (e.g., frontotemporal dementia) when compared to dysfunction in other cognitive domains (e.g., memory). Although neuropsychological testing has shown clear deficits in visuospatial attention in patients with MCI and AD, very little is known about the neural oscillatory activity that underlies these deficits. The current study aims to partially remedy these knowledge gaps by utilizing the spatial precision and exquisite temporal resolution (i.e., millisecond) of magnetoencephalographic (MEG) imaging. Briefly, persons with AD, MCI, and demographically-matched controls will complete two cognitive tasks during MEG recording; one examining multispectral visual entrainment activity and another investigating visuospatial attention processing. The resulting MEG data will be transformed into the time-frequency domain and imaged using a beamforming approach. The output dynamic functional maps of electrical neural activity will be used to examine baseline and task-related entrainment and oscillatory activity among regions serving visual and visuospatial processing. In particular, we will identify the statistically anomalous neural oscillations in patients with MCI and AD, and then link these neural data to regional Aβ deposition and overall performance (e.g., general and domain-specific cognition, functional capacity, etc.). Our Aims are: (1) To quantify the cortical dynamics during visual entrainment at specific frequencies (i.e., 20, 35, 40, and 45 Hz) in patients with MCI or mild AD, and decifer the relationship between local gamma activity and quantitative Aβ deposition, and (2) to identify deficits in the tracking of attended visual stimuli in patients with MCI and mild AD, and determine how this relates to cognitive performance. To this end, we will utilize the latest MEG and source reconstruction techniques, neural oscillatory analysis methods, quantitative Aβ PET imaging, and neuropsychological assessments to delineate the neurophysiological bases of cognitive impairments in patients with MCI and AD. This research will aid in illuminating the neural dynamics underlying cognitive dysfunction in those with MCI and AD, with the primary goals of scientific discovery and developing the research and clinical skills of the applicant to produce a successful physician-scientist.