Disambiguating natural aging from Alzheimer's disease through changes in oral neuromechanics

项目总结 许多与年龄相关的口腔健康问题，如咀嚼功能障碍、吞咽困难、牙周病和牙齿脱落 与阿尔茨海默病(AD)有关。大脑皮质和生物力学在口腔运动行为中的变化 阿尔茨海默病的发生和发展与年龄相关痴呆(ARD)的发生和发展密切相关。这在很大程度上 由于对神经机械过程的理解存在根本差距，在单个大规模活动的水平上 神经元和神经元网络，这是健康衰老的基础。这代表着一个重要的问题，因为在他们 AD/ARD病理性衰老的皮质机制在很大程度上仍不清楚。 这项拟议的研究的目标是调查口面部感觉运动-认知神经网络的变化 健康的年龄相关感觉运动变化以及缺乏感觉输入如何影响这些大脑皮层的相互关系 与口腔结构和老年恒河猴AD样损伤(病理性衰老)的存在有关。中环 假设是口面部大规模神经活动和连通性动力学的不同模式 感觉运动皮质(OSMcx)和腹外侧额叶皮质(VLFcx)将有助于消除健康和病理性的歧义 衰老。这一假设将通过追求三个具体目标来检验：(1)确定健康年龄的神经元相关性-- 进食行为的相关变化，(2)确定口服体感后皮质表征的变化 感觉神经阻滞，以及(3)确定OSMcx-VLFcx网络中神经元反应和皮质相互作用的变化 在药物诱导的AD样损害之后。因此，我们可以评估和比较感觉丧失和 衰老时的广告样损伤。这项拟议的研究使用了一种创新的方法，利用独特的感官 不同脑神经对口腔区的神经支配及诱导AD样反应的药理学模型 老年恒河猴的损伤。我们将记录长期植入的多个微电极的皮质活动 OSMcx-VLFcx中的阵列同时使用双平面视频放射成像和三维跟踪舌头和颌骨运动学 XROMM工作流程(运动形态的X射线重建)，当年轻人和老年人进行自然 进食行为。所提出的研究对于(1)定义皮质、生物力学和免疫组织学具有重要意义 健康和病理性衰老的概况，(2)确定可能导致老年心脏病发生和发展的因素 AD，以及(3)识别易受AD影响的皮质区域。使用古老的恒河猴具有直接的翻译价值 评估阿尔茨海默病药物或皮质治疗的潜在途径。从建议中获得的知识 这项研究对及早识别可能有风险的慢性口腔健康问题患者具有重要意义 用于开发AD或ARD。它还可能有助于制定更有效的干预措施，侧重于提高口语能力 对这一群体的健康结果进行评估，从而预防或减缓AD或ARD的发病或进展。

PROJECT SUMMARY Many age-related oral health problems, such as masticatory dysfunction, dysphagia, periodontal disease, and tooth loss have been associated with Alzheimer’s disease (AD). How cortical and biomechanical changes in oromotor behavior contribute to the onset and progression of AD and age-related dementias (ARD) are widely unknown. This is largely because of a fundamental gap in understanding the neuromechanical processes, at the level of large-scale activity of single neurons and neuronal networks, that underlie healthy aging. This represents an important problem because until they are understood, the cortical mechanisms underlying pathological aging in AD/ARD will remain largely incomprehensible. The goal of the proposed research is to investigate changes in the orofacial sensorimotor-cognitive neuronal network that underlie healthy age-related sensorimotor changes and how these cortical correlates are affected by absent sensory inputs to oral structures and by the presence of AD-like impairments (‘pathological aging’) in old rhesus macaques. The central hypothesis is that differential patterns of the dynamics of large-scale neural activity and connectivity in the orofacial sensorimotor cortex (OSMcx) and the ventrolateral frontal cortex (VLFcx) will help disambiguate healthy and pathological aging. This hypothesis will be tested by pursuing three specific aims: (1) to identify the neuronal correlates of healthy age- related changes in feeding behavior, (2) to identify changes in cortical representations of oral somatosensation following sensory nerve block, and (3) to identify changes in neuronal responses and cortical interactions in OSMcx-VLFcx networks following drug-induced AD-like impairments. Thus, we can evaluate and compare the added burden of sensory loss and AD-like impairments on aging. The proposed research uses an innovative approach that leverages the unique sensory innervation of the oral region by different cranial nerves and the use of a pharmacological model to induce AD-like impairments in old rhesus macaques. We will record cortical activity from multiple chronically implanted microelectrode arrays in OSMcx-VLFcx simultaneously with 3D tracking of tongue and jaw kinematics using biplanar videoradiography and the XROMM workflow (X-ray Reconstruction of Moving Morphology) while young and old subjects engage in natural feeding behavior. The proposed research is significant for (1) defining cortical, biomechanical, and immunohistological profiles of healthy and pathological aging, (2) determining potential contributing factors to the onset and progression of AD, and (3) identifying cortical regions that are vulnerable to AD. Using old rhesus macaques has direct translational value to evaluate potential avenues for pharmacological or cortical therapies for AD. The knowledge gained from the proposed study has important implications for earlier identification of individuals with chronic oral health issues who may be at risk for developing AD or ARDs. It may also inform the development of more effective interventions focused on enhancing oral health outcomes in this group and thus preventing the onset or allaying the progression of AD or ARD.