Oropharyngeal dysphagia and amyloid beta pathology in the TgF344-AD rat model of Alzheimer's disease.

Abstract

Introduction: Dysphagia is a major consequence of Alzheimer's disease (AD) that is understudied and undertreated. Neuropathology in AD occurs early in the disease progression, but little is known about pathologies underlying functional swallowing changes; this knowledge gap is a barrier to developing effective treatment. We hypothesized that an established AD rat model (TgF344-AD) would demonstrate significant deficits in oromotor/swallowing function versus Wild Type (WT) with corresponding amyloid beta pathology in brain structures critical to swallowing.

Methods: Nine male TgF344-AD and 6 Wildtype Fisher 344 rats underwent deglutition assessments and PET imaging using the radiotracer [¹¹C]PiB to assess brain and brainstem amyloid beta (Aβ) pathology at 11 months of age-a time point corresponding to early-middle stage AD progression. A priori brain regions of interest (ROIs) included those commonly associated with Aβ pathology and more specific swallowing associated structures such as brainstem nuclei and cortical motor areas. Deglutition was assessed using a videofluoroscopic swallow study and a pasta biting task.

Results: Significantly increased levels of Aβ in the AD group were found in regions critical to swallowing motor control including the secondary motor area, thalamus, nucleus ambiguus, and hypoglossal nuclei. The AD group demonstrated significant changes in aerodigestive coordination, including delayed swallow onset, increased apnea duration, and increased frequency of aberrant post-swallow inhale pattern that was correlated with nucleus ambiguus Aβ levels. The AD group also exhibited altered oral processing including reduced bolus size and mastication rate.

Conclusion: The TgF344-AD rat model of Alzheimer's exhibits robust changes in oral processing and respiratory-swallow coordination that parallel clinical AD dysphagia. At this early-middle stage timepoint, Aβ pathology is primarily impacting cerebral swallowing networks as well as the nucleus ambiguus and hypoglossal nuclei in the brainstem. Our finding of increased Aβ in the nucleus ambiguus warrants further study as this motor nucleus plays a role in swallowing, respiration, and vocalization-all factors that are known to be impacted by AD in the clinical population.