Tongue and laryngeal exercises improve tongue strength and vocal function outcomes in a Pink1-/- rat model of early Parkinson disease.

Parkinson disease (PD) causes voice and swallow dysfunction even in early stages of the disease. Treatment of this dysfunction is limited, and the neuropathology underlying this dysfunction is poorly defined. Targeted exercise provides the greatest benefit for offsetting voice and swallow dysfunction, and previous data suggest the hypoglossal nucleus and noradrenergic-locus coeruleus (LC) may be involved in its early pathology. To investigate relationships between targeted exercise and neuropathology of voice and swallow dysfunction, we implemented a combined exercise paradigm that included tongue force and vocalization exercises early in the Pink1-/- rat model. We tested the hypotheses that (1) tongue and vocal exercise improves tongue force and timing behaviors and vocalization outcomes, and (2) exercise increases optical density of serotonin (5-HT) in the hypoglossal nucleus, and tyrosine hydroxylase immunoreactive (Th-ir) cell counts in the LC. At two months of age Pink1-/- rats were randomized to exercise or non-exercise treatment. Age-matched wildtype (WT) control rats were assigned to non-exercise treatment. Tongue force and timing behaviors and ultrasonic vocalizations were measured at baseline (two months) and final (four months) timepoints. Optical density of 5-HT in the hypoglossal nucleus and TH-ir cell counts in the LC were obtained. Pink1-/- rats produced greater tongue forces, faster tongue contraction, and higher-intensity vocalization following exercise. There were no differences in LC TH-ir. The non-exercised Pink1-/- group had reduced density of 5-HT in the hypoglossal nucleus compared to the WT control group. The changes to tongue function and vocalization after targeted exercise suggests exercise intervention may be beneficial in early PD.

Dysphagia in Parkinson Disease: Part I - Pathophysiology and Diagnostic Practices.

Purpose of Review: Dysphagia affects the majority of individuals with Parkinson disease (PD) and is not typically diagnosed until later in disease progression. This review will cover the current understanding of PD pathophysiology, and provides an overview of dysphagia in PD including diagnostic practices, gaps in knowledge, and future directions. Recent Findings: Many non-motor and other motor signs of PD appear in the prodrome prior to the manifestation of hall- mark signs and diagnosis. While dysphagia often presents already in the prodrome, it is not routinely addressed in standard neurology examinations. Summary: Dysphagia in PD can result in compromised efficiency and safety of swallowing, which significantly contributes to malnutrition and dehydration, decrease quality of life, and increase mortality. The heterogeneous clinical presentation of PD complicates diagnostic procedures which often leads to delayed treatment. Research has advanced our knowledge of mechanisms underlying PD, but dysphagia is still largely understudied, especially in the prodromal stage.

Pink1-/- Rats Demonstrate Swallowing and Gastrointestinal Dysfunction in a Model of Prodromal Parkinson Disease.

Early motor and non-motor signs of Parkinson disease (PD) include dysphagia, gastrointestinal dysmotility, and constipation. However, because these often manifest prior to formal diagnosis, the study of PD-related swallow and GI dysfunction in early stages is difficult. To overcome this limitation, we used the Pink1-/- rat, a well-established early-onset genetic rat model of PD to assay swallowing and GI motility deficits. Thirty male rats were tested at 4 months (Pink1-/- = 15, wildtype (WT) control = 15) and 6 months (Pink1-/- = 7, WT = 6) of age; analogous to early-stage PD in humans. Videofluoroscopy of rats ingesting a peanut-butter-barium mixture was used to measure mastication rate and oropharyngeal and pharyngoesophageal bolus speeds. Abnormal swallowing behaviors were also quantified. A second experiment tracked barium contents through the stomach, small intestine, caecum, and colon at hours 0-6 post-barium gavage. Number and weight of fecal emissions over 24 h were also collected. Compared to WTs, Pink1-/- rats showed slower mastication rates, slower pharyngoesophageal bolus speeds, and more abnormal swallowing behaviors. Pink1-/- rats demonstrated significantly delayed motility through the caecum and colon. Pink1-/- rats also had significantly lower fecal pellet count and higher fecal pellet weight after 24 h at 6 months of age. Results demonstrate that swallowing dysfunction occurs early in Pink1-/- rats. Delayed transit to the colon and constipation-like signs are also evident in this model. The presence of these early swallowing and GI deficits in Pink1-/- rats are analogous to those observed in human PD.

Early ultrasonic vocalization deficits and related thyroarytenoid muscle pathology in the transgenic TgF344-AD rat model of Alzheimer's disease.

