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

摘要 吞咽困难是阿尔茨海默病(AD)的一个主要后果，对此研究不足，因此治疗不足 尽管发病率很高，卫生保健系统的成本也很高。阿尔茨海默病(炎症、淀粉样变性、 磷酸化tau)出现在中枢和外周神经系统中，在疾病进展的早期和在 与吞咽功能相关的大脑区域和肌肉系统。有效治疗的障碍 阿尔茨海默病的吞咽困难是缺乏：(A)对与以下相关的中枢和外周病理的了解 吞咽困难，以及(B)对关键时间点干预的对照研究，包括早期干预和后期干预 疾病过程。拟议的研究对解决这些障碍具有重要意义，并具有严谨性，因为我们 将把我们实验室目前使用的成熟的翻译研究方法应用于老化和 帕金森氏症。我们的科学前提是阿尔茨海默病的病理发生在中枢和外周神经 系统在疾病进展的早期，运动干预可以减轻由 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 肌肉是吞咽过程中的主要参与者，我们的中心假设是病理表现在 舌肌和脑干、皮质下和皮质区域与口咽吞咽和 及早实施舌头练习会带来更好的吞咽效果。我们将深入了解 利用已建立的TgF344-AD大鼠模型，从生理、形态、病理等方面探讨其发病机制。 脑部和舌部肌肉的生物能量、神经成像和行为分析。可行性数据表明， 口腔运动和吞咽功能障碍，脑干发炎的证据，以及β-淀粉样蛋白增加 在12月龄TgF344-AD大鼠与吞咽相关的脑区。舌头运动干预 是仿照临床实践中使用的那些。然而，这些临床方案并未得到优化，原因是 人类研究中的障碍，如并存疾病的存在、坚持治疗令人困惑，以及有限的机会 纸巾。目标1将验证TgF344-AD大鼠表现出口部运动和吞咽障碍的假设 舌肌和大脑结构中对吞咽功能至关重要的行为和明显的病理。目标2 我将检验这样一种假设，即早期实施舌头练习可以改善口腔运动和吞咽功能 并调节TgF344-AD大鼠的病理。这项研究具有创新性，将提供一种新的 对AD吞咽缺陷的机制的理解，询问相对 未探索AD在吞咽相关系统中的病理和生理功能，并建立 早期与晚期舌操干预对阿尔茨海默病的疗效比较。康复服务通常不提供给 AD患者因受益不确定。为了推进循证治疗，我们必须提供临床前治疗 数据。由于人口的庞大和不断增加，这项基础性工作产生了很大的影响 与AD相关的吞咽困难患者可以从拟议研究中优化的治疗中受益。

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.