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: 10634762
• 负责人: Fritzie Arce-McShane
• 金额: $ 138.89万
• 依托单位: UNIVERSITY OF WASHINGTON
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10634762
• 关键词: 3-Dimensional; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease patient; 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; Movement; Muscarinic Acetylcholine Receptor; Muscle; Nerve Block; Neuromechanics; Neurons; Oral; Oral health; Outcome; Parietal Lobe; Pattern; Periodontal Diseases; Peripheral Nerves; Pharmaceutical Preparations; 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; antagonist; attenuation; cognitive performance; density; effective intervention; feeding; frontal lobe; healthy aging; innovation; kinematics; memory retrieval; nerve supply; neural; nonhuman primate; oral behavior; orofacial; pathological aging; pharmacologic; prevent; reconstruction; response; sensory input; sensory integration; somatosensory; 3-Dimensional; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease patient; 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; Movement; Muscarinic Acetylcholine Receptor; Muscle; Nerve Block; Neuromechanics; Neurons; Oral; Oral health; Outcome; Parietal Lobe; Pattern; Periodontal Diseases; Peripheral Nerves; Pharmaceutical Preparations; 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; antagonist; attenuation; cognitive performance; density; effective intervention; feeding; frontal lobe; healthy aging; innovation; kinematics; memory retrieval; nerve supply; neural; nonhuman primate; oral behavior; orofacial; pathological aging; pharmacologic; prevent; reconstruction; 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 许多与年龄有关的口腔健康问题，例如咀嚼功能障碍，吞咽困难，牙周疾病和牙齿脱落 与阿尔茨海默氏病（AD）有关。皮质和生物力学如何改变Oromotor行为 有助于AD和与年龄相关的痴呆症（ARD）的发作和进展，这是广泛的未知。这很大程度上 由于理解神经力学过程的根本差距 神经元和神经元网络是健康衰老的基础。这代表了一个重要的问题，因为直到他们 可以理解，AD/ARD中病理老化的皮质机制将在很大程度上难以理解。 拟议的研究的目的是调查口腔感觉运动神经元网络的变化，这些变化 基础健康与年龄相关的感觉运动变化以及这些皮质相关性如何受到感觉输入的影响 到口服结构，并通过旧恒河猕猴中存在类似AD的障碍（“病理老化”）。中央 假设是大规模神经元活动和连通性动力学的差异模式 感觉运动皮层（OSMCX）和腹外侧额叶皮层（VLFCX）将有助于消除健康和病理的歧义 老化。该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 - 喂养行为的相关变化，（2）以确定口服体验的皮质表示的变化 感觉神经阻滞和（3）确定OSMCX-VLFCX网络中神经元反应和皮质相互作用的变化 遵循药物引起的广告样障碍。这，我们可以评估和比较感官丧失的燃烧和 关于衰老的广告状障碍。拟议的研究使用一种创新的方法来利用独特的感官 通过不同的颅神经和使用药物模型诱导AD样 旧恒河猕猴的障碍。我们将记录来自多个慢性植入微电极的皮质活性 只需使用Biplanar视频摄影和下颌运动学的3D跟踪，在OSMCX-VLFCX中进行阵列 Xromm工作流程（X射线移动形态的重建），而老年人则自然参与 喂养行为。拟议的研究对于（1）定义皮质，生物力学和免疫组织学很重要 健康和病理衰老的特征，（2）确定潜在的促成因素 AD和（3）识别容易受到AD的皮质区域。使用旧恒河猕猴具有直接的翻译价值 评估AD药物或皮质疗法的潜在途径。从拟议中获得的知识 研究对可能有危险的慢性口腔健康问题的个体的早期识别具有重要意义 用于开发广告或ARDS。它还可能为开发更有效的干预措施而介绍，以增强口头 该组的健康结果，从而阻止了AD或ARD的发展或消除。