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

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.

项目概要 许多与年龄相关的口腔健康问题，例如咀嚼功能障碍、吞咽困难、牙周病和牙齿脱落 皮质和生物力学如何改变口腔运动行为与阿尔茨海默病（AD）有关。 AD 和年龄相关性痴呆 (ARD) 的发病和进展的影响尚不清楚。 由于在理解神经机械过程方面存在根本差距，在单个神经元的大规模活动水平上 神经元和神经网络是健康衰老的基础，这是一个重要的问题，因为直到它们出现。 尽管人们已经了解了 AD/ARD 病理性衰老背后的皮质机制，但在很大程度上仍然难以理解。 本研究的目的是调查口面部感觉运动认知神经网络的变化 年龄健康相关的感觉运动变化的基础，以及这些皮质相关因素如何受到感觉输入缺失的影响 老年恒河猴的口腔结构和 AD 样损伤（“病理性衰老”）的存在。 假设是口面部大规模神经活动和连接的动态差异模式 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 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相关性。 进食行为的相关变化，（2）识别以下口腔躯体感觉的皮质表征的变化 感觉神经阻滞，以及 (3) 识别 OSMcx-VLFcx 网络中神经反应和皮质相互作用的变化 因此，我们可以评估和比较感觉丧失和 AD 样损伤所带来的额外负担。 拟议的研究采用了一种利用独特感官的创新方法。 不同脑神经对口腔区域的神经支配以及使用药理学模型诱导 AD 样症状 我们将记录多个长期植入的微电极的皮层活动。 OSMcx-VLFcx 中的阵列同时使用双平面视频射线照相对舌头和下颌运动进行 3D 跟踪， XROMM 工作流程（移动形态学的 X 射线重建），而年轻和年长的受试者则参与自然 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）确定导致衰老发生和进展的潜在因素 AD，以及（3）识别易受 AD 影响的皮层区域，使用老年恒河猴具有直接的转化价值。 评估 AD 药物或皮质疗法的潜在途径 从拟议的方案中获得的知识。 研究对于及早识别可能面临风险的患有慢性口腔健康问题的个体具有重要意义 它还可以为开发更有效的干预措施提供信息，重点是加强口腔。 该群体的健康结果，从而预防 AD 或 ARD 的发生或减缓其进展。