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Brain Prize Lecture – Genomics of vascular dementia and stroke
Brain Prize Lecture – Genomics of vascular dementia and stroke - Professor Elisabeth Tournier-Lasserve

Élisabeth Tournier-Lasserve, France, will be presenting the Brain Prize Lecture at the 33rd ECNP Congress in September.

Élisabeth Tournier-Lasserve, along with Marie-Germaine Bousser, Hugues Chabriat and Anne Joutel, was awarded the 2019 Brain Prize for their outstanding research on the most common hereditary form of stroke, CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy). This work showed that CADASIL is a cerebral small vessel disease caused by highly stereotyped mutations in the NOTCH3 gene on chromosome 19. These mutations result in an accumulation of the NOTCH3 protein in the walls of the small blood vessels, which is the starting event in the pathogenic pathway. Their work allowed the development of diagnostic tests and animal models currently used for preclinical assays.

Tournier-Lasserve is currently professor of Medical Genetics at Université de Paris 7, director of the National French Reference Genetics Diagnostic Lab for Neurovascular Disorders in Saint Louis Hospital in Paris (Assistance Publique des Hôpitaux de Paris), and director of the GeneMedStroke team at INSERM U1141 Research Lab.

Here she is interviewed by ECNP Press Officer, Tom Parkhill.

How did you get involved in the CADASIL project?
CADASIL was not known when we started this work; it didn’t even have a name. The recognition of the condition springs from a clinical observation of Professor Marie-Germaine Bousser. She had a 50-year-old patient without any risk factors who presented with an ischemic stroke. He also had white matter lesions which showed up on a CT scan, this was pre-MRI! She came to me because she had been told that I had a patient with a similar condition. Later, we realised that two of the patient’s offspring, both around 30 years old, had also had ischemic strokes and no vascular risk factors. So this made us realise that we were dealing with an inherited condition.

Did you think of yourself as a geneticist?
In fact when that story began I was an assistant professor in neurology at Pitié Salpêtrière Hospital. I then went to the US, where I did a post-doc on molecular biology of the central nervous system, at the NIH in Bethesda, in Bob Lazzarini’s lab. When I came back to France I realised that the new genomic tools which were appearing might help us identify which gene was involved in this disorder. Anne Joutel was a PhD student in my lab at that time, and we decided to identify the gene. Starting from this single patient and his relatives we were able to map and then clone the gene. Indeed 57 members of this family agreed to participate to this study, 19 of whom had white matter lesions. After that we were able to identify 50 additional families, from all over Europe. This allowed us to identify the gene using positional cloning. It was difficult work, but it led to very important results from different points of view: the development of diagnostic tools, imaging characterisation of this disorder, genetic counselling, development of animal models, etc. It took the three years of Anne’s PhD to identify the gene, and we published in 1996. You need to remember that these were early days for gene mapping. The human genome sequence was not known yet!

What are you doing now?
The identification of CADASIL and its causative mutations was a breakthrough in the field. Several other genes involved in rare cerebral small vessel disease were later on identified by different teams, including ours. However, testing all these genes in patients with familial cerebral small vessel disease leads to the diagnosis in only 20% of them, meaning that in 80% of patients we don’t know the gene which is causing the condition. So one of the major objectives of my team is to identify these missing genes. Of course, the strategy is now very different to what we did in the past. We use novel tools such as exome and genome sequencing, as well as new statistical tools.

This work benefits from the tight collaborations we have with Professor Chabriat’s team at Lariboisière Hospital, which is focused on imaging biomarkers in cerebral small vessel disease.

As regard to the pathophysiology of CADASIL, Professor Joutel’s team at INSERM has done tremendous work using multidisciplinary approaches and is now conducting preclinical trials for this condition.

So CADASIL is a rare disease but with bigger implications?
Well that’s interesting. If you look at the big genomic databases such as ExAC or the gnomAD database there is sequencing information on more than 250,000 people. The last gnomAD version has around 72,000 who have had their whole genome sequenced. CADASIL type mutations are present in more than one in 1,000 people in this control database, suggesting that CADASIL is probably the second most frequent Mendelian disorder, just after polycystic kidney disease. It’s however likely that some of these mutations will lead to severe disease, and others to much milder disease, but we don’t know yet.

In addition to CADASIL, the NOTCH3 story has also been important in trying to understand common, sporadic cerebral small vessel disease, which represents 20% of stroke patients, and is the main cause of vascular dementia, and the second cause of dementia after Alzheimer’s.

At the beginning then, this was seen as a rare disease. Was funding difficult?
In the beginning, funding sources were not obvious. We worked mostly with institutional money. Once we started to get results the funding was easier. But what really helped was working on a good subject, and with people we liked and who were supportive. The four winners of the Brain Prize, Marie-Germaine Bousser, Hugues Chabriat, Anne Joutel and myself, have been working together for since around 1986, more than 30 years. We’re still collaborating. That’s very important. A supportive environment has helped us in many ways. For example in the 1980s MRI was not easily available, but a friend was able to let us use an MRI on Saturdays, when it wasn’t in normal clinical use.

What has winning the Brain Prize meant to you and your co-workers?
This has been really important, and for several reasons. Firstly because it acknowledges the translational nature of the science; we started with a single patient, and then we moved into genomics, imaging, pre-clinical trials, mouse models, and then coming back to the patients.

Secondly it’s important because it recognises the significance of cerebro-vascular disorders. Generally this is not considered as neuroscience: neuroscientists say “that’s cardiovascular”. But when we talk to cardiovascular specialists they say “but that’s neuroscience”. So it was great to have the visibility given by such a prestigious prize recognising these points Patients’ associations were also very happy about the Brain Prize award, and the visibility it gave to the field. It’s really important that a disease is recognised and given a name. Indeed, we found that, before NOTCH3 gene identification, 30% of CADASIL patients had been misdiagnosed as having multiple sclerosis, and many were given immunosuppressants.

Élisabeth Tournier-Lasserve’s Plenary Lecture
PL.03 – Brain Prize Lecture: Genomics of vascular dementia and stroke
Sunday, 13 September, 13:00-13:30

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The Brain Prize, awarded annually by the Lundbeck Foundation and worth 10 million DKK (around €1.3m) to the winners, is the world’s most prestigious prize for neuroscience research. Each year a Brain Prize winner gives a special lecture at the ECNP Congress https://www.lundbeckfonden.com/en/thebrainprize/winners/
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