Alzheimer’s disease: simplified diagnosis, with more reliable criteria

How many patients receive an incorrect diagnosis of Alzheimer’s disease? The answer is a surprisingly high number: over a third! To reduce the number of errors, the diagnostic criteria must be the most reliable possible, especially at the very early stages of the disease. For the last decade, an international team of neurologists, coordinated by Bruno Dubois (Inserm/Pierre and Marie Curie University/AP-HP Joint Research Unit 975) has been working towards this. In the June issue of The Lancet Neurology journal, we see how the researchers have developed a simplified diagnosis based on the most specific criteria of the disease. A challenge primarily for research, but also for clinical practice.

Alzheimer’s disease is a neurodegenerative disease. It is the most common (70%) form of dementia. In France, the number of people with Alzheimer’s disease and other forms of dementia is estimated at between 750,000 and one million, and is expected to reach 1.29-1.40 million patients by 2030. Alzheimer’s disease results from a loss of neurons. The lesions are caused by an accumulation of some brain proteins. The pathology begins with memory problems. This is followed by problems of orientation in space and in time, behavioural problems and loss of autonomy. However, these symptoms are not specific to Alzheimer’s disease. The real challenge is to know how to distinguish this disease from other types of dementia, and establish the diagnosis as reliably and as early as possible.

In 2005, an international group of neurologists, coordinated by Bruno Dubois at Inserm, came together to redefine the diagnostic criteria established in 1984. Until then, it had been necessary to await the death of a patient in order to establish a diagnosis of Alzheimer’s disease with certainty by examining the lesions in his/her brain. And in the living, only a probability of disease could be inferred, and only at a late stage, based on a certain threshold of severity of dementia.

In 2007, the international team shattered these concepts. The researchers introduced new diagnostic criteria, particularly biomarkers. These are genuine signatures of the disease, and are present from the initial symptoms (prodromal stage).

The publication of these results constituted a revolution. Researchers then observed that with these new criteria, “36% of their patients included in a therapeutic trial based on previous clinical criteria did not have Alzheimer’s disease,” reports Bruno Dubois. And although this analysis involved only a subgroup of patients, the implications are serious. Patients did not receive the correct treatment and/or care. And flawed patient selection might have had an impact on the lack of efficacy observed for the new treatment.

Since 2007, many studies have been published. And the international group decided to analyse this literature to make the diagnostic algorithm for Alzheimer’s disease simpler and more reliable. 

“We have reached the end of the road; we have arrived at the essence, something refined, resulting from an international consensus”, indicates Prof. Dubois. The diagnosis of Alzheimer’s disease will henceforth rely on “just a couple of clinical-biological criteria for all stages of the disease” (see box).

Most of the time, the diagnosis of Alzheimer’s disease is based primarily on a suggestive clinical picture. It is subsequently confirmed or rejected using a biomarker.

As regards the clinical picture, there are three scenarios:

–      typical cases (80-85% of all cases): impairment of episodic long-term memory (known as amnestic syndrome of the hippocampal type and corresponding to difficulty remembering a list a words, even with clues, for example)

–      atypical cases (15-20% of cases): atrophy of the posterior part of the cerebral cortex or logopenic aphasia (impairment of verbal memory where the patient inverts the syllables of a word when repeating it, for example), or frontal brain damage (which results in behavioural problems)

–      preclinical states: asymptomatic at-risk (patients without symptoms, but who are fortuitously discovered to have positive biomarkers during scientific studies), and presymptomatic (with a genetic mutation)

One of the following two biomarkers is required:

–      in the cerebrospinal fluid (obtained by lumbar puncture): abnormal levels of brain proteins (reduced beta amyloid protein and increased tau protein)

–      in the brain by PET (positron emission tomography) neuroimaging: elevated retention of amyloid tracer

This simpler and more reliable algorithm is important, primarily for research (therapeutic trials, characterisation of the disease, monitoring of patient cohorts, etc.). Outside of research, the use of biomarkers, which is expensive and/or invasive, currently remains limited to young patients or difficult or complex cases in expert centres.

Neurons are oversensitive to cellular stress from the outset in Huntington’s disease

Neurons cannot properly defend themselves against Huntington’s disease, right from the onset of the pathology. This has been discovered by a team of Inserm researchers from the Paris-Seine Biology Institute (IBPS) (Inserm/CNRS/Pierre and Marie Curie University) and their American and Australian colleagues. The cause is the failure of an important mechanism involved in cellular longevity. In addition to this result, the present study shows the importance of restoring the ability of the neurons to resist stress in order to delay the manifestations of the disease. This work is leading to a new approach for treating neurodegenerative diseases. The results of this work are published in PLoS Biology.

