When motor symptoms become evident in patients with Parkinson's disease (PD), more than 70% of the dopaminergic neurons are already lost. At this stage neuroprotective treatment can be less effective, as the neuronal function is difficult to restore once it is lost. The identification or early markers of disease is thus crucial for making a difference in the management and treatment of Parkinson's disease. We already know that certain clinical presentations (such as the impairment of the REM sleep or hyposmia) as well as being a carrier of specific gene mutations (such as the gene GBA and LRRK2) can greatly increase the risk of developing PD. People with these features are called Prodromal PD subjects.

Treating subjects that will develop PD in a prodromal stage will be actually very promising.

However, we are still lacking biomarkers able to predict the development of PD in subjects at high risk of this condition, such as prodromal subjects.

Inflammation is one of the pathogenic mechanisms implicated in PD. Different studies have shown that inflammatory cells in patients with PD are more reactive and present differences in gene expression. To assess the activation and differences in regulation of the gene expression machinery in pre-motor stages of the disease can be informative in understanding how pathogenic mechanisms of PD start to develop, and thus possibly how to contrast them, as well as around possible levels of risks of developing PD in prodromal subjects.

One of the mechanisms that regulate the inflammatory response are the epigenetic mechanisms, which are DNA changes that can affect when and how genes are expressed. Epigenetic mechanisms, such as methylation, can be influenced by internal mechanisms of the cells but also by the interaction with factors from the environment where we live (such as the exposure to toxin, certain medication, pollutions). Therefore, studying the methylation profiles of a target tissue and the correlation with the exposure to certain environmental triggers can be very informative of these changes.

With the present project we propose to study the epigenetic (methylation) changes in a circulating blood cell (monocytes) in a cohort of prodromal subjects for PD, to compare them with the signatures from subjects with PD and control subjects, and to correlate these data with the information from a questionnaire exploring the exposure to different environmental triggers.

Our analysis will allow us to establish (1) whether methylation changes in the inflammatory cells correlate with the exposure to specific environmental factors that can be targeted by preventive treatment, and (2) whether changes in the inflammatory cells specifically found in patients with PD are already present in prodromal stages, suggesting an early activation of the immune response in the onset of the disease and offering a new biomarker for detection of early stages of disease.

This project has the potential to target a broad range of subjects with PD and their family members because it can allow (1) the identification of possible biomarkers that can be informative to suggest participation in neuroprotective clinical trials even before development of motor symptoms. If validated, the same biomarkers can be also studied in subjects with no prodromal symptoms with PD and assess their predictive values in predicting PD through longitudinal studies; (2) the clarification of the role and the timeline of the activation of the immune response in Parkinson's disease and thus suggest possible preventive treatments; (3) increase our understanding of the effect of exposure to specific neurotoxic and environmental factors on the inflammatory cells in PD; (4) proper discussion with family members of subjects with PD, with certain genetic mutations or with prodromal symptoms, about their risks of developing PD.

The results of this research will need to be validated in a validation cohort and in a larger population. Thus, we expect this could lead to possible applicability in about 4 years.