Background: Alzheimer's disease (AD) is a progressive neurologic disease and the most common cause of dementia. Classic pathology in AD is characterized by inflammation, abnormal presence of tau protein, and aggregation of ß-amyloid that disrupt normal neuronal function and lead to cell death. Deficits in communication also occur during disease progression and significantly reduce health, well-being, and quality of life. Because clinical diagnosis occurs in the mid-stage of the disease, characterizing the prodrome and early stages in humans is currently challenging. To overcome these challenges, we use the validated TgF344-AD (F344-Tg(Prp-APP, Prp-PS1)19/Rrrc) transgenic rat model that manifests cognitive, behavioral, and neuropathological dysfunction akin to AD in humans. Objectives: The overarching goal of our work is to test the central hypothesis that pathology and related behavioral deficits such as communication dysfunction in part manifest in the peripheral nervous system and corresponding target tissues already in the early stages. The primary aims of this study are to test the hypotheses that: (1) changes in ultrasonic vocalizations (USV) occur in the prodromal stage at 6 months of age and worsen at 9 months of age, (2) inflammation as well as AD-related pathology can be found in the thyroarytenoid muscle (TA) at 12 months of age (experimental endpoint tissue harvest), and to (3) demonstrate that the TgF344-AD rat model is an appropriate model for preclinical investigations of early AD-related vocal deficits. Methods: USVs were collected from male TgF344-AD (N = 19) and wildtype (WT) Fischer-344 rats (N = 19) at 6 months (N = 38; WT: n = 19; TgF344-AD: n = 19) and 9 months of age (N = 18; WT: n = 10; TgF344-AD: n = 8) and acoustically analyzed for duration, mean power, principal frequency, low frequency, high frequency, peak frequency, and call type. RT-qPCR was used to assay peripheral inflammation and AD-related pathology via gene expressions in the TA muscle of male TgF344-AD rats (n = 6) and WT rats (n = 6) at 12 months of age. Results: This study revealed a significant reduction in mean power of ultrasonic calls from 6 to 9 months of age and increased peak frequency levels over time in TgF344-AD rats compared to WT controls. Additionally, significant downregulation of AD-related genes Uqcrc2, Bace2, Serpina3n, and Igf2, as well as downregulation of pro-inflammatory gene Myd88 was found in the TA muscle of TgF344-AD rats at 12 months of age. Discussion: Our findings demonstrate early and progressive vocal deficits in the TgF344-AD rat model. We further provide evidence of dysregulation of AD-pathology-related genes as well as inflammatory genes in the TA muscles of TgF344-AD rats in the early stage of the disease, confirming this rat model for early-stage investigations of voice deficits and related pathology.

Assays of tongue force, timing, and dynamics in rat and mouse models.

Communication and swallowing are highly complex sensorimotor events that are tightly linked to respiration and vital to health and well-being. The tongue is a complex organ, often described as a muscular hydrostat, that is crucial for maintaining airway patency, preparing and safely transporting food/liquid, and rapidly changing position and shape for speech. As with any complex behavior, tongue function can be compromised with aging, diseases/conditions, trauma, or as a pharmacologic side effect. As such, modeling lingual function and dysfunction for basic and translational research is paramount; understanding how the nervous system controls tongue function for complex behavior is foundational to this work. Non-invasive access to tongue tissues and kinematics during awake behavior has been historically challenging, creating a critical need to measure tongue function in model systems. Germane to this field of study are the instruments and assays of licking/lapping and drinking, including tongue force and timing measures, many of which were designed or modified by Dr. Stephen C. Fowler. The focus of this paper is to review some of the important contributions of measuring tongue behaviors in awake rats and mice and how these have been modified by other researchers to advance translational science.

Rat Models of Vocal Deficits in Parkinson's Disease.

Parkinson's disease (PD) is a progressive, degenerative disorder that affects 10 million people worldwide. More than 90% of individuals with PD develop hypokinetic dysarthria, a motor speech disorder that impairs vocal communication and quality of life. Despite the prevalence of vocal deficits in this population, very little is known about the pathological mechanisms underlying this aspect of disease. As such, effective treatment options are limited. Rat models have provided unique insights into the disease-specific mechanisms of vocal deficits in PD. This review summarizes recent studies investigating vocal deficits in 6-hydroxydopamine (6-OHDA), alpha-synuclein overexpression, DJ1-/-, and Pink1-/- rat models of PD. Model-specific changes to rat ultrasonic vocalization (USV), and the effects of exercise and pharmacologic interventions on USV production in these models are discussed.