Rôle de la huntingtine au cours de la mitose ©Inserm/Elias, Salah

Huntington’s disease is a hereditary neurodegenerative disease, the symptoms of which include involuntary movements (chorea), and cognitive and psychiatric problems. The disease can become apparent at any age, but generally does so at around 40 years. It develops over many years, with progressive loss of autonomy, and death after an average of 15-20 years. There is currently no curative or preventive treatment. However, appropriate care can improve a patient’s condition.

Approximately 6,000 people would be affected by this disease in France, and there are probably more who carry the genetic mutation that causes the disease. Genetic, epigenetic and environmental factors may help to explain the differences between patients, both in terms of diversity and severity of the symptoms encountered and in the age at which the disease appears.

Huntington’s disease is caused by mutations in the huntingtin gene and the production of abnormally formed proteins of the same name. The mutant huntingtin generates continuous cellular stress that leads to the death of some neurons, especially in the striatum (central part of the brain). From this postulate, the researchers proposed a hypothesis that studying this disease might help in understanding how neurons resist stress in neurodegenerative diseases.

“Up to now, we thought that neurons were able to adapt to this stressful situation, and to resist it by fully mobilising their abilities to compensate. What we discovered was that resistance to stress is defective in these neurons from the very outset, and that it is lower than that of a normal cell,” points out Christian Néri, an Inserm Research Director at the Paris-Seine Biology Institute (IBPS) (Inserm/CNRS/Pierre and Marie Curie University). “This is an unexpected situation, caused by early abnormalities that block the mechanisms responsible for the longevity of adult neurons. This raises the question of the “biological age” of neurons in neurodegenerative diseases,” he adds.

The scientist and his French, American and Australian colleagues worked on a small worm (Caenorhabditis elegans) which, because it is transparent, means that its neurons are easy to manipulate and observe. Using versions of these animals in which the mutant huntingtin gene is introduced into the neurons, they studied the effects of huntingtin at genome level with the help of mathematical modelling. They demonstrated an inhibition of the FOXO proteins, which are known to play an important role in longevity and resistance to stress. In centenarians, the FOXO genes may be effective in fighting cellular stress. The secret of their longevity might be explained by better “equipment” for resisting stress.

The researchers confirmed these results in other models of the disease, bringing to light the close relationships between cellular longevity and resistance to neurodegenerative diseases.

Above all, however, this research, which is central to Inserm’s International Associated Laboratory (LIA) for “Neuronal Longevity,” shows the importance of restoring neuronal capacity for resistance to stress in delaying the manifestations of the disease.

This therapeutic avenue might be of particular relevance for combating the very initial stages of Huntington’s disease and other neurodegenerative diseases.

neri 1

neri 2

Picture 1 The researchers used systems biology to decipher the complexity of the toxic effects of mutant huntingtin on the neuronal genome. They analysed the expression of this genome using mathematical models based on gene interaction networks. The result is illustrated here in stylised 3D form.

Picture 2 The researchers worked on small transparent worms. These are transgenic C elegans nematodes that model the neuronal pathology found in Huntington’s disease. Morphological abnormalities in the neuronal axons of the live animal can be seen with the help of fluorescent markers.


How a stem cell sees red

Many medical situations require a supply of red blood cells—anaemia, road accidents and chemotherapy, for example. But there is a genuine shortage of blood. Researchers throughout the world are therefore working hard to find solutions to alleviate these shortages, and their sights are set on the potential for creating an unlimited supply of red blood cells, platelets, etc., from stem cells as required. Naomi Taylor, an Inserm Research Director, and her team at the Molecular Genetics Institute of Montpellier (CNRS/Montpellier University) have just taken an important step in this direction. They show that two substances—glucose and glutamine—dictate the route taken by a blood stem cell in becoming a red blood cell or some other type of blood cell.
This research is published in the journal Cell Stem Cell.

The lifespan of a blood cell can vary greatly—from several decades for some lymphocytes to 120 days for a red blood cell, 8 days for platelets, or just 1 day for neutrophils. The body therefore has to replace some of these specific cell types on a daily basis to ensure that the requirement for “new” blood is met, while maintaining the equilibrium between the different types of blood cells.

Many research studies carried out in the last few decades have focused on elucidating the role of certain cytokines in promoting the multiplication of blood stem cells and their differentiation into red blood cells, white blood cells, or platelet precursor cells Thus EPO has become well known for stimulating and promoting the multiplication of red blood cells, whereas GM-CSF, for example, stimulates the multiplication of monocyte/macrophage type cells, the famous circulating “scavenger” cells Cytokines such as EPO and GM-CSF are used to help with haematopoietic reconstitution after surgery, during cancer chemotherapy, following a bone marrow transplant or during infection with the AIDS virus (HIV) for example.

