Studying the Parkinson’s disease metabolome and exposome in biological samples through different
analytical and cheminformatics approaches: A pilot study

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease, with an increasing
incidence in recent years due to the ageing population. Genetic mutations alone only explain <10% of
PD cases, while environmental factors, including small molecules, may play a significant role in PD.
Studying the metabolome and exposome will help develop a better understanding of the disease. For
that purpose, in the present work, 22 plasma (11 PD, 11 control) and 19 feces samples (10 PD, 9
control) were analyzed by non-target high resolution mass spectrometry (NT-HRMS) coupled to two
liquid chromatography (LC) methods (reversed phase (RP) and hydrophilic interaction liquid
chromatography (HILIC)). A cheminformatics workflow was optimized using open software (MS-DIAL
and patRoon) and open databases (all public MSP-formatted spectral libraries for MS-DIAL,
PubChemLite for Exposomics and the LITMINEDNEURO list for patRoon). Furthermore, five disease-
specific databases and three suspect lists (on PD and related disorders) were developed, using
PubChem functionality to identifying relevant unknown chemicals. The results showed that non-
target screening with the larger databases generally provided better results compared with smaller
suspect lists. However, two suspect screening approaches with patRoon were also good options to
study the role of specific chemicals in PD. The combination of chromatographic methods (RP and
HILIC) as well as two ionization modes (positive and negative) enhanced the coverage of chemicals in
the biological samples. While most metabolomics studies in PD have focused on blood and
cerebrospinal fluid, we found a higher number of relevant features in feces, such as alanine betaine
or nicotinamide, which can be directly metabolized by gut microbiota. This highlights the potential
role of gut dysbiosis in PD development. Finally, since some chemicals derived from the
environmental exposure (ethylparaben) were found statistically higher in the PD group,
environmental exposures should be taken into consideration in further non-target studies of PD.
Keywords: Liquid-Chromatography (LC), Non-target high resolution mass spectrometry (NT-HRMS),
Metabolomics, Exposomics, Parkinson’s Disease, Gut dysbiosis

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