The Scientific Projects of the IHU-A-ICM

Photography of Saint-Louis de l'Hôpital de la Pitié Salpetrière chapel

©Institut du Cerveau - ICM

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The projects

The scientific project is structured around 12 themes:
▪ Prevent the progression of Parkinson’s disease – In Charge : Stéphane Hunot, Mary Vidailhet
▪ Find new bio-markers for a more effective and accelerated diagnosis in Alzheimer’s disease – In Charge : Bruno Dubois, Charles Duyckaerts
▪ Repair the nervous system for the clinical improvement of patients with multiple sclerosis – In Charge : Catherine Lubetzki, Anne Baron
▪ Understand and manage motivation disorders : a new approach in cognitive sciences and psychiatry – In Charge : Laurent Cohen, Richard Levy
▪ Anticipate and understand the development of epileptic seizures – In Charge : Michel Baulac, Stéphane Charpier.
▪ Development of the CENIR, pioneering neurophysiology and neuroimaging platform – In Charge : Stéphane Lehéricy
▪ Creation of a multidisciplinary platform of data management, bio-informatics and bio-statistics, ICONICS – In Charge : Ivan Moszer
▪ Implementation of new experimental models for improved translational research to a pre-competitive level – In Charge : Anne Baron
▪ Development of a cell culture and electrophysiology platform for molecule screening – In Charge : Patrick Michel
▪ Development of a platform for clinical trials dedicated to neuroscience – In Charge : Jean-Christophe Corvol, Lucette Lacomblez
▪ Building a new culture of excellence in a teaching approach on diseases of the nervous system – In Charge : Vincent Meininger
▪ Reinforce excellence in other subjects of strategic importance In Charge : Alexis Brice

Parkinson Project

This project aims to prevent the progression of Parkinson’s disease, to understand the mechanisms involved in neurodegeneration in order to develop appropriate therapeutic solutions.

Some highlights :

The ICEBERG study to identify markers, to follow and predict the progression of the disease

The ICEBERG cohort is at the centre of the IHU’s Parkinson clinical project, which goal is to study predictive conversion and progression factors of Parkinson’s disease.

The ICEBERG study conducted by Mary Vidailhet and Stéphane Lehéricy at the Institut du Cerveau – ICM on 330 patients, at risk individuals and healthy subjects over 7 years, aims to identify and validate markers to predict and follow the progression of lesions caused by Parkinson’s disease, from the onset of the first symptoms to the clinical expression stage. The current stage focuses on biomarker research. A marker has been identified in a pre-symptomatic form of Parkinson’s disease, in which patients present isolated behaviour disorders in REM sleep*. Researchers have indeed highlighted, by brain imaging, a decrease of the signal in a small structure of the brain stem.

The major challenge for the coming years is to be able to :
– slowdown the evolution of Parkinson’s disease, limit disorders and develop personalised medicine
– prevent the onset of symptoms in at risk subjects through the development of both effective diagnostic tools and targeted therapeutics.

*Ehrminger M et al., The coeruleus/subcoeruleus complex in idiopathic rapid eye movement sleep behaviour disorder. Brain. 2016 Apr.

Discovery of a new gene involved in an early and very severe form of Parkinson’s disease

Thanks to a collaboration between neurologists and geneticists for the collection of DNA samples and the evaluation of patients and Institut du Cerveau – ICM teams, which have identified VPS13C gene, involved in an early form of Parkinson’s disease and have tested its relevance in experimental models. The protein it encodes is essential to neuron protection through the maintenance of mitochondrial function. These results provide a better understanding of the mechanisms leading to neuron degeneration, thus opening the way to new therapeutic approaches. Moreover, they will enable the implementation of a diagnostic tool for these rare and very severe forms of the disease, in order to manage them as quickly as possible. This project has been coordinated by Professor Alexis Brice and Suzanne Lepage.

Lesage S. et al. Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy, American Journal of Human Genetics. 2016 March 3;98(3):500-13

A viral peptide protecting neurons

Stéphane Hunot from Etienne Hirsch’s team and Daniel Gonzales Dunia at the University of Toulouse have identified a neuroprotective viral peptide on models of Parkinson’s disease which has resulted in a publication in Nature Communication, and a valuation by a patent.

Alzheimer Project

The purpose of the Alzheimer’s project is to identify new bio-markers for a more effective and accelerated diagnosis of Alzheimer’s disease.

Some highlights :

The INSIGHT study for a better understanding of the causes of the disease

The INSIGHT study, conducted in partnership with the IHU, the Memory Institute (IM2A), the Plan-Alzheimer Foundation, AMIVID and Pfizer and coordinated by Professor Dubois, is a groundbreaking study on Alzheimer’s disease. It is indeed one of the first in the world to follow more than 320 at risk healthy subjects in order to understand how and why Alzheimer’s disease occurs in some people and not in others and to identify the factors of the onset of Alzheimer’s disease. This study bears high ambitions in the understanding of the disease.