However, it seems that these cytokines, although they play a decisive role, are not enough to ensure commitment to the various blood cell lineages. The question thus arises regarding the additional parameters and factors that direct the haematopoietic stem cells more effectively toward one cell type rather than another.

In the course of differentiation, many cell divisions take place during which the daughter cells acquire their unique characteristics. This process does not require energy alone; it also requires molecules such as amino acids, nucleotides and lipids to synthesise proteins, DNA and RNA, and membranes, respectively, for the new cells.
In the present study, Leal Oburoglu, a final year PhD student, showed that glutamine, the most abundant amino acid in the blood, is indispensable for a blood stem cell to become a red blood cell, particularly because it enables the production of nucleotides. Tests conducted in vitro in the laboratory and then in vivo in mice showed that blocking the use of glutamine or its transporter prevents blood stem cells from becoming red blood cells. Under these conditions, the blood stem cells will then differentiate into monocyte/macrophage type cells.

Conversely, if glucose breakdown to provide energy in the form of ATP (glycolysis) is prevented, nucleotide synthesis is then enabled. This has the overall effect of increasing the production of red blood cells from haematopoietic stem cells (erythropoiesis).

CP Cell


In other terms, the coordinated and targeted use of glutamine and glucose for nucleotide synthesis may enable the stem cell to provide more red blood cells.
For the first time, a study has brought to light that metabolic resources outside the cell control the destiny of the blood stem cell.
For Naomi Taylor and Sandrina Kinet, who coordinated this study: “It is fascinating to think that one day we may be able to bring about differentiation of blood stem cells ‘on demand’ by influencing the metabolic state of the cell.”

Can injuries to the skin be painless?

When the body receives an injury to the skin, a signal is sent to the brain, which generates a sensation of pain. Teams led by Priscille Brodin in Lille[1] and Laurent Marsollier in Angers[2] have studied lesions in patients with Buruli ulcer, a tropical disease. In an article published in the journal Cell, they show that, despite the extent and severity of these wounds, they are less painful than others that seem relatively minor (e.g. scratches, low-degree burns). They discovered an analgesic mechanism that limits the transmission of pain signals to the brain. An understanding of this mechanism may be useful in developing new drugs for pain relief.

Buruli ulcer (caused by infection with Mycobacterium ulcerans) is the third most prevalent mycobacterial disease, after tuberculosis and leprosy. This tropical disease, which mainly affects children, causes ulcerative cutaneous lesions. The destruction of skin tissue is caused by mycolactone, a toxin secreted by the bacterium. Despite their size, the lesions are not especially painful in the early stages of the disease, explaining why patients are slow to seek medical help. The researchers explored the mechanism that causes these lesions to be painless.

schéma ulcère buruli

© Inserm / Conception Clerc-com – Simar Thibault

Until then, it had been thought that the lack of pain in the early stages of the disease was related to the destruction of nervous tissue. In the present study, the researchers show using infected mice that this hypothesis is not supported by nerve degeneration, which occurs only in the advanced stages of the disease. They also injected the toxin into mice to observe its effects on the animals’ sensitivity. The researchers show that the presence of the toxin can inhibit pain on its own, with no effect on the nerves.

“The bacterium, or more specifically its toxin, mycolactone, can interact with neurons and prevent the transmission of nerve signals, explaining the painless nature of the lesions,” explains Laurent Marsollier, a research fellow at Inserm.

A state-of-the-art imaging technique was used to demonstrate that mycolactone interacts with a neuronal receptor (angiotensin receptor 2), causing leakage of potassium. The potassium efflux causes neuronal hyperpolarisation, limiting the transmission of nerve impulses—which carry the pain signal—at local level.

The researchers then blocked the expression of this neuronal receptor in mice infected with the bacterium. Blocking the receptor prevented it from interacting with the mycolactone toxin, which re-established the animals’ sensitivity to pain, thus providing in vivo confirmation of the mechanism identified.

The Mycobacterium ulcerans bacterium employs a novel infection strategy by using the toxin it secretes to prevent the pain associated with the lesions it causes.

“The discovery of this mechanism, which limits pain in the cutaneous lesions during the early stages of the disease, opens up new possibilities in the search for new drugs to prevent pain,” says Priscille Brodin, Inserm Research Director and co-author of this study.

Indeed, the molecule that can block the action of the receptor does not belong to the class of analgesics in current use, such as paracetamol or opiates such as morphine. Generally speaking, clinicians are hoping for new drugs to fight pain, since the existing drugs all have limitations of greater or lesser importance in the context of personalised medicine.

Finally, according to the researchers, the receptor identified may be a target of choice, since another study[3] showed that blocking it led to the reduction of pain in patients with herpes infections.


