This renewal is an expansion of work by the PI who recently relocated at Hackensack University Medical Center. This proposal focuses on exploring neural basis of dysphagia in idiopathic Parkinson's disease (PD). Dysphagia in PD is generally considered secondary to disease-related bradykinesia and rigidity. However, anti- PD drugs and surgical interventions, which are efficacious for the treatment of the primary clinical features affecting the limb function in PD, are not found to produce consistent or positive effects in the treatment of the dysphagia. These clinical findings suggest that oropharyngeal dysphagia in PD may not be linked solely to a reduction in basal ganglia dopamine activity. Other neurotransmitter systems or nondopaminergic mechanisms may also be involved. We hypothesized that oropharyngeal dysphagia in PD is associated with biological and neuochemical changes in the sensori-motor structures of the pharynx. The neural alterations in the sensory nerves could impair initiation of reflex swallowing, whereas those in the motor nerves could result in slowness of muscle contraction. We also hypothesized that the possible neuropathological changes such as degeneration-induced nerve fiber loss or a deduction in specific neuropeptide containing nerve fibers may occur in a nerve-dependent or tissue region-specific manner. Specifically, distinct regions of pharyngeal mucosa (lateral pharyngeal walls, epiglottis, postcricoid and arytenoids regions) and muscles (fast out layer of the pharyngeal constrictors) innervated by the X nerve are predominantly affected. This hypothesis gains support from our new findings which showed that both the pharyngeal mucosa triggering oropharyngeal swallowing and the swallowing-related fast out layer (FOL) of the pharyngeal constrictor muscles are innervated mainly by the branches derived from the X nerve. Importantly, our pilot studies also provided evidence for the selective involvement of the FOL in PD. We found that the FOL in PD pharynx became very slow as a result of fast-to-slow myosin heavy chain (MHC) transformation. These hypotheses will be tested with the following 2 specific aims.
Specific Aim 1 is to explore morphometric and neurochemical changes in the sensory and motor nerves and axon terminals innervating the mucosa and muscle fibers in PD pharynx. Changes in the intraepithelial nerve fiber density and neuropeptide immunoreactive nerve fibers supplying the pharyngeal mucosa will be determined. Alterations in the motor nerves and endplates innervating the pharyngeal and tongue muscles will be also documented using quantitative techniques.
Specific Aim 2 is to determine muscular alterations in the PD pharynx and tongue. The muscle mass, fiber size, enzyme- histochemical activities, fiber type and MHC expression patterns will be analyzed using morphological, immunocytochemical and electrophoretic techniques. The data are critical for a better understanding of the pathophysiological mechanisms of dysphagia in PD and for the development of novel therapies to treat this life-threatening disorder.

Public Health Relevance

While idiopathic Parkinson's disease (PD) results in dysphagia which affects millions of Americans, the pathophysiological mechanisms of dysphagia are poorly understood. The proposed work is to test our hypothesis that PD-induced dysphagia is associated with degenerative changes in both the sensory and motor nerve fibers innervating swallowing-related structures in the oral and pharyngeal regions. This research will provide biological basis of neurogenic dysphagia which is critical for the development of novel therapies to treat this disorder.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Motor Function, Speech and Rehabilitation Study Section (MFSR)
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Shekim, Lana O
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Hackensack University Medical Center
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Sanders, Ira; Mu, Liancai; Amirali, Asif et al. (2013) The human tongue slows down to speak: muscle fibers of the human tongue. Anat Rec (Hoboken) 296:1615-27
Sanders, Ira; Mu, Liancai (2013) A three-dimensional atlas of human tongue muscles. Anat Rec (Hoboken) 296:1102-14
Mu, Liancai; Sobotka, Stanislaw; Chen, Jingming et al. (2013) Alpha-synuclein pathology and axonal degeneration of the peripheral motor nerves innervating pharyngeal muscles in Parkinson disease. J Neuropathol Exp Neurol 72:119-29
Mu, Liancai; Sobotka, Stanislaw; Chen, Jingming et al. (2013) Parkinson disease affects peripheral sensory nerves in the pharynx. J Neuropathol Exp Neurol 72:614-23
Mu, Liancai; Sanders, Ira (2010) Human tongue neuroanatomy: Nerve supply and motor endplates. Clin Anat :
Mu, L; Sanders, I (2010) Sihler's whole mount nerve staining technique: a review. Biotech Histochem 85:19-42
Mu, Liancai; Sanders, Ira (2008) Newly revealed cricothyropharyngeus muscle in the human laryngopharynx. Anat Rec (Hoboken) 291:927-38
Mu, Liancai; Sanders, Ira (2007) Neuromuscular specializations within human pharyngeal constrictor muscles. Ann Otol Rhinol Laryngol 116:604-17
Mu, Liancai; Su, Hungxi; Wang, Jun et al. (2007) Myosin heavy chain-based fiber types in the adult human cricopharyngeus muscle. Muscle Nerve 35:637-48
Mu, Liancai; Wang, Jun; Su, Hungxi et al. (2007) Adult human upper esophageal sphincter contains specialized muscle fibers expressing unusual myosin heavy chain isoforms. J Histochem Cytochem 55:199-207

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