Mechanisms of swallowing dysfunction and rescue in a translational rat model of Alzheimer's disease

阿尔茨海默病转化大鼠模型吞咽功能障碍及救援机制

• 批准号: 10752510
• 负责人: NADINE P CONNOR
• 金额: $ 76.81万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10752510
• 关键词: Address; Adherence; Affect; Age Months; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-Protein; Amyloidosis; Analysis of Covariance; Aspiration Pneumonia; Behavior; Behavioral; Behavioral Assay; Biochemistry; Bioenergetics; Biological; Biological Assay; Bite; Bolus Infusion; Brain; Brain Pathology; Brain Stem; Brain region; Caregiver Burden; Caring; Central Nervous System; Characteristics; Clinical; Clinical Protocols; Clinical Trials; Controlled Study; Data; Degenerative Disorder; Deglutition; Deglutition Disorders; Disease; Disease Progression; Early Intervention; Effectiveness; Evidence based treatment; Exercise; Experimental Designs; Female; Functional disorder; Future; Gliosis; Goals; Health; Healthcare Systems; High Prevalence; Human; Immunohistochemistry; Impaired cognition; Impairment; Inflammation; Intake; Intervention Studies; Knowledge; Laboratories; Link; Logistic Regressions; Mastication; Measures; Modeling; Morphology; Motor; Muscle; Muscle function; Neurobiology; Oral; Oropharyngeal; Outcome; Parkinson Disease; Pathologic; Pathology; Peripheral; Peripheral Nervous System; Personal Satisfaction; Persons; Phosphorylation; Physiological; Physiology; Polymerase Chain Reaction; Population; Positioning Attribute; Preparation; Prevalence; Prevention; Process; Property; Quality of life; Randomized; Rattus; Rehabilitation therapy; Research; Signs and Symptoms; Structure; System; Testing; Tissues; Tongue; Translating; Translational Research; Work; abeta oligomer; behavioral impairment; clinical practice; clinically relevant; comorbidity; cost; design; exercise intervention; functional decline; improved; in vivo; inflammatory marker; innovation; insight; male; microPET; muscular structure; muscular system; neural; neuroimaging; neuron loss; novel; pre-clinical; prevent; skeletal; tau Proteins; tau-1; translational approach; treatment optimization

Abstract Dysphagia is a major consequence of Alzheimer’s disease (AD) that is understudied and thus undertreated despite high prevalence and high cost to heath care systems. Pathology in AD (inflammation, amyloidosis, phosphorylated tau) occurs in the central and peripheral nervous systems early in disease progression and in brain regions and muscle systems associated with swallowing functions. Barriers to effectively treating dysphagia in AD are the lack of: (a) an understanding of central and peripheral pathology associated with dysphagia, and (b) controlled studies of interventions at crucial timepoints, including early versus later in the disease process. The proposed research is significant in addressing these barriers and rigorous in that we will apply established translational research approaches currently used in our labs in models of aging and Parkinson disease. Our scientific premise is that pathology in AD occurs in the central and peripheral nervous systems early in disease progression and that exercise interventions can mitigate deficits induced by the presence of pathology and potentially change the course of sensorimotor decline in function. Because tongue muscles are primary actors in the swallowing process, our central hypotheses are that pathology manifests in tongue muscle and brainstem, subcortical, and cortical regions associated with oropharyngeal swallowing and that early implementation of tongue exercise leads to better swallowing outcomes. We will gain insight into mechanisms by using the well-established TgF344-AD rat model and conducting physiological, morphological, bioenergetic, neuroimaging, and behavioral assays in the brain and tongue muscles. Feasibility data show the oromotor and swallowing dysfunction, evidence of inflammation in the brainstem, and increased beta-amyloid in brain regions associated with swallowing in 12-month-old TgF344-AD rats. The tongue exercise intervention is modeled after those used in clinical practice. However, these clinical protocols are not optimized due to barriers in human research, such as presence of co-morbidities, adherence confounds, and limited access to tissues. Aim 1 will test the hypothesis that TgF344-AD rats demonstrate deficits in oromotor and swallowing behaviors and manifest pathology in tongue muscles and brain structures critical to swallowing function. Aim 2 will test the hypothesis that early implementation of tongue exercise improves oromotor and swallow function and modulates pathology in TgF344-AD rats. This research is innovative and will provide a new understanding of mechanisms that underlie swallowing deficits in AD, query relationships among relatively unexplored AD pathology and physiological function in swallow-related systems, and establish the effectiveness of early versus late tongue exercise intervention for AD. Rehabilitation is often not provided to patients with AD due to uncertain benefit. To advance evidence-based treatment, we must provide preclinical data. This foundational work has a high impact because of the large and increasing population of people with AD-associated dysphagia who can benefit from treatments optimized in the proposed studies.

抽象的 吞咽困难是阿尔茨海默病 (AD) 的一个主要后果，但对该疾病的研究和治疗不足 尽管患病率很高，而且卫生保健系统的成本也很高。 AD 病理学（炎症、淀粉样变性、 磷酸化 tau) 发生在疾病进展早期和晚期的中枢和周围神经系统中。 与吞咽功能相关的大脑区域和肌肉系统。有效治疗的障碍 AD 中的吞咽困难缺乏： (a) 对与以下疾病相关的中枢和外周病理学的了解 吞咽困难，以及（b）关键时间点干预的对照研究，包括早期与后期的干预研究 疾病过程。拟议的研究对于解决这些障碍具有重要意义，并且严格在于我们 将应用我们实验室目前在衰老模型中使用的已建立的转化研究方法 帕金森病。我们的科学前提是 AD 的病理发生在中枢和周围神经 疾病进展早期的系统和运动干预可以减轻由疾病引起的缺陷 病理的存在并可能改变感觉运动功能下降的过程。因为舌头 肌肉是吞咽过程的主要参与者，我们的中心假设是病理表现在 舌肌和脑干、皮层下和与口咽吞咽相关的皮层区域 早期实施舌头锻炼可以带来更好的吞咽效果。我们将深入了解 通过使用成熟的TgF344-AD大鼠模型并进行生理、形态、 大脑和舌头肌肉的生物能量、神经影像和行为测定。可行性数据表明 口腔运动和吞咽功能障碍、脑干炎症证据以及β-淀粉样蛋白增加 12 个月大的 TgF344-AD 大鼠与吞咽相关的大脑区域。舌头运动干预 是根据临床实践中使用的模型进行建模的。然而，由于以下原因，这些临床方案并未得到优化： 人类研究中的障碍，例如共病的存在、依从性混淆以及获得药物的机会有限 组织。目标 1 将检验 TgF344-AD 大鼠表现出口腔运动和吞咽缺陷的假设 对吞咽功能至关重要的舌头肌肉和大脑结构的行为和明显病理学。目标2 将检验早期进行舌头锻炼可以改善口部运动和吞咽功能的假设 并调节 TgF344-AD 大鼠的病理学。这项研究具有创新性，将提供新的思路 了解 AD 吞咽缺陷背后的机制，查询相对 吞咽相关系统中未探索的 AD 病理学和生理功能，并建立 早期与晚期舌头运动干预对 AD 的有效性。通常不提供康复服务 AD患者由于获益不确定。为了推进循证治疗，我们必须提供临床前 数据。由于人口众多且不断增加，这项基础工作具有很大的影响 患有 AD 相关吞咽困难的人可以从拟议研究中优化的治疗中受益。