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A Tool to Predict Cognitive Decline Within 10 Years of Parkinson’S Disease Onset

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An international study with the participation of physicians from the AP-HP Paris public hospitals network and researchers from Inserm, UPMC and CNRS within the Brain & Spine Institute (ICM) has identified a clinical-genetic score to predict cognitive impairment in Parkinson’s disease sufferers. Cognitive impairment is one of the most debilitating characteristics to manifest in certain patients with the disease. The ability to predict its emergence within ten years of the onset of Parkinson’s is of major importance for their treatment and for the set-up of targeted clinical trials.

This study, published in The Lancet Neurology and funded notably by the National Institutes of Health (NIH), brings together U.S. teams from Harvard Medical School and Brigham and Women’s Hospital (Boston).

 

After several years of living with Parkinson’s, patients can suffer cognitive impairment in addition to the movement disorders characteristic of the disease. In their study, the researchers built an algorithm to identify those patients most subject to this impairment. It was developed using clinical and genetic data from 9 cohorts of patients with Parkinson’s from Europe and North America, i.e. roughly 3,200 patients who were followed over a 30-year period, from 1986 to 2016. 

In France, the DIG-PD cohort, sponsored by AP-HP and coordinated by Prof. Jean-Christophe Corvol from the Department of Neurology and Head of the Clinical Investigation Center at Pitié Salpêtrière Hospital, is part of the project, which is called “Drug Interaction With Genes in Parkinson’s Disease – DIG-PD”. In the French cohort, over 400 patients were followed annually for 6 years.

A number of factors were taken into account and analyzed. Age at disease onset, motor and cognitive severity, education level, sex, depression, as well as β-glucocerebrosidase gene mutation status turned out to be the biggest predictors of cognitive impairment and were included in the prediction model developed by the researchers. The study also revealed that education could play a role in the onset of impairment and that this factor could be associated with potential patient “cognitive reserve”.

Based on this data, the clinical score developed by the researchers precisely and reproducibly predicts the onset of cognitive disorders within 10 years of that of Parkinson’s disease. It was developed thanks to the clinical and genetic analysis of the 9 cohorts, i.e. the analysis of over 25,000 associated elements of data.

This tool is of considerable importance for the prognosis of cognitive impairment in patients with Parkinson’s disease. It could also be used to identify more precisely those at high risk of developing such disorders to enable them to anticipate treatment or participate in targeted clinical trials.

Opening of medically assisted procreation to female couples and single women

©Inserm/Lasalle, Bruno – Human egg fertilized

Today, the National Consultative Ethics Committee (CCNE) has decided to open up medically assisted procreation (MAP) to female couples and single women in France.

In a report released on June 19, the National Academy of Medicine has advocated egg preservation for women who wish to do so.

Medically assisted procreation (MAP) involves manipulating an egg and/or sperm to produce fertilization. This makes it possible to overcome certain difficulties in conceiving, without necessarily treating the causes of infertility.

According to the National Institute of Statistics and Economic Studies (Insee), more than 25,000 babies were born by MAP in France in 2014.

It is estimated that one in seven couples consults a doctor because they are having difficulty conceiving a child, according to the Biomedicine Agency. Around one in ten couples is treated for infertility problems, especially by MAP.

Regarding in vitro fertilization, artificial insemination, etc. Inserm researchers are at your disposal to answer your questions.

Read the Inserm information file on MAP (in French)

Read the “Fertility: our future generations in danger” article published in issue no. 36 of  Science&Santé.

FGF 19: a New Factor to Fight Skeletal Muscle Wasting

Skeletal muscle wasting, a process commonly associated with aging but also seen with various chronic diseases (obesity, cancer, kidney failure), situations of immobilization (accidents, post-operative periods) or prolonged weightlessness (astronauts), strongly impacts quality of life. Researchers from the Cardiovascular, Metabolism, Diabetology and Nutrition (CarMeN) laboratory (Inserm/Inra/Université Claude Bernard Lyon 1/Insa Lyon) in Lyon (France), led by Hubert Vidal, Inserm Research Director, in collaboration with the team of Dr. Jérome Ruzzin from the Department of Biology of the University of Bergen (Norway), have discovered that a hormone produced by the intestine called fibroblast growth factor 19 (FGF19), is able to increase skeletal muscle mass in mice and increase the size of human muscle cells in culture. The researchers have also shown that FGF19 protects from muscle wasting in various experimental mouse models, highlighting its potential therapeutic value. These results were published in Nature Medicine on June 26, 2017.