© OMS / Dr A. Chauty, AFRF, Benin

[1] Joint Research Unit 1019, “Center for Infection and Immunity of Lille” (Inserm – CNRS – Institut Pasteur Lille – University of Lille Nord de France), and formerly Inserm Avenir Team Institut Pasteur Korea

[2] Inserm Unit 892 – Inserm Avenir “ATOMycA” Team (Inserm – CNRS – University of Angers)

[3] Rice, A.S., Dworkin, R.H., McCarthy, T.D., Anand, P., Bountra, C., McCloud, P.I., Hill, J., Cutter, G., Kitson, G., Desem, N., et al. (2014). EMA401, an orally administered highly selective angiotensin II type 2 receptor antagonist, as a novel treatment for postherpetic neuralgia: a randomised, double-blind, placebo-controlled phase 2 clinical trial. Lancet.

The Inserm Ethics Committee publishes two notes on embryo research and gender research

At their first big annual meeting, which took place on Tuesday 17 June this year at the Auditorium of Georges Pompidou European Hospital, several working groups from the Inserm Ethics Committee, including the “Embryo and Development” and “Gender and Health Research” groups, delivered their opinions in the form of notes.

These constitute an interim report with recommendations for practical measures that can be taken at Inserm to develop embryo research under the best ethical conditions, and make scientists aware of the impact of gender on health research.


©Inserm/ E. Valjent

The Inserm Ethics Committee, all members of which were reappointed last year, has the role of creating dialogue between the world of medical research and society. It currently comprises seven working groups addressing different themes. These groups may be requested to reflect on ethical questions, or may do so on their own initiative.

Synopsis of the note from the “Embryo and Development” group

This group is interested in research that involves obtaining germ cells and gametes from stem cells, cognitive embryo research, and embryo research likely to improve infertility treatment and the outcomes of medically assisted reproduction.

The working group concludes its reflection by giving indications that might be considered in order to advance embryo research:

  • Facilitate and promote embryo research, by developing information for the public and for decision-makers, by identifying this research theme more clearly among those likely to be funded by public bodies, and by more rational organisation of the collection, storage and distribution of frozen embryos intended for research in dedicated “embryo bank” type structures.
  • Review the regulation of this research, which must remain equally strict, but which should be more appropriate, more consistent and more straightforward.
  • Tailor consent procedures to the type of embryo donated to research and to the time at which this donation becomes effective. This revocable consent might be given for one (or several) categories of research instead of for a specific project.
  • Draw up guidelines or recommendations with researchers and practitioners in medically assisted reproduction whenever necessary, such as criteria for freezing embryos or procedures for destroying them, for example. These guidelines and recommendations should be revised regularly and simply in line with technological advances and developments.

Read the entire content of the note on the Ethics Committee website in French

Synopsis of the note from the “Gender and Medical Research” group

The “Gender and Medical Research” group was established to raise awareness among Inserm’s researchers of male/female equality. It also aims at being heard beyond Inserm’s laboratories, by participating in public debates that are accessible to all—patients, physicians and those involved in health research.

Sex-based differences in the area of public health have been well documented in epidemiological surveys. However, it must be acknowledged that studies aimed at understanding such differences from a gender perspective remain rare in France, in contrast to Anglo-American and other European countries.

The gender dimension is also often neglected in biomedical research. There are few studies that reflect on the contribution of social factors to differences between the sexes in terms of physiology and pathology.

The group proposes the following courses of action:

  • Survey those research projects carried out at Inserm that have a gender dimension, in collaboration with the human and social sciences laboratories.
  • Organise educational workshops on the concept of gender and the interaction between gender and health, with the following aims:

– Making researchers aware of the fact that biology should not mask the role played by social constructs in health behaviours.

– Questioning clinical procedures for management, treatment, screening and follow-up through the gender prism.

– Developing new methodological approaches for research with the inclusion of gender as factor in understanding the normal and pathological.

– Areas of research touched on will include reproductive health, endocrinology, cardiology, neuroscience, etc., and the implications for public health.

  • Draw up recommendations for Ethical Research Committees (CPP in French) and Regional Spaces for Ethical Reflection (ERRE in French) to introduce the question of gender in the examination of clinical research protocols in accordance with recent European regulations.

Read the entire content of the note on the Ethics Committee website in French

For Hervé Chneiweiss, Chairman of the Inserm Ethics Committee, this first big meeting: “is not only a time to report on our first year’s work; it is also a time for engaging in dialogue with our colleagues and the wider public, listening to their criticisms, and hearing their questions, all of which will contribute to our work in the coming year.”

