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  • Periodic Reporting for period 1 - PROPAG-AGEING (The continuum between healthy ageing and idiopathic Parkinson Disease within a propagation perspective of inflammation and damage: the search for new diagnostic, prognostic and therapeutic targets)
H2020

PROPAG-AGEING Report Summary

Project ID: 634821
Funded under: H2020-EU.3.1.1.

Periodic Reporting for period 1 - PROPAG-AGEING (The continuum between healthy ageing and idiopathic Parkinson Disease within a propagation perspective of inflammation and damage: the search for new diagnostic, prognostic and therapeutic targets)

Reporting period: 2015-09-01 to 2017-02-28

Summary of the context and overall objectives of the project

The main aim of PROPAG-AGEING project is to understand why, while some people grow old in good health, reaching in some cases the extreme longevity, others develop Parkinson’s disease. According to the most recent researches, Parkinson’s disease (PD) and ageing share several basic mechanisms, and the disease can be considered the result of an accelerated, wrong ageing. PROPAG-AGEING researchers intend to explore this hypothesis. To this aim, they will use the most advanced approaches to study the clinical and molecular characteristics of PD patients, comparing them with healthy controls and with a unique source of “super-controls”: the centenarians, i.e. people who reached the extreme longevity avoiding or postponing the major age-related diseases.
PROPAG-AGEING project is divided in two phases, indicated as “discovery phase” and “validation phase”. In the discovery phase, PROPAG-AGEING partners will analyse highly informative samples, including both PD patients and centenarians, that are part of existing cohorts previously recruited in the framework of national and international projects. These analyses will be performed using highly advanced technologies, the so called “omic analysis”, that allow to deeply investigate the molecular characteristics of a sample. From this analysis, we expect to identify a limited set of promising molecular signatures of PD. In parallel, we will analyse the clinical characteristics of the PD patients, by comprehensively analysing the available medical data, including, where available, the magnetic resonance imaging data. In the validation phase, we will confirm these signatures both in other samples from the existing cohorts and in a newly recruited cohort including the healthy siblings of PD patients. In parallel, the validation will be performed in a refined experimental model: we will derive dopaminergic neurons (the cell type mainly involved in PD) from the skin cells of PD patients and centenarians, in order to compare them in vitro.
We expect that, using this innovative approach, we will discover previously unappreciated commonalities between the mechanisms of PD and of the ageing process. In this way we will greatly expanded the knowledge on PD and we will identify early biomarkers of the disease, that will possibly provide new diagnostic, prognostic and therapeutic targets.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

In the first 18 months of the project, the activity of PROPAG-AGEING partners has been focused on:
1. The achievement of the ethical approvals both for the discovery and the validation phase. Each partner has submitted a formal request to the competent Ethical Commission to ask for the permission of share and analyse PROPAG-AGEING samples. In addition, the four centers that will recruit the siblings of PD patients (AUSL-ISNB, UMG-GOE, SAS and UCL) have asked for the relative permission. Recruitment will be performed according to a protocol opportunely standardised between the 4 recruiting centers. Finally, both the discovery and validation studies have been deposited in the the German Clinical Trials Register (DRKS) and are publicly available at the following links:

https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00009427

https://drks-neu.uniklinik-freiburg.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011260

2. The set-up of the PROPAG-AGEING database. To allow a comprehensive analysis of the clinical and demographical data of the samples, the partners have agreed to upload the data in common database. The database is password-protected and the information are completely anonymized, in order to accomplish with the current privacy standards.

3. The harmonization of the existing cohorts and selection of the samples to be analysed in the discovery phase. The data deriving from the different cohorts have been harmonized in order to make comparable the measurements deriving from different recruitments and collections. In addition, imaging data from PD patients produced in different centres have been compared and normalized in order to perform statistical analyses. Finally, the partners have chosen the most informative samples within each cohort. These samples will be analysed in the next months using different omic approaches.

4. The set-up of the experimental approaches for the analysis of the samples. In addition, the characterization of the basic blood markers and the metabolomic analyses on PD and controls samples started.

The reprogramming of dermal fibroblasts from centenarians and PD patients. Cells derived from skin biopsies of centenarians and PD subjects have been treated in order to “de-differentiate” them. In the next months, the same cells will be re-differentiated in dopaminergic neurons.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

PROPAG-AGEING addresses PD, one of the most important diseases of the elderly, affecting 6.3 million people worldwide, 1.2 million people in the sole Europe. The number of patients is continually growing due to the ageing of the population.
Levodopa is currently the most effective therapy for the treatment of PD, but the treatment is symptomatic and not able to cure nor to modify the the course of the disease. In addition, no treatments for the early treatment (before the motor symptoms are evident) and the prevention of PD are available.
By using a new conceptual approach, that is embedding PD in the ageing process, PROPAG-AGEING has the potential to unveil previously unappreciated mechanisms of the disease and to provide new targets that can be used as biomarkers for the early diagnosis and as therapeutic target of PD. As a consequence, PROPAG-AGEING has a valuable impact at different levels:
- It will greatly expand the scientific knowledge on PD
- It will provide the medical community with new tools for the diagnosis, prognosis and therapy of the disease
- It will contribute to a better management of the disease, reducing health care utilization and costs and the socio-economic burden of the disease.

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