 

Fibroblast growth factor 19 (FGF19), an enterokine (hormone secreted by the intestine) well known for its effects on biliary acid metabolism in the liver, is also able to target other tissues and play a glucose-regulation and lipid-homeostasis role. When investigating the therapeutic potential of FGF19 in metabolic diseases such as type 2 diabetes and obesity, the researchers showed that mice treated with FGF19 for 7 days gained less weight and adipose tissue despite eating more than the untreated mice. Under these conditions, the researchers have shown that skeletal muscle mass and muscle strength increases in the treated animals, thereby identifying for the first time a new role of FGF19.

At the molecular level, the researchers have identified a signaling pathway that mediates the hypertrophic effects of FGF19 in muscle and show that this effect is the consequence of enlarged muscle fiber size, irrespective of the type of fiber.

The researchers then demonstrated the therapeutic potential of FGF19 using various mouse models of muscle wasting, including glucocorticoid-treated mice, genetically-obese mice and aged mice. In each model, they demonstrated the capacity for treatment with FGF19 to maintain or increase muscle mass and strength. “For the first time, this demonstrates a potential use of FGF19 to fight skeletal muscle wasting and possibly also in agronomics to increase livestock muscle mass,” concludes Hubert Vidal and his collaborators. They envisage setting up clinical trials to validate these observations in humans.

Omega-3 Essential for the Brain from Adolescence into Adulthood

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Omega-3 fatty acids are crucial for the brain. Deficiency in these acids can lead to depressive mood. A new study led by Inserm and Inra researchers from Unit 901, “Mediterranean Institute of Neurobiology” (Inserm/Université d’Aix-Marseille) and UMR 1256, “Nutrition and Integrated Neurobiology” (Inra/Université de Bordeaux) reveals the mechanisms of disease that develop in adult mice on a low omega-3 diet since adolescence. It also demonstrates therapeutic approaches. The results have been published in The Journal of Neuroscience.

The rapid growth of western societies has been associated with significant dietary changes. The western diet is low in omega-3 essential fatty acids, which are found in large quantities in oily fish such as salmon as well as in chia seeds, nuts, and soy. This type of diet is a risk factor for mental health disorders such as depression and stress. It is important therefore to gain a better understanding of the mechanisms linking imbalanced diet to mental health disorders.

An Inserm team based at Marseille’s Mediterranean Institute of Neurobiology, in collaboration with an Inra team from Bordeaux, has developed a mouse model of omega-3 deficiency lasting from adolescence into adulthood. The researchers observed that introducing this low omega-3 diet from adolescence onward reduces the level of fatty acids in both the prefrontal cortex (which is involved in complex cognitive functions such as decision-making, executive control, and reasoning) and in the nucleus accumbens (which is involved in the reward system and the regulation of emotions), resulting in anxious behaviors and reduced cognitive function in adulthood.

The researchers then investigated the mechanisms underlying these results, and discovered that two primary forms of neuronal learning (in the synapses, the communication zones between neurons) are altered in the prefrontal cortex and the nucleus accumbens in omega-3-deficientmice.

With a view to developing innovative therapeutic solutions, the scientists showed that two methods were effective in completely restoring both the brain function and the emotional and cognitive behavior of omega-3-deficient adult mice. “We simply had to enhance the capacity of mGlu5 (the receptor for glutamate, the most important neurotransmitter in the central nervous system) in the neurons in order to re-establish communication, or inhibit the degradation of the main cannabinoid naturally secreted by the brain, which controls synaptic memory,” explained Olivier Manzoni and Sophie Layé, the researchers who led the study.
These results suggest that nutrition is a key environmental factor that influences brain function and behavior until adulthood, long after the end of the perinatal period. This study identifies nutritional risk factors for neuropsychiatric disorders, and points toward new therapeutic options for behavioral disorders associated with omega-3 deficiency.