H1N1 influenza: Vaccination induces an immune memory response comparable to that of a moderate infection

How long does the immune memory response produced by vaccination last? Is it similar to that induced by the infection itself? New information on the A(H1N1) pandemic influenza virus has just been brought to light by researchers at Joint Research Unit 1135, Cimi-Paris (Centre for Immunology and Infectious Diseases – Inserm – Pierre and Marie Curie University). They have shown that the immune response induced by vaccination is still strong one year later, and that it is similar to that produced by a moderate infection. Their findings have been published in the Journal of Clinical Investigation.

Influenza A virus subtype H1N1, originating in pigs, birds and humans, swept across the world between June 2009 and August 2010. While this pandemic was smaller and less severe than that of 1918, it affected young, healthy people too, in some cases causing very serious illness and death. These people were not naturally immune to the new virus strain, which was different from those that cause influenza epidemics every winter. However, some people had been vaccinated and it would be interesting to know how long their immune response to the pandemic A(H1N1) strain lasted, and if it was comparable to that induced by the infection itself.

The researchers sought to answer these two questions by conducting

the first ever study to compare vaccinated subjects with infected patients on the basis of so many immune response parameters

says the principal author Béhazine Combadière, Inserm research director at Cimi-Paris. At present, there is only one standard criterion for evaluating the efficacy of an influenza vaccine: the level of antibodies in the blood, which is correlated with the level of protection afforded. “We pushed our scientific assessment as far as possible, taking into consideration no less than eight parameters, adds Béhazine Combadière. These eight parameters covered both humoral immunity (where the antibodies bind to the virus and neutralise it) and cell-mediated immunity (where the white blood cells or T cells kill the cells infected by the virus). Thus, for example, in regard to humoral immunity the researchers focused not only on the level of antibodies in the blood, but also on serum avidity (i.e. the strength or affinity with which antibodies bind to virus antigens).

The study was also original in that the researchers compared vaccinated subjects with infected patients. It included 50 volunteers who received a monovalent vaccine that targeted the pandemic H1N1 strain only and contained an adjuvant (designed to boost the effect of the vaccine, which had a low viral strain content). The vaccinated subjects were compared with 61 patients infected with A(H1N1) influenza. The infection was mild to moderate in 48 of the patients and severe in the remaining 13. The latter had to be admitted to hospital and treated with antiviral therapy after developing acute respiratory distress syndrome. The assessment was carried out one year after exposure to the virus or one year after vaccination.

The researchers showed first of all that the immune response induced by the vaccine was still strong one year later. They also identified similarities and differences between the three groups of people, depending on the immune response parameters. Thus, the effect of vaccination was similar to that of a moderate infection on several immune parameters. Both vaccination and moderate infection also caused a more significant migration of T cells to the mucosa.

The researchers then decided to investigate whether different immune response profiles existed, regardless of vaccination or infection status. They identified three profiles. The first one included a majority of vaccinated and moderately-infected subjects. Therefore, this research shows that different people have a different immune response capacity. It also confirms that influenza vaccination can induce an immune memory response of similar strength and quality to that produced by a moderate infection.

This study may have implications in terms of adjusting or optimising vaccination strategies. It could be used to improve vaccine efficacy assessment protocols. As a result, two parameters could be added to the antibody level: markers of T cell migration to the mucosa and the potential cytotoxic activity of one category of T cells (CD8).

Mild hearing impairment may indicate greater underlying problems

Scientists from the Institut Pasteur, INSERM, Collège de France, and Pierre and Marie Curie University, in collaboration with a team from the University of Auvergne, identified mice models that mimic high-frequency hearing impairment in humans, with a strong low-frequency sound interference. Their work sheds light on the anomalies causing the hearing impairment and reveals cochlear defects that profoundly affect the way sound frequencies are processed. This work could explain the pronounced masking effect experienced by some hearing-impaired individuals when trying to discriminate high-frequency sounds in noisy environments. The scientists suggest that more substantial auditory assessments would enable clinicians to improve diagnosis of these auditory impairments and provide better care for individuals who, despite showing only a mild hearing impairment using standard audiometric evaluations, should be fitted with hearing aids that appropriately target the defective sound frequencies and correct the hearing impairment.


Despite an audiometric evaluation revealing mild hearing impairment only, some patients experience severe difficulties in understanding speech because of profound sound interference in noisy environments. This represents a major handicap in their daily lives. By studying mice carrying a mutation that affects a subpopulation of auditory hair cells, scientists were able to observe a clinical profile similar to that of these patients. The project was led by Dr. Aziz El-Amraoui and Professor Christine Petit, head of the Genetics and Physiology of Hearing Unit (Institut Pasteur/INSERM UMRS 1120/Pierre and Marie Curie University/Collège de France), in tight collaboration with the neurosensory biophysics team from the INSERM joint research unit UMR 1107 at the University of Auvergne led by Professor Paul Avan.

