Study Rationale:
Parkinson's disease (PD) research benefits from knowledge of disease-specific risk and resilience factors and elucidation of pathophysiological concepts on the emergence of neurodegeneration. Presently, the propagation of alpha-synuclein aggregation in PD is proposed to start in the periphery, i.e. in the enteric nervous system and the olfactory bulb. Aberrations within the gastrointestinal and nasal microbiomes may play a role in the initiation of this process and may facilitate propagation of alpha-synuclein pathology, through the initiation of peripheral inflammation.
Hypothesis:
Here we will focus on these two ports of entry for potential pathogenic agents in PD and hypothesize that changes in microbial community structure and function in the gastrointestinal tract as well as the nasal cavity accompany PD from its onset and progression. We specifically hypothesize that microbiome-derived small molecule signatures may provide an early means of diagnosing PD.
Study Design:
Our interdisciplinary team is unique as it consists of experts with active facilities enabling large-scale recruitment as well as specialists in high-resolution microbiome characterization (integrated multi-omics) and bioinformatic analyses. The study design of the project is such that it will allow us to address the following objectives: (i) Development of a microbiome biomarker model for Parkinson's disease based on microbiome metabolic signatures in feces and/or nasal lavages from an existing PD cohort, (ii) Validation of the biomarker cohort on a new cross-sectional and longitudinal cohort, (iii) Assessment of the applicability of the biomarker for early diagnosis of high-risk cohorts (i.e., REM sleep behavior disorder), and (iv) Contribution to the understanding of disease development by characterizing PD-specific microbiota together with inflammatory markers in peripheral blood.
Impact on Diagnosis/Treatment of Parkinson's disease:
Fulfillment of the study objectives is of particular relevance in relation to not only the development of future disease-modifying neuroprotective therapies that would require intervention at the earliest stages of disease but also the identification of preventive strategies for the conversion to PD. Therefore, this study aims to have a durable and significant impact on better identification, prevention, treatment and management of PD.
Next Steps for Development:
The identification of specific microbiome-derived metabolomic biomarkers may require further validation in additional cohorts. Furthermore, the identified signatures will need to be translated into a clinically applicable test.