Biological Determinants and Neural Compensation of Dysphagia in Parkinson's Disease

Biological Determinants and Neural Compensatory Mechanisms of Oropharyngeal Dysphagia in Parkinson's Disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder and frequently leads to oropharyngeal dysphagia, a swallowing disorder that strongly affects patient health and quality of life. Dysphagia in PD is associated with aspiration pneumonia, malnutrition, and impaired medication intake, which together represent one of the leading causes of morbidity and premature mortality in these patients. Despite its clinical relevance, the underlying biological mechanisms of dysphagia in PD are not fully understood, and current treatment strategies are limited.

The purpose of this study is to investigate the clinical, biological, and neural determinants of oropharyngeal dysphagia in patients with PD, and to explore compensatory mechanisms of the brain that may counteract swallowing difficulties. We hypothesize that dysphagia in PD is linked not only to disease severity and progression but also to specific biological markers and neural plasticity in the swallowing network.

This is a prospective, cross-sectional observational study including 100 patients with PD. Swallowing function will be systematically assessed using flexible endoscopic evaluation of swallowing (FEES), a gold standard method for detecting penetration and aspiration. Additional clinical data will be collected, including motor and non-motor symptoms, disease severity, and quality of life measures. Biological assessments will include blood-based biomarkers related to inflammation and neurodegeneration. Furthermore, functional magnetic resonance imaging (fMRI) will be used to examine cortical and subcortical activity patterns associated with swallowing and to identify potential compensatory activation in dysphagic and non-dysphagic patients.

By integrating clinical, biological, and imaging approaches, this study aims to provide a comprehensive characterization of dysphagia in PD. The findings are expected to improve the understanding of disease mechanisms and to identify predictors of dysphagia onset and severity. Ultimately, this knowledge may help to guide the development of targeted therapeutic strategies, reduce the risk of severe complications, and improve quality of life for patients with Parkinson's disease.

Background and Rationale Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide and is characterized by progressive motor and non-motor symptoms. Among its complications, oropharyngeal dysphagia (OD) is one of the most clinically relevant. Up to 80% of patients develop swallowing impairment during the course of the disease, often without recognizing its presence. Dysphagia is associated with aspiration pneumonia, malnutrition, dehydration, and impaired medication intake, representing a leading cause of morbidity and premature mortality in PD. Despite its high prevalence and impact, the underlying mechanisms of PD-related dysphagia are not fully understood, and current treatment options are limited.

Dysphagia in PD appears to be caused by a combination of central and peripheral factors. On the central level, dopamine deficiency contributes to motor dysfunction, including bradykinesia or freezing of swallowing. Cortical involvement and impaired sensorimotor integration may further reduce swallowing efficiency. On the peripheral level, impaired pharyngeal sensory function and reduced secretion of Substance P have been linked to silent aspiration and insufficient protective reflexes. Evidence from aging research and initial PD studies suggests that compensatory neural activity in cortical swallowing networks may mitigate the risk of aspiration in some patients. However, the clinical, biological, and neural determinants of preserved swallowing function and compensation in PD remain poorly defined.

Objectives and Hypotheses

The overarching objective of this study is to identify biological determinants and neural compensatory mechanisms of oropharyngeal dysphagia in PD. The specific aims are:

To characterize the prevalence, severity, and clinical phenotype of dysphagia in PD using standardized instrumental diagnostics.

To investigate biological determinants of swallowing impairment, including inflammatory and neurodegenerative markers in blood and saliva, sensory function, and proteomic signatures.

To examine neural correlates of swallowing function using task-based and resting-state functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI), and muscle volumetry.

To identify clinical and biological factors associated with preserved neural compensation in PD, which may serve as potential therapeutic targets.

We hypothesize that dysphagia in PD is linked not only to disease progression but also to distinct biological markers and altered neural activity patterns. We further hypothesize that compensatory neural activation can be demonstrated in patients with mild dysphagia and that these mechanisms are modulated by clinical and biological determinants.

Study Design This is a prospective, cross-sectional observational study conducted at Heinrich-Heine-University Düsseldorf. A total of 100 patients with idiopathic PD across different disease stages will be recruited. The inclusion criterion is the ability to eat and drink orally and comply with study procedures. Exclusion criteria are tube feeding, other neurological or structural causes of dysphagia, severe comorbidities, or contraindications to MRI.

All participants will undergo a standardized study protocol consisting of three examination blocks:

Clinical and Instrumental Swallowing Assessment Swallowing will be assessed using Flexible Endoscopic Evaluation of Swallowing (FEES), which is considered a gold standard for detecting penetration, aspiration, and pharyngeal residue. The FEES protocol will include assessment of secretion management, swallowing of different consistencies, medication swallowing, dual-task swallowing (cognitive and motor load), pharyngeal sensitivity testing, and reflexive cough testing. Dysphagia severity and phenotype will be classified using validated scales.

Clinical, Biological, and Functional Assessments Clinical data will include demographics, disease duration, Hoehn & Yahr staging, motor severity (UPDRS), non-motor symptoms, cognitive testing, frailty, sarcopenia, nutritional status, hydration, immunosenescence, and quality of life measures. Biological samples (saliva and blood) will be collected for biomarker analysis, including Substance P, inflammatory cytokines, and proteomic profiling. Smell and taste testing will be performed to assess sensory function.

Neuroimaging All participants will undergo MRI scanning, including structural MRI, diffusion tensor imaging, muscle volumetry, and functional MRI during swallowing and sensory stimulation tasks. Task-based fMRI will examine cortical and subcortical swallowing networks, dual-task swallowing under cognitive or motor load, and pharyngeal sensory stimulation. Resting-state fMRI will be used to investigate functional connectivity. DTI will assess white matter integrity in swallowing-related pathways.

Outcome Measures The primary outcome is the presence and severity of dysphagia as determined by FEES.

Secondary outcomes include:

Biological markers associated with dysphagia severity. fMRI activation patterns reflecting neural compensation. Relationships between clinical phenotype, biomarkers, and imaging findings. Identification of predictors of preserved swallowing function.

Expected Impact This study will provide a comprehensive, multimodal characterization of oropharyngeal dysphagia in PD by integrating clinical, biological, and neuroimaging data. It will improve the understanding of disease mechanisms, identify predictors of dysphagia onset and severity, and shed light on neural compensatory mechanisms. Ultimately, the findings are expected to guide the development of targeted therapeutic strategies, support earlier diagnosis, and improve patient care. In the long term, the study may contribute to reducing complications such as aspiration pneumonia and malnutrition, improving quality of life, and lowering the healthcare burden associated with PD-related dysphagia.

Inclusion Criteria:

.- Patients with idiopathic Parkinson's disease diagnosed according to the MDS diagnostic criteria

• Participation possible in all disease stages, regardless of the presence or absence of subjective or objective oropharyngeal dysphagia
• Cognitive ability sufficient to comply with the study paradigm
• Daily oral intake of food and fluids (exclusion of patients with exclusive tube feeding)

Exclusion Criteria:

• Presence of other conditions associated with oropharyngeal dysphagia, such as stroke, head and neck cancer, neuroinflammatory diseases, neuromuscular disorders, or other brain injuries
• Presence of electronic stimulation devices (e.g., pacemaker, deep brain stimulation) or other contraindications for MRI imaging
• Diagnosis of asthma or COPD (due to performance of the cough reflex test in "Block 1: Assessment of OD and pharyngeal hyposensitivity")