The mice being studied presented a misleadingly mild hearing loss, observed only for high-frequency sounds, sound frequencies that are normally processed at the cochlear base. However, scientists found significant morphological defects in this very area. The outer hair cells at the cochlear base were unable to respond to high-frequency sounds and their corresponding hair bundles, which act as antennas for sound reception, were markedly misshaped (see photo).

Subjecting the mice to interfering sounds led the scientists to discover an unexpected phenomenon: the low frequency sounds (two octaves lower, and at much lower intensity) significantly masked the high-frequency sounds. The scientists were then able to identify that the fully functioning cochlear apex, which normally processes low-frequency sounds, was behind the masking effect. However, in the mutant mice where the cochlear base had lost all sensitivity, the cochlear apex encoded both low- and high-frequency sounds. In a healthy cochlea, high-frequency sounds cannot even reach the apical region because of the base-to-apex varying physical characteristics of the basilar membrane. However, hair bundle anomalies in mutant mice seem to allow high-frequency sound vibrations to travel along another pathway with very different physical characteristics.

Transposed to humans, this study suggests that some individuals with seemingly optimistic audiograms should indeed be urged to use hearing aids. To avoid the misleading interpretations of standard audiometric tests, individuals with high–frequency hearing impairment vulnerable to interference by low-frequency sounds should undergo complementary clinical evaluations. This would notably allow for a more detailed study of the frequency responses of their auditory sensory cells. Accordingly, the prescribed auditory hearing aids should appropriately focus on the selective restoration of high-frequency sound detection, while taking into account the prevention of low-frequency sound interference.

Illustration: Hair bundles of the auditory outer hair cells from a normal mouse (upper) and a mutant mouse (lower) observed by scanning electron microscopy. – Copyright Institut Pasteur – V. Michel & K. Kamiya
This study was funded by the ERC-hair bundle grant (2011-ADG_20110310), LABEX Lifesenses, the Japan Society for the Promotion of Science, the Uehara Memorial Foundation, Réunica-Prévoyance, Humanis, Irène Errera-Hoechstetter, the Fondation BNP-Paribas and the Fondation Voir et Entendre.

Yves Lévy, new Chairman and Chief Executive Officer of Inserm

Yves Lévy has just been appointed by the Council of Ministers as Chairman and Chief Executive Officer of the French National Institute of Health and Medical Research (Inserm).

Professor Yves Lévy is a specialist in immunology, a physician who is also a researcher and academic. His research activity is directed at understanding the development of the immune system and its pathology. He has also coordinated and developed some twenty national and international clinical trials of immunotherapies and vaccines for HIV infection, certain immunodeficiencies and infectious diseases. His scientific career has always combined basic and clinical research.

Yves-Levy©Inserm/F Guenet

Since 1985 he has worked successively in several Inserm research units. Since 1999, he has been Director of the team “Lymphoid Development under Normal Conditions and Under HIV Infection” in Inserm Unit 955. From 1996 to the present day Yves Lévy has directed the Department of Clinical Immunology and Infectious Diseases at Henri Mondor de Créteil Hospital.
In 2006, Yves Lévy became Scientific Director of the vaccine programme of the French National Agency for Research on AIDS and Viral Hepatitis (ANRS). In 2011, he created the “Vaccine Research Institute” labex (laboratory of excellence) under the Investissement d’Avenir (Investment for the Future) programme. His science programme is based on recent advances in basic immunology, genomics and the knowledge of systems biology, and the development of innovative tools for evaluating the immune response.
From 2010 to 2012, Yves Lévy was Vice-Dean of the Faculty of Medicine, Paris-Est Créteil University (UPEC). He subsequently became a special advisor to the Minister for Higher Education and Research.
At 56 years of age, Yves Lévy succeeds Prof. André Syrota, who has directed Inserm since October 2007. The creation in 2009 of the French National Alliance for Life Sciences and Health (Aviesan), with the aim of providing better coordination and visibility for biomedical research, and of which he was Chairman, is one of the major reforms promoted by André Syrota.
4 broad objectives for Inserm
For the coming years, Yves Lévy has set the following 4 objectives for Inserm:
• maintain very high level basic research,
• attain an international level of excellence in the technologies associated with the life and health sciences,
• contribute to defining an authentic national policy on public health and assistance to public decision making,
• strengthen the links with patient associations, and work towards a better dissemination of scientific culture
This policy will be based on a sustained willingness to decompartmentalise the different areas of biomedical research, and encourage dialogue between research organisations, especially within the framework of the Aviesan alliance. Finally, Yves Lévy hopes to increase social dialogue within the Institute. On this latter point, Yves Lévy, as the new Chairman and CEO, insists that “It is important that there be no hiatus between research policy, the creation of alliances, the definition of an overall strategy and the assumption of ownership and responsibility by the research players.”
These objectives will enable Inserm, the leading biomedical research organisation in Europe, to strengthen its position and attractiveness, and to expand its partnerships at international level.

