This research project aims to explore peripheral mechanisms of swallowing, speech and voice (SSV) disorders in Parkinson's disease (PD) for developing novel therapies for these conditions. This application addresses a focus area of the FY22 Parkinson's Research Program (PRP): “Biological mechanisms or biomarkers of non-motor symptoms that could lead to the development of treatments for Parkinson's disease (PD) – sensory dysfunction.”

The human tongue, larynx and pharynx are key organs controlling swallowing, speech and voice (SSV) and their dysfunction results in SSV disorders. Nearly 90% of patients with Parkinson's disease (PD) experience SSV problems at some point during the course of the disease. Difficulty swallowing, also known as dysphagia, can lead to drooling, choking, coughing, difficulty taking pills, taking a long time to eat, weight loss, and dehydration. During swallowing, food or liquid may go into the trachea (aspiration) and then pass down into lungs. Dysphagia can be particularly devastating, as it adversely impacts the quality of life and is associated with increased risk of aspiration pneumonia, the leading cause of death in up to 73% of patients with PD. PD patients may also have hypokinetic dysarthria with slurred or slow speech that can be difficult to understand.

Dysarthria is a particularly disabling problem that influences social interactions and alters daily living activities. SSV disorders were thought to be caused by the same dopaminergic problem as that impairing limb movements; however, their response to PD treatments has been inconsistent or poor. The lack of effectiveness of dopaminergic treatment in alleviating SSV symptoms points to a different mechanism of SSV impairment in PD. Our studies of the PD pharynx demonstrated the presence of phosphorylated α-synuclein (PAS) in pharyngeal nerves and muscles in cadaveric tissue from subjects with PD. Notably, PD patients with dysphagia had more PAS lesions in the pharyngeal nerves as compared with those without dysphagia. These findings suggest that neuromuscular degeneration induced by PAS lesions may underlie SSV disorders in PD.

This research proposes to detect PAS pathology in 40 human post-mortem whole-mount (tongue-larynx) specimens, including 20 clinically diagnosed and neuropathologically confirmed PD patient samples and 20 age-matched healthy controls. We will examine sensory and motor nerves, as well as muscles and mucosa of the tongue and larynx. The tissue samples will be prepared to document and quantify PAS lesions, expression of E6 associated protein (E6-AP), degenerated axons, denervated and atrophied muscle fibers, and altered muscle fiber types. The differences in PAS severity between nerves, muscles and mucosa, as well as the association between PAS severity and SSV severity, will be examined. Using postmortem specimens will allow us to visualize the distribution of PAS lesions in the tissues studied. The results will determine whether the upper airway nerves are affected indiscriminately or selectively by PAS pathology.

Determining the distribution of PAS lesions in the upper airway holds great promise for developing nerve-specific and/or organ-related (i.e., larynx and tongue) therapies to treat SSV disorders. For example, if voice disorders in PD are caused by vocal fold atrophy as a result of recurrent laryngeal nerve degeneration, atrophied vocal fold can be treated with our recently developed nerve-muscle-endplate grafting (NMEG) technique.

Notably, NMEG will not require extensive specialized training, thus enabling transferability to surgeons to treat vocal fold atrophy and laryngeal protection deficits. Our recent studies showed that focal injections of nerve growth factor (NGF) and basic fibroblast growth factor (FGF-2) into the denervated muscle could enhance nerve regeneration and preserve muscle mass. This procedure may be useful for treating vocal fold denervation and atrophy causing voice disorders in PD. Another candidate therapeutic is a native protein called E6-AP. E6-AP colocalizes with PAS lesions in the brain and can dissolve PAS aggregates at high levels. It could be a plausible drug candidate to treat PAS nerve damage contributing to SSV disorders.

The results of this project will enable the next steps toward clinical application. We expect to begin human clinical studies within 2 to 3 years after successful completion of the proposed research. Clinical application of the research data to diagnosis, treatment, and prevention of SSV disorders will directly and substantially benefit military Service Members and Veterans experiencing SSV deficits in PD. Currently, there are few medical or surgical interventions that successfully address SSV impairments. Clearer understanding of the mechanism of neuromuscular degeneration in PD could help inform medical and/or surgical interventions to preserve SSV function. Restoration of upper airway functionality will allow more Service Members to remain on active duty and improve quality of life for Veterans and civilians with PD.