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

通过改变口腔神经力学来消除自然衰老与阿尔茨海默病的关系

• 批准号: 10256795
• 负责人: Fritzie Arce-McShane
• 金额: $ 127.11万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2021-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10256795
• 关键词: 3-Dimensional; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease therapy; Anatomy; Animals; Area; Ataxia; Behavior; Biomechanics; Brain; Brain scan; Chronic; Cognitive; Cranial Nerves; Deglutition; Deglutition Disorders; Dementia; Development; Early identification; Esthesia; Evaluation; Event; Exhibits; Feeding behaviors; Food; Functional disorder; Goals; Impairment; Implant; Individual; Jaw; Knowledge; Late Onset Alzheimer Disease; Learning; Link; Liquid substance; Macaca mulatta; Magnetic Resonance Imaging; Mastication; Measures; Methods; Microelectrodes; Mission; Modeling; Morphology; Motor; Muscarinic Acetylcholine Receptor; Muscle; Nerve Block; Neuromechanical Changes; Neuromechanics; Neurons; Oral; Oral health; Outcome; Parietal Lobe; Patients; Pattern; Periodontal Diseases; Peripheral Nerves; Pharmaceutical Preparations; Pharmacology; Positioning Attribute; Prefrontal Cortex; Process; Property; Public Health; Research; Risk; Roentgen Rays; Scopolamine; Sensory; Shapes; Structure; Surface; System; Tactile; Testing; Texture; Thinness; Tongue; Tooth Extraction; Tooth Loss; Tooth structure; Trigeminal nerve structure; United States National Institutes of Health; afferent nerve; age related; aging brain; attenuation; base; cognitive performance; density; effective intervention; feeding; frontal lobe; healthy aging; innovation; kinematics; memory retrieval; motor impairment; nerve supply; nonhuman primate; oral behavior; orofacial; pathological aging; prevent; reconstruction; relating to nervous system; response; sensory input; sensory integration; somatosensory

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.

项目摘要 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。如何皮质和生物力学的变化，在orthopathic行为 导致AD和年龄相关性痴呆（ARD）的发病和进展的原因尚不清楚。这主要是 由于在理解神经机械过程方面存在根本性的差距，在单个神经元的大规模活动水平上， 神经元和神经元网络，是健康衰老的基础。这是一个很大的问题，因为直到他们 尽管我们对AD/ARD病理性衰老的皮质机制还不清楚，但仍将在很大程度上无法理解。 这项研究的目的是调查口面感觉运动认知神经元网络的变化， 健康的年龄相关的感觉运动变化的基础，以及这些皮层相关性如何受到缺乏感觉输入的影响 口腔结构和老年恒河猴中AD样损伤（“病理性衰老”）的存在。中央 假设是，口面神经大规模神经活动和连接动力学的差异模式 感觉运动皮层（OSMcx）和腹外侧额叶皮层（VLFcx）将有助于区分健康和病理 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）确定口腔躯体感觉皮层表征的变化， 感觉神经阻滞，以及（3）识别OSMcx-VLFcx网络中神经元反应和皮质相互作用的变化 药物引起的类AD损伤因此，我们可以评估和比较感觉丧失的额外负担， 类似AD的衰老障碍。拟议的研究使用了一种创新的方法，利用独特的感官 不同颅神经对口腔区域的神经支配和使用药理学模型诱导AD样 老年恒河猴的损伤。我们将从多个长期植入的微电极记录皮层活动 OSMcx-VLFcx中的阵列，同时使用双平面视频放射成像进行舌和颌运动学的3D跟踪， XROMM工作流程（运动形态的X射线重建），而年轻和老年受试者从事自然 摄食行为本研究对于（1）确定皮质、生物力学和免疫组织学的定义具有重要意义 健康和病理老化的概况，（2）确定潜在的影响因素的发病和进展， AD，以及（3）识别易受AD影响的皮质区域。用老猕猴有直接的翻译价值 评估AD的药物或皮质疗法的潜在途径。从建议中获得的知识 这项研究对早期识别可能处于风险中的慢性口腔健康问题个体具有重要意义 发展AD或ARDs。它还可以为制定更有效的干预措施提供信息，这些干预措施的重点是提高口腔健康。 因此，本发明的目的在于改善该组的健康结果，从而预防AD或ARD的发作或减轻其进展。