Epileptic seizure: a primitive brain activity with mechanisms that are conserved across species

Everything seems to distinguish a fly from a man. However, as remarkable as it may seem, Inserm researchers led by Christophe Bernard and Viktor Jirsa at the Institute of Systems Neuroscience (INS) – Inserm U1106 in Marseille have just shown that epileptic seizures follow simple mathematical rules that are conserved across species. The epileptic seizure is a form of neuronal activity that is encoded in every healthy brain, but expressed only in pathological situations. By identifying these basic principles, the researchers were able to precisely classify seizures into 16 distinct types, a classification which will be very useful to clinicians for planning increasingly personalised treatments and seeking new drugs. This research is published in the journal Brain.

Photo CP Brain epilepsieWhat is an epileptic seizure? For centuries this question has represented an enigma for patients and those close to them, as well as for researchers and physicians. Seizures often occur without any warning sign, with clinical manifestations that can be spectacular (examples?) For researchers and physicians, the seizure is considered a very difficult problem to solve, involving highly complex mechanisms.

A major breakthrough has just been made by two teams from the Institute of Systems Neuroscience (INS) – Inserm U1106 in Marseille. Combining theoretical neuroscience with basic and clinical research, the researchers have provided evidence that the principles governing the onset, middle and end of focal epileptic seizures (a very common form of epilepsy) are very simple and do not vary from one region of the brain to another or from one species to another, from fly to man.

The starting point is simple: any healthy brain can have a seizure, for instance after an electric shock, head trauma, etc., without being or without necessarily becoming epileptic. In other words, this brain activity which constitutes a seizure exists in a latent state in every one of us. The seizure is naturally encoded in our neurons. It is always possible, but in a “healthy” brain, the probability of occurrence is very small.

We will therefore use a metaphor to describe the main outcome. Let us represent the brain’s activity as a character travelling in a country made up of mountains, valleys, plains, beaches, etc. The different areas of the country represent as many activities in which the brain is involved (e.g. reading a book, riding a bicycle, etc.). In this country, there is one very particular place—a forbidden zone surrounded by a very high barrier. This forbidden zone is always there; it forms part of the landscape, but our character cannot enter it. This forbidden zone is the epileptic seizure. Extreme conditions are required in order to enter it—after an electric shock for example.

The researchers at the Institute of Systems Neuroscience have constructed a mathematical model that describes what happens from the time the barrier is crossed (onset of seizure) until the time the character finishes by leaving the forbidden zone (end of seizure) and returns to normal activity outside of it. They showed that the trajectories for entering and exiting the seizure follow simple and precise mathematical rules. They also showed that the seizure is the simplest—or most primitive—form of activity that the brain can generate.

“The mathematical model predicts the existence of 16 types of seizures, which enables a precise classification of seizures, a classification which will be highly useful to clinicians treating these seizures and seeking new treatments,” explains Christophe Bernard, a Research Director at Inserm.

The researchers then verified the predictions of the mathematical model experimentally, by analysing the seizures recorded for different species, including man (using an international database).

They were thus able to show that the rules for entry into and exit from the seizure were invariable, from fly to man. The same forbidden zone is therefore present in most regions of the brain across species.

Why is epilepsy so difficult to treat?

By using an experimental mouse model of epilepsy, the researchers have demonstrated that the forbidden zone can be entered at many locations. Furthermore, there are many ways of damaging the barrier. This multiplicity of opportunities explains why treatments must be tailored to every patient, because crossing the barrier does not necessarily take place at the same location from one individual to another.

This research is of major importance, not only because it contributes to demystifying epilepsy, but also because it supplies a conceptual framework for better understanding the mechanisms of seizures and proposing new solutions for treatment.

What is happening in patients who have seizures?
In patients, the barrier is damaged, and it is much easier to enter the forbidden zone. This destruction of the barrier is a very common phenomenon. It occurs naturally in the course of ageing, and this is why the frequency of epilepsy increases with age. Children are also very prone to epileptic seizures, because their barrier is not high enough. Many pathological conditions, such as autism, Alzheimer’s disease and Huntington’s disease, are associated with epileptic seizures, because the destructive effects generated in the brain by these pathologies ultimately erode the barrier.
For this reason, epilepsy may exist alone or in association with other pathologies. Pathological conditions and diseases only unmask an activity that potentially exists in every one of us.

Cancer: life two years after diagnosis

On 10 June, at a special colloquium, the French National Cancer Institute (INCa) and Inserm will present and debate the results of a large survey of 4349 people with cancer conducted two years after diagnosis. Known as VICAN2 for “Vie après le Cancer à deux ans du diagnostic” (Life after Cancer two years post-diagnosis), this survey conducted in 2012 represents the only national study that reports on the living conditions of people with cancer.



