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.

摘要