Frontotemporal degeneration and motor neurone disease: biomarkers for studying the presymptomatic phase
Changed on 13/04/2021
Frontotemporal degeneration and motor neurone disease develop silently over decades before the first symptoms start to appear. As part of an interdisciplinary collaboration involving the Paris Brain Institute and Inria, researchers have been able to identify the blood biomarkers for these neurodegenerative diseases using artificial intelligence. This will make it possible to track the invisible development of these diseases and to devise treatments capable of slowing them down, mitigating the damage they cause and even preventing them. This research was published in the JNNP (Journal of Neurology, Neurosurgery & Psychiatry).
Frontotemporal degeneration (FTD) and motor neurone disease (or amyotrophic lateral sclerosis - ALS) are terminal neurodegenerative diseases for which there is currently no cure. By the time symptoms first appear - ordinarily between the age of 50 and 60 for FTD and between 50 and 70 for MND - it is likely to be too late for doctors to be able to do anything.
Prior to this, the diseases develop in silence over a period of decades, with no indication as to when symptoms will appear. This is true even for patients in whom a mutation in the c9orf72 gene has been clearly identified, who are almost certain to develop the disease.
Biomarkers for each phase of the disease
These are the patients that our study focused on, explains Olivier Colliot, director of the Aramis project team at the Inria Paris research centre. Our aim was to find biomarkers that would enable us to distinguish presymptomatic patients (those with no symptoms) from control patients and confirmed cases. Not only were we successful in doing so, but we did it with markers that could be obtained via a simple blood test.
Three teams were involved: for the Paris Brain Institute, it was Isabelle Le Ber’s team; for Inria, meanwhile, it was the Aramis project team in Paris (a joint undertaking involving the CNRS, Inserm, Sorbonne University and the Paris Brain Institute) and the Dyliss project team from the Inria Rennes - Bretagne Atlantique research centre (Emmanuelle Becker).
This breakthrough was made as part of a partnership between Inria and the Paris Brain Institute, which dates back to 2012. The researchers from the Paris Brain Institute were responsible for overseeing the biological and medical side of things: it was they who decided to focus research on “microRNA”, small fragments of genetic material which regulate gene expression.
Titre
Des biomarqueurs pour chaque phase de la maladie
Verbatim
C’est sur ces patients que notre étude a porté. L’objectif était de trouver des biomarqueurs permettant de distinguer le sujet présymptomatique (sans symptôme) du sujet témoin et du malade déclaré. Nous y sommes parvenus, qui plus est avec des marqueurs accessibles avec une simple prise de sang.
Auteur
Olivier Colliot
Poste
Directeur de l’équipe Aramis du centre Inria de Paris
Symptoms appearing between the age of 50 and 70
Frontotemporal degeneration (FTD) and motor neurone disease (or amyotrophic lateral sclerosis - ALS) are terminal neurodegenerative diseases for which there is currently no cure. By the time symptoms first appear - ordinarily between the age of 50 and 60 for FTD and between 50 and 70 for MND - it is likely to be too late for doctors to be able to do anything.
Prior to this, the diseases develop in silence over a period of decades, with no indication as to when symptoms will appear. This is true even for patients in whom a mutation in the c9orf72 gene has been clearly identified, who are almost certain to develop the disease.
Biomarkers for each phase of the disease
These are the patients that our study focused on, explains Olivier Colliot, director of the Aramis project team at the Inria Paris research centre. Our aim was to find biomarkers that would enable us to distinguish presymptomatic patients (those with no symptoms) from control patients and confirmed cases. Not only were we successful in doing so, but we did it with markers that could be obtained via a simple blood test.
Three teams were involved: for the Paris Brain Institute, it was Isabelle Le Ber’s team; for Inria, meanwhile, it was the Aramis project team in Paris (a joint undertaking involving the CNRS, Inserm, Sorbonne University and the Paris Brain Institute) and the Dyliss project team from the Inria Rennes - Bretagne Atlantique research centre (Emmanuelle Becker).
This breakthrough was made as part of a partnership between Inria and the Paris Brain Institute, which dates back to 2012. The researchers from the Paris Brain Institute were responsible for overseeing the biological and medical side of things: it was they who decided to focus research on “microRNA”, small fragments of genetic material which regulate gene expression.
What is a microRNA?
microRNAs are small ribonucleic acids (RNAs) which target messenger RNAs in order to damage them or prevent their translation. One microRNA is able to regulate multiple genes and one gene can be regulated by multiple microRNAs.
Four microRNAs selected out of 589 possible candidates using artificial intelligence
The two Inria teams (Dyliss in Rennes and Aramis in Paris) worked to develop a machine learning model - an artificial intelligence tool - as part of Virgilio Kmetzsch's PhD, which they jointly supervised. Out of a possible 589 microRNAs, the machine learning model identified those four felt to be the most suitable, an enormous sorting operation which underlined the benefits of having biologists and computer scientists working together.
We ran into a few stumbling blocks when designing the model, explains Virgilio Kmetzsch. We had never used data on microRNAs before, as this is a very recent field of research. Out of the research cohort, there were only 67 people who had the c9orf72 gene mutation: frontotemporal degeneration and motor neurone disease are rare conditions.
The goal: to treat patients before the first symptoms emerge
Despite the difficulties, the researchers achieved what they set out to do. Their model is capable of determining if a subject is at the presymptomatic stage or if they already have symptoms, based on the level of expression of the four microRNAs.
This is the first time that a microRNA signature for the presymptomatic and symptomatic stages has ever been identified, explains Olivier Colliot. Our new tool will enable us to develop a deeper understanding of the mechanisms involved in both frontotemporal degeneration and motor neurone disease, in addition to supporting research into treatments capable of being administered prior to the first symptoms appearing.
Biomarkers for determining the disease's “clock”
However, we should strike a note of caution when discussing this new development: the patients in the study have only been monitored for three years, which is a very short period of time for these diseases. That said, knowledge and understanding of microRNAs could well improve over time.
As we track patients for another few years, we hope to be able to find markers that evolve with the disease, explains Olivier Colliot, a sort of clock that would indicate the optimal time to begin treatment.
Previous research carried out by the Paris Brain Institute had revealed other biomarkers through the use of brain imaging. In subjects carrying the c9orf72 mutation, a degeneration of certain regions of the brain was observed. These lesions, which could be seen from 40 years of age onwards, shed additional light on the presymptomatic stage of both frontotemporal degeneration and motor neurone disease.
How can these medical images be combined with the expression levels of four microRNAs? Once again, the answer lies in biologists and computer scientists working together.
Our researchers in Paris and Rennes have been working with the Paris Brain Institute on the integration of multimodal data, explains Olivier Colliot. The machine learning model will evolve in order to factor in imaging, which will enable us to deepen our understanding of the different stages of the two diseases.
Inria and the Paris Brain Institute - eight years of working together
Inria and the Paris Brain Institute have been working together since 2012. It was then that Aramis, a joint project team, was set up to study neurodegenerative diseases through a combination of neuroscience and computer science, with a particular focus on medical imaging. In 2017, Inria and the Paris Brain Institute expanded into genetic and genome-related aspects, as part of the Project Lab Neuromarkers. Combining different methods gives researchers more data to work with - the difficulty then lies in using them simultaneously, with new methods and algorithms.
Aramis project team // Inria de Paris
Aramis is a project team that specialises in algorithms, models and methods for images and signals in both healthy and diseased human brains.
Dyliss project team // Inria Rennes - Bretagne Atlantique
Dyliss is a project team that specialises in research into bioinformatics, focusing on the automated use and discovery of formal knowledge in the life sciences.
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