Morphological alterations detectable in patients’ blood

The identification of blood markers to diagnose Alzheimer’s disease at an early stage and predict its evolution is a major challenge. A study of Marie-Claude Potier’s team shows for the first time that blood cells from patients with Alzheimer’s disease develop specific morphological alterations (endosomes). This discovery raises the hope of being able to diagnose the disease through a simple blood test.

Corlier F et al. Modifications of the endosomal compartment in peripheral blood mononuclear cells and fibroblasts from Alzheimer’s disease patients. Translational Psychiatry. 2015 Jul 7.

Multiple Sclerosis Project

The multiple sclerosis research program aims to develop therapeutic solutions to repair the nervous system of patients with multiple sclerosis and to identify biomarkers of the disease severity.

Some highlights

Estimate the evolution of multiple sclerosis through a cutting-edge technique

Thanks to an innovative program of multi-modal imaging in tomography by positron emission (PET SCAN), Bruno Stankoff and Catherine Lubetzki’s team was able to visualize the demyelination and remyelination of neurons. This method could enable the identification of patients according to their ability to renew damaged myelin, and thus guide therapeutic management. By using another tracer (flumazenil) in PET SCAN, researchers were able to quantify neuronal degeneration and to locate it in MS patients.

Freeman L, et al. The neuronal component of gray matter damage in multiple sclerosis: A [11 C]flumazenil positron emission tomography study. Ann Neurol. 2015 Aug 21.

Bodini B, et al., Benzothiazole and stilbene derivatives as promising PET myelin radiotracers for multiple sclerosis. Ann Neurol. 2016 Apr 21. doi: 10.1002/ana.24667.

Slow down the progression and foster remyelination

Several clinical trials coordinated by Catherine Lubetzki are ongoing to test drugs against the progression of the disease.

A treatment against primary progressive forms

The Oratorio protocol coordinated by Caroline Papeix has tested the efficiency of Ocrelizumab against a placebo in patients with primary progressive forms of MS, the extremely encouraging results of this study show a 24% reduction of the risk of worsening of the disability.

Repair damaged myelin through skin cells

Turn skin cells into nerve cells to repair the damage caused by multiple sclerosis and some leukodystrophies, is the challenge taken up by Brahim Nait Oumesmar and Anne Baron Van Evercooren’s team. These extremely encouraging results would enable the consideration of a cell therapy from the affected patients’ own cells. This team has also highlighted that human neural stem cells have a dual therapeutic effect : anti-inflammatory and promyelinating.

Mozafari S et al., Skin-derived neural precursors competitively generate functional myelin in adult demyelinated mice. J Clin Invest. 2015 Sep 1 ;125(9):3642-56. doi: 10.1172/JCI80437.

Marteyn A. et al. Modulation of the Innate Immune Response by Human Neural Precursors Prevails Over Oligodendrocyte Progenitor Remyelination to Rescue a Severe Model Of Pelizaeus-Merzbacher Disease. Stem Cells 2015.

The Multiple Sclerosis Project teams have demonstrated an inhibitory role of endothelin 1 in remyelination and demonstrate that this molecule constitutes a new pharmacological target for remyelination (publication in the prestigious Neuron magazine in collaboration with Children Hospital, Washington DC.

Motivation Project

The Motivation Project was chosen, in accordance with the IHU concept to set up sustainable structures, which would not have been possible on the basis of usual funding.

In the Behavioural Neuropsychiatry Unit clinical area(UNPC)

The unit is integrated in the diseases of the nervous system center and has 6 week hospital beds. The UNPC has enabled :
▪ The opening of a recruitment procedure of patients with pathologies requiring a neuropsychiatric approach;
▪ to set up clinical research projects including apathy and motivation in cohorts of patients;
▪ to build a reflection on research programs on neuro-behavioural disorders in pathologies of the nervous system.

The dialogue between neurologists and psychiatrists allows better patients care, to offer them a better diagnosis and appropriate therapeutic solutions.

Since the UNPC was opened in November 2013, 250 patients were examined. The most frequently selected diagnostics are neurodegenerative diseases and severe depressive disorders imitating dementia. 80% of patients received, at the end of their stay, a new diagnosis or a confirmed diagnosis, and 77% of a treatment adapted to their situation and different from that of their arrival.

In the research field, of the PRISM platform to study human behaviour.

It is consisting of two entities :

1 – PRISME-Virtual Reality develops and, adapts new models of virtual reality for behavioural and cognitive neuroscience. The platform also settles new equipment, and new treatment protocols applied to neuropsychiatric diseases.

