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

摘要/项目摘要 美国人口日益老龄化，阿尔茨海默病(AD)的流行 而其常见的前驱症状--轻度认知障碍(MCI)预计将在未来几年大幅上升。 因此，全国迫切需要进一步了解这些神经的神经生理学基础- 退行性疾病。最近的研究表明，动物的伽马频段神经振荡活动受到干扰 AD的模型。此外，伽马频率的视觉刺激已被证明可以增加对 淀粉样蛋白-β(A-β)和过度磷酸化的tau在小鼠模型中的作用，同时改善认知能力。尽管 这些突破性的发现，对阿尔茨海默病患者体内伽马振荡活动的研究仍然很少。 与此相关的是，视觉空间注意过程是最早和最严重影响认知功能的过程之一 在MCI和AD。这一领域的功能障碍也被证明是识别阿尔茨海默氏症的更具体的指标 与其他形式的痴呆症(如额颞痴呆)相比，与其他形式的功能障碍相比 认知域(例如，记忆)。尽管神经心理测试显示视觉空间存在明显缺陷 MCI和AD患者的注意力，对这些患者背后的神经振荡活动知之甚少 赤字。目前的研究旨在通过利用空间精确度和 精细的时间分辨率(即毫秒)脑磁图(MEG)成像。简单地说，有以下情况的人 AD、MCI和人口统计学上匹配的对照组将在脑磁图记录期间完成两个认知任务；一个 研究多光谱视觉夹带活动，以及另一项研究视觉空间注意加工。 得到的脑磁图数据将被变换到时频域，并使用波束形成进行成像 接近。电神经活动的输出动态功能图将用于检查基线和 在提供视觉和视觉空间处理的区域之间与任务相关的夹带和振荡活动。在……里面 特别是，我们将识别MCI和AD患者的统计异常神经振荡，然后 将这些神经数据与区域Aβ沉积和总体性能(例如，一般和特定领域的)联系起来 认知、功能能力等)。我们的目标是：(1)量化视觉夹带过程中的大脑皮质动力学 MCI或轻度AD患者的特定频率(即20、35、40和45赫兹)，并确定两者之间的关系 局部伽马活动和定量Aβ沉积之间的关系，以及(2)在追踪参加试验中的缺陷 MCI和轻度阿尔茨海默病患者的视觉刺激，并确定这与认知表现之间的关系。对这件事 最后，我们将利用最新的脑磁图和震源重建技术，神经振荡分析方法， 定量Aβ正电子发射计算机断层扫描和神经心理学评估以描绘神经生理学基础 轻度认知障碍和阿尔茨海默病患者的认知障碍。这项研究将有助于阐明神经动力学。 MCI和AD患者潜在的认知功能障碍，主要目标是科学发现和 培养申请者的研究和临床技能，以培养出一名成功的内科科学家。

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.