Background to the survey “Cancer: life two years after diagnosis”

The incidence of cancer has been increasing for several decades, but advances in treatment have significantly contributed to reducing the mortality associated with this disease. Although the prognosis remains poor for some cancer locations, the prospects for recovery and long-term survival are showing favourable trends in France for many cancers. Thus 3 million people in France have been or are currently affected by cancer. Cancer remains a hard trial both physically and psychologically. For several years after their diagnosis, people have to cope with the risk of a recurrence, and the side-effects of the disease and treatment, as well as resuming their daily lives.

In order to better know and understand these everyday difficulties, the French National Cancer Institute (INCa) wished to repeat the survey, which was first conducted in 2004 under the aegis of the (French Government) Directorate for Research, Studies, Evaluation and Statistics, on the lives of people two years following their cancer diagnosis. The National Cancer Institute entrusted the survey to Inserm Unit 913, SEESSTIM[1] . This research was conducted through a partnership with the French National Health Insurance Fund for Salaried Workers (CNAMTS), the French Agricultural Social Insurance Fund (MSA), and the Independent Workers’ Health Insurance Scheme (RSI).

Main results of the survey “Cancer: Life Two years After Diagnosis”

The VICAN2 survey addresses the different aspects of life for people with cancer from the initial care for their illness, and their relationship with the care system, to the state of their health two years after diagnosis, the impact of the illness on resources and employment, and problems encountered in their everyday and social lives. It emphasises:

The burden of inequalities

The results of this survey illustrate the scale of the impact of cancer on the existence of those affected, and indicate the burden of health inequalities, all along the person’s pathway. These inequalities sometimes reflect missed opportunities suffered by younger and older people in accessing care; however, they are mostly associated with socioeconomic problems, which sometimes carry as much if not more weight than the location of the cancer, the treatments received or the sequelae experienced. Cancer thus seems to be a factor that aggravates the person’s preexisting social inequalities.

News of the diagnosis is usually given under the right conditions

The survey explores the circumstances of diagnosis. Although the manner in which the diagnosis is given to the patient has advanced since 2004, it is still considered too inhumane by 18% of those surveyed. People with less formal education and lower incomes express this opinion even more often. However, the most obvious variations are seen to be associated with the age and gender of those surveyed: women and younger people most often consider that their diagnosis was given to them in an abrupt manner (This is the case for 28% of women aged from 18 to 40 years).

An apparent improvement in the sharing of information with caregivers

The proportion of people satisfied with their involvement in the choice of treatments has progressed.

Moreover, the proportions of those surveyed who believe that the information provided by caregivers was excessive or over-complicated, or that they themselves were poorly able to formulate their questions, have all considerably decreased in this new survey compared with 2004.

A close association between the impact of the disease and location of the cancer

Results show a general deterioration in quality of life caused by cancer; however, this deterioration greatly depends on the location (more frequent for lung cancer, and more rare for prostate cancer), the treatment received and the sequelae experienced.

Apart from than these medical factors, the quality of life measured also depends on possible situations of social fragility (low income, unemployment).

A very marked impact on work situation also

Cancer has an impact on work situation: at the time of diagnosis, eight out of ten people were employed, compared with six out of ten two years later.

The loss of employment more strongly affects the less well educated, younger people and older people, those working as operatives (manual and non-manual workers), who have an insecure work contract or are employed by SMEs.

Moreover, the severity of the cancer underscores the inequalities—the worse the initial prognosis, the greater the difference observed between those working as operatives and those working in management. Thus for a cancer with “a good prognosis,” the rate of staying in employment two years after diagnosis is 89%, for people working in management and 74% for operatives, as against respectively 48% and 28% for cancers with a poor prognosis.

Discrimination infrequent but still present

One out of ten of those surveyed claim that they have already experienced prejudice or discrimination directly related to their disease from their close associates. Women and younger people surveyed are the most likely to report such experiences.

Discrimination is experienced by up to 25% of people who declare that their household has financial problems (compared with 4% of those who claim to be “comfortable”). Social inequalities are thus reflected in the experience of discrimination at the hands of close associates.

These results will be discussed at a colloquium organised on Tuesday 10 June by the National Cancer Institute, bringing together all stakeholders, particularly patients and representatives of patient associations. This reflection will help to support the actions of the 2014-2019 Cancer Plan, which is especially aimed at limiting the social and economic consequences of the disease, facilitating the consideration of cancer in the workplace, continuation of schooling and study, and authorises a “right to be forgotten” for those seeking loans.

[1] Sciences Économiques et Sociales de la Santé et Traitement de l’Information Médicale (Economics and Social Sciences, Health Care Systems and Societies)