2 – PRISME-Real-Life is designed to study, cognitive functions, human behaviour and social interactions in ecological conditions. It is mainly about: testing large numbers of subjects for a better estimate of the general population, settling environments as close as possible to those of everyday life, using wireless measurement systems so that the participants are free to move. Academic and industrial partners have access to the facilities and are guided by the team to develop appropriate protocols.

It has allowed to start 17 experimental projects, including 644 participants, particularly to :

– Characterise motivation disorders

Mathias Pessiglione’s team develops a range of tests to better characterise motivation disorders, including different types of apathy, in order to be able to compare the efficiency of treatments.

– Study The circuits involved in motivation

A study, conducted in healthy volunteers and coordinated by Jean-Christophe Corvol aims to characterise the circuits involved in motivation and how they can be affected and modulated.

– Quantitatively evaluate apathy

Thanks to the PRISM platform, an innovative project, EcoCapture, developed by Richard Levy aims to investigate apathy. Through body sensors, apathetic patients’ behaviours will be analysed in semi-ecological situation. The objective is to use the collected data to put back to work people who have had a neurological deficit, with decision-making or behaviour disorders.

In the education field, various initiatives in the academic field, and regarding “civil society”.

Epilepsy Project

The objective of this project is to anticipate and understand the development of epileptic seizures.

Some highlights in 2015 :

Emergency treatment of seizures in patients with epilepsy

A patient in status epilepticus, an epileptic seizure which does not stop spontaneously and persisting beyond 5 minutes, should be treated as quickly as possible, otherwise the brain will be damaged. In order to improve patients care, Vincent Navarro, from Stéphane Charpier’s team and several teams of the Assistance Publique have coordinated a study to test the interest of adding an immediate second antiepileptic treatment to the treatment given in emergency (benzodiazepines). This multicenter therapeutic trial has involved in France 13 pre-hospital PARAMEDIC teams and 26 hospital teams welcoming patients in status epilepticus. Vincent Navarro and his staff’s objective is to find a way to stop even more quickly epileptic patients’ seizures. This study has revealed the lack of statically significant difference between both treatments, but it appears as a desire to improve the diagnostic and therapeutic management of epileptic states, and in the perspective of strengthening specific care units, such as that of the Neuro-critical care unit at the Pitié-Salpêtrière Hospital, AP-HP.

V Navarro, et al, Levetiracetam and clonazepam in status epilepticus: A prehospital double-blind randomised trial. Lancet Neurology, 2016; 15(1):47-55.

Identify epileptic states biomarkers

Other studies are currently ongoing to identify, in humans and in animals, relevant biomarkers in epileptic states, in order to identify neuronal death at risk subjects. The functional consequences of the treatments used to stop epileptic states are currently being explored through a collaboration between the neurological intensive care unit and Stéphane Charpier’s team.

Genes involved in focal epilepsies

After the identification of a new gene, DEPDC5, associated with forms of focal epilepsy, Stéphanie Baulac and Eric Leguern’s team has discovered that, in some cases, mutations of this gene also caused a focal malformation of the cerebral cortex. This lesion could be due to a somatic mutation (neither inherited nor transmitted) of DEPDC5 that occurs in brain cells during embryonic development and adds to the mutation inherited from one’s parents. It is the first time such a mechanism is described in focal epilepsy.

Baulac S et al. Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations. Ann Neurol. 2015 Apr;77(4):675-83.

Markers of an epileptic seizure ?

Epileptic seizures can happen at any time. A key question is thus the prediction and anticipation of seizures. In close interaction with clinical neurology units, Stéphane Charpier’s team has highlighted, in patients with focal epilepsy, a particular activity before the onset of seizures. Through advanced electrophysiology techniques, researchers have detected fast rhythms specific to the region triggering the seizure and recorded before the seizure happens. These fast rhythms thus become electrophysiological markers that could, in the future, develop a tool to predict epileptic seizures. This discovery is very important because it allows us to understand which mechanisms are present prior to the epileptic seizure.

Alvarado-Rojas C et al. Different mechanisms of ripple-like oscillations in the human epileptic subiculum. Ann Neurol. 2015 Feb ;77(2):281-90.

How do generalized seizures disrupt conscious processes ?

During generalized seizures, in which epileptic activities affect the entire cerebral cortex, patients undergo an interruption of their conscious processes and are unable to deal effectively with incoming sensations. Using a genetic model of absence epilepsy, a type of generalized child epilepsy leading to a disruption of cognitive tasks and conscious perception, Stéphane Charpier’s team has just showed that these crises undo at any time cortical neurons’ ability to integrate external information in a reliable and reproducible way. It is the first “real-time” demonstration of a neural mechanism participating in the interruption of conscious perception mechanisms during generalized seizures. An additional study in young patients with epilepsy soon will be conducted in collaboration with the Rothschild Hospital.

