Luxembourg and neurodegeneration: the National Centre of Excellence in Research on Parkinson’s Disease

A multidimensional approach to Parkinson’s Disease

The National Centre of Excellence in Research on Parkinson’s Disease (NCER-PD) was launched back in 2015 with the support of the National Research Fund (Fonds National de la Recherche – FNR). The project is coordinated by the Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg and brings together the Luxembourg Institute of Health (LIH), IBBL, the Centre Hospitalier de Luxembourg (CHL) and, as of 2018, the National Health Laboratory (Laboratoire National de Santé – LNS). The strength of the consortium, collectively referred to as ‘Team Luxembourg’, lies in its multidisciplinary nature, which integrates expertise in systems biomedicine, clinical assessments and research, biomedical IT, biospecimen processing and storage and neuropathology. NCER-PD is divided in two phases, with Phase I running from June 2015 until November 2019 and Phase II from December 2019 until May 2023. Phase I comprises three main projects, namely the set-up of a PD cohort (known as HELP-PD), systems biology approaches for the identification of biomarker signatures (DIAGNOSIS), and the development of an international resource of PD genetic variants associated with familial and sporadic forms of PD (VARIANT-DB). This multidimensional holistic approach which underpins Phase I – and which encompasses clinical assessments, molecular genetics and biomarker discovery – resulted in a comprehensive model for cohort recruitment, taking into account multiple aspects such as regulatory, ethical and biospecimen biobanking considerations. This unique study design was published in a prestigious international journal in October 2018 and is now ready to be rolled out to other diseases too, thus making NCER-PD an invaluable tool in the implementation of translational medicine.

IBBL and the HELP-PD cohort

IBBL has been particularly involved in setting up Luxembourg’s first PD cohort under HELP-PD (Healthy Ageing of the Luxembourgish Population with a focus on Parkinson’s Disease). The cohort includes PD patients from Luxembourg and the Greater Region, as well as matched healthy controls. Through annual follow up visits and device-based assessments, a large dataset on all disease stages and forms of Parkinsonism – from early non-motor signs to progression data – is generated, with the ultimate goal of identifying predictive and progression biomarkers for PD. Indeed, the HELP-PD cohort will be used to validate the diagnostic biomarker signatures developed under DIAGNOSIS. IBBL has been ensuring kit production and delivery to collection centres, as well as logistics, processing and storage of blood, urine and saliva samples. Upon patient consent, cerebrospinal fluid (CSF), stool and skin biopsies are also collected, processed and stored. In addition, IBBL carries out method validations, such validation of DNA extraction from stool, to ensure that the aliquots derived through its processing methods are fit-for-purpose.

Fostering translational medicine medicine

Building on the successes of Phase I, ‘Team Luxembourg’ submitted a proposal in late 2018 detailing three projects to be included in Phase II, namely Stratification & Treatment, Biomarkers & Mechanisms and Data & Analytics. These will be the continuation of the three corresponding Phase I projects. Specifically, HELP-PD will provide the basis for Stratification & Treatment, with the goal of establishing a cohort of early-stage PD patients (known as Enriched Risk Cohort for PD – ERiC-PD) to identify at-risk individuals. IBBL will be supporting Phase II transversally across all three projects. Aside from continuing the provision of sample collection, logistics, processing and storage services, the biobank will store of a post-mortem collection of human brains from volunteers, in close cooperation with the LNS. This collection will support the Stratification and Treatment initiative by allowing the neuropathological validation of the clinical diagnoses made within the study. The brain bank is expected to recruit up to 30 subjects annually into each of the target and control groups. Furthermore, under the Biomarkers & Mechanisms project, IBBL will reprogram fibroblast cells from skin biopsies obtained in Phase I into induced pluripotent stem cells (iPSCs), which will subsequently be differentiated into different types of neurons. The patient-specific cellular models thus generated closely reproduce the affected neurons in PD patients and can therefore be used to validate discovered biomarkers and investigate the molecular mechanisms underlying their role in PD. “This is a truly exciting phase of the project”, comments Estelle Sandt, project manager of NCER-PD at IBBL. “Our consortium will essentially ‘convert’ skin cells into patient-specific brain cells. NCER-PD is thus redefining the boundaries of science and enabling the transition to true translational medicine”, she concludes.