Periodic Reporting for period 3 - 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)
Période du rapport: 2018-09-01 au 2019-08-31
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, unhealthy ageing. PROPAG-AGEING researchers intend to explore this hypothesis. To this aim, we have used the most advanced approaches to study the clinical and molecular phenotype of PD, comparing it 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. In this way we greatly expanded the knowledge on PD.
PROPAG-AGEING project is divided in two phases, indicated as “discovery phase” and “validation phase”. In the discovery phase, PROPAG-AGEING partners have analysed the most informative subjects, including both PD patients and centenarians, that are part of existing cohorts previously recruited in the framework of national and international projects. These analyses have been performed using highly advanced technologies, the so called “omic analysis”, that allow to deeply investigate the molecular characteristics of a sample. In parallel, we analysed 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 confirmed these signatures both in other samples from the existing cohorts and in a newly recruited cohort including the healthy siblings of PD patients, who can be at higher risk to develop PD. This cohort has an extremely high value for the study of early diagnosis and progression of the disease. In parallel, the validation has been performed in a refined experimental model, that is dopaminergic neurons (the cell type mainly involved in PD) derived from the skin cells of PD patients and centenarians.
PROPAG-AGEING project is divided in two phases, indicated as “discovery phase” and “validation phase”. In the discovery phase, PROPAG-AGEING partners have analysed the most informative subjects, including both PD patients and centenarians, that are part of existing cohorts previously recruited in the framework of national and international projects. These analyses have been performed using highly advanced technologies, the so called “omic analysis”, that allow to deeply investigate the molecular characteristics of a sample. In parallel, we analysed 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 confirmed these signatures both in other samples from the existing cohorts and in a newly recruited cohort including the healthy siblings of PD patients, who can be at higher risk to develop PD. This cohort has an extremely high value for the study of early diagnosis and progression of the disease. In parallel, the validation has been performed in a refined experimental model, that is dopaminergic neurons (the cell type mainly involved in PD) derived from the skin cells of PD patients and centenarians.
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://drks-neu.uniklinik-freiburg.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 centers have been compared and normalized in order to perform statistical analyses. Finally, the partners have chosen the subjects with the most informative phenotypes within each cohort.
4. Meta-analysis on demographic and clinical characteristics of PROPAG-AGEING samples
5. The set-up of the experimental approaches for the analysis of the samples.
6. The genomic, epigenomic, metabolomic, proteomic, transcriptomic, miRNomic characterization of the selected samples and their validation in additional samples/by different approaches
7. The blood analaysis of target biomarkers in selected samples
8. The reprogramming of dermal fibroblasts from centenarians and PD patients to iPSCs cells and their differentiation to dopaminergic neurons
9. The analysis of neuroimaging data from PD patients
10. The development of analytical tools for the comprehensive analysis of clinical and experimental data
11. The recruitment of 340 siblings of PD patients.
12. The gut microbioata analysis of the siblings of PD patients.
Collectively, our results suggest that while peripheral (blood and serum) biomarkers of age do not detect age-acceleration effects in de novo PD patients, biomarkers specific for the CNS identify deviations compared to the aging trajectories. Furthermore, an alteration of inflammatory pathways is found at the peripheral level. Finally, PROPAG-AGEING had the merit to recruit a large, multi-center cohort of sibslings of PD patients, a cohort of extremely high value for the early diagnosis and progression of the disease. These results have been disseminated mainly to colleagues within the scientific community, in the framework of several worldwide meetings and in several scientific publications.
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://drks-neu.uniklinik-freiburg.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 centers have been compared and normalized in order to perform statistical analyses. Finally, the partners have chosen the subjects with the most informative phenotypes within each cohort.
4. Meta-analysis on demographic and clinical characteristics of PROPAG-AGEING samples
5. The set-up of the experimental approaches for the analysis of the samples.
6. The genomic, epigenomic, metabolomic, proteomic, transcriptomic, miRNomic characterization of the selected samples and their validation in additional samples/by different approaches
7. The blood analaysis of target biomarkers in selected samples
8. The reprogramming of dermal fibroblasts from centenarians and PD patients to iPSCs cells and their differentiation to dopaminergic neurons
9. The analysis of neuroimaging data from PD patients
10. The development of analytical tools for the comprehensive analysis of clinical and experimental data
11. The recruitment of 340 siblings of PD patients.
12. The gut microbioata analysis of the siblings of PD patients.
Collectively, our results suggest that while peripheral (blood and serum) biomarkers of age do not detect age-acceleration effects in de novo PD patients, biomarkers specific for the CNS identify deviations compared to the aging trajectories. Furthermore, an alteration of inflammatory pathways is found at the peripheral level. Finally, PROPAG-AGEING had the merit to recruit a large, multi-center cohort of sibslings of PD patients, a cohort of extremely high value for the early diagnosis and progression of the disease. These results have been disseminated mainly to colleagues within the scientific community, in the framework of several worldwide meetings and in several scientific publications.
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 combining the use of a new conceptual approach (embedding PD in the ageing process) and the deep clinical/molecular characterization of the samples, PROPAG-AGEING has provided a list of potential early biomarkers of the disease, greatly expanding the scientific knowledge on PD.
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 combining the use of a new conceptual approach (embedding PD in the ageing process) and the deep clinical/molecular characterization of the samples, PROPAG-AGEING has provided a list of potential early biomarkers of the disease, greatly expanding the scientific knowledge on PD.