Williams et al. Integrative properties and transfer function of cortical neurons initiating absence seizures in a rat genetic model. In press. J of Physiology.2016

A persistence of the excitability of neurons in isoelectric coma

A translational project has shown, in patients and in a rodent model, the persistence of the excitability of cortical neurons and of cortical responses to sensory stimulation during isoelectric coma.

Bioinformatics/Biostatistics Project

The Bioinformatics/Biostatistics Project was initiated in 2013 with the recruitment of the scientific coordinator and now has 7 specialists. This platform works for the development of methods dedicated to the analysis of multi-modal data (RGCCA) : genetics, genomics, transcriptomics, epigenomics, metabolomics , clinical and neuro-imaging. The team has also established a complete pipeline (processing, analysis, interpretation, visualisation) of genetic variant data (” gene panel “, ” whole-exome sequencing “), in connection with the Genotyping-Sequencing platform. 30 projects involving 20 scientific and medical teams have started.

Clinical Research Project

The Clinical Research Project members have successfully implemented the activities of the clinical research platform, dedicated to neuroscience. The CIC and CET achieved, in 2015, 3000 patient visits (consultations or HDJ) in 80 ongoing clinical trials. Privileged partnerships with private partners have been continued or initiated.

Care Project

The Care Project has continued its efforts with the recruitment of a coordinator for the implementation with the ARS Ile de France of the handicap center Ile-de-France. An agreement is being signed between the ARS Ile-de-France and the IHU.

Educational Project

The Education Project actions are described in the socioeconomic impacts point (actions taken for spreading knowledge, education). For the first time in 2015, the IHU-A-Institut du Cerveau – ICM organised with the Engineers College the “Brain to Market” Summer School. Scientists and engineers were brought together to share their knowledge and produce a common project. The theme chosen for this first edition was Multiple Sclerosis (MS). Participants benefited from the intervention of researchers and specialists of MS, but also from professionals from companies and startups such as Sanofi, Genzyme, Ad Scientiam or even Brain e-Novation, companies incubated at the Institut du Cerveau – ICM. Guided by a coach, participants have created in multi-disciplinary teams a project responding to pathology problems with a highly valuable potential. These projects were the subject of an assessment by a jury of experts and some of them are currently under feasibility study. This Summer School, true meeting place to create a long term network and catalyst for innovative projects, is a real success and the first of a long series to come.

Several international workshops were organised, as well as exchange programmes of clinicians between Yale and The Pitié-Salpêtrière hospital, paramedical trainings.

Strategy Project

The Strategy Project action plan was materialised with the arrival of Dr. Bassem Hassan, who has been ranked first in the framework of the international ” new teams ” call for tenders (CT). He is heading the “Brain development” team and has been awarded the “Distinguished Investigator” price by the Paul G. Allen foundation. His team’s scientific project is to understand genetic control mechanisms from cellular specification and transpose these basic approaches on pathology models.

Imaging Project

The Imaging Project has helped developing the silo imaging platforms in the IHU context in association with the Institut du Cerveau – ICM. These platforms are now fully operational with an associated management entity and technological research developments in the following areas: multimodal imaging, walking platform, integrated electrophysiology, MEG EEG. During 2015, the silo imaging has organised a series of courses which were a success. These platforms have also enabled the publication of many articles supporting the IHU’s translational research program.

This year, the arrival of the PET-MRI, first clinical and research mixed facility on a French site, will contribute both to research on neuro-degenerative diseases, and to care improvement. This innovative imaging technique allows to improve diagnostic performance, to monitor the evolution of lesions in the brain and to test the effectiveness of medication. Its acquisition was made possible through an exceptional fundraising in collaboration with two of its founding members, the APHP and the Foundation for Research on Alzheimer’s.

Experimental Model Project

Among the Experimental Model Project’s major events, 2015 was marked by the development of new animal models to improve translational research in order to confirm identified potential therapeutic targets. The Institut du Cerveau – ICMice platform, which has 1500 square meters dedicated to the creation and phenotyping of new animal models, has developed methods to explore the central and peripheral nervous system (ElectroNeuroMyoGram, Electromyogram, Somesthesic Related Potential), tools to study animal behaviour and to perform stereotactic surgery. The main research areas developed on the platform are the study of Alzheimer’s, Parkinson’s, Epilepsy, multiple Sclerosis, ALS and Huntington’s diseases.

Cell Culture Project

The Cell Culture Project deployment is now carried out and this program results in the existence of platforms with an associated management entity and technological research developments. Three platforms have developed a service activity (rates) and technological development : Cell Culture and screening, iPS cell Culture, electrophysiology and screening. The development of a CRISPR approach for the genetic manipulation of stem cells is ongoing.

An improvement of the technological offer is now available through the implementation of a second electrophysiology station for extracellular recordings of the potential of electric fields on brain slice (in vitro) or on zebrafish (in vivo).