Discovery of a new mechanism involved in the migration of cancer cells

A team of young researchers under the supervision of Guillaume Montagnac, Inserm research leader at Gustave Roussy, in collaboration with the Institut Curie and the Institut de Myologie (Myology Institute), has discovered a new mechanism which facilitates cell migration. On the surface of its membrane, the cell develops multiple small hooks which help it to attach to fibres outside the cell and move along them. This action helps us to understand better how a cell escapes from the tumour mass and moves around the body to form a new focus. This research is published in the 16th June issue of the American journal Science.

Cell migration is a normal process which is essential to life. In oncology it is involved in the formation of new metastases.

“Up till the present, we knew that the cell relied on certain structures to anchor itself within its environment. We have now identified new cell structures known as ‘clathrin-coated pits’, already known to be important for other cell functions. The cancer cell uses them as hooks to attach to other structures in order to move around, These novel structures underlie some 50% of cell adhesion to surrounding structures,” declared  Guillaume Montagnac, Leader of the ATIP-Avenir team, attached to Inserm Unit 1170, Normal and abnormal haematopoiesis”, at Gustave Roussy.  

Recognised in 1964, these clathrin pits are small invaginations of the cell membrane which allow it to renew itself or to help molecules to enter the cells. The cell uses them particularly to supply itself with nutritional material (iron, cholesterol, etc.).

Using fluorescence methods, the researchers succeeded in demonstrating with an aggressive human breast cancer line, known for its marked propensity to metastasise, that the clathrin pits adhere to collagen fibres and surround them. The pit squeezes the fibre, so strengthening its hold and allowing it to move.  

“Our Gustave Roussy team is one of the few with an interest in cell membrane dynamics when the cell is placed in 3D matrices under conditions close to normal ones. By studying these clathrin pits in 3D we were able to see the phenomenon when we were not expecting it,” concluded Guillaume Montagnac.

A breast cancer cell with actin (engine of migration) in red, the clathrin pits (cell hooks) in green and collagen fibres in blue

Summer festivals: no respite for the ears

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With summer comes the festival season, which begins in France on June 21, with the traditional Music Day.

It is also an opportunity to inform festival goers, and young people in particular, about the risk of hearing loss involved, especially at concerts with amplified music.

Hearing is a partnership between the ear and the brain. The ear captures sound waves and transmits the vibrations to the cochlea. The hair cells transform them into electrical signals that are transmitted to the brain via the cochlear nerve. This is where sound is processed, interpreted, and memorized.

The human ear captures sound intensities ranging from 0 to 120 dB, the level at which the structures of the inner ear can be damaged. Very high sound levels can therefore destroy the hair cells and damage the fibers of the cochlear nerve, leading to irreversible hearing loss.

There is, however, a wide range of individual tolerance to noise, with some genes in particular apparently influencing sensitivity to acoustic trauma.

This is why it is highly advisable to wear earplugs and to limit your exposure to high-intensity sounds.

The Inserm researchers working on this topic are available to answer your questions.

Neuronal Self-Defense Against Alzheimer’s Disease

Neurons

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It is known that IGF-1 (insulin-like growth factor) is needed for development and also plays a role throughout the body’s life. Previously, the team led by Martin Holzenberger (Inserm/UPMC Unit 938, Saint-Antoine Research Center) has shown that this hormone is involved in longevity and in Alzheimer’s disease. The team has recently conducted further research on IGF-1 and the response of neurons to this kind of neurodegeneration. These new results have been published in Brain.

Secreted by the liver and stimulated by growth hormone, IGF-1 (insulin-like growth factor) is able to stimulate the growth and maturation of bone and other organs, regulate energy metabolism, and control the aging of the whole body. In its previous work, the Holzenberger team had demonstrated in mice that when the number of IGF-1 receptors present in the neurons was reduced by genetic mutation, the level of IGF-1 in the blood decreased and the mice had a longer lifespan.

In this new study, published in the journal Brain, Martin Holzenberger and Saba Aïd have conducted further research on IGF and Alzheimer-type neurodegeneration. These researchers first show that inhibiting IGF-1 receptors in the neurons of mice led to a much later presentation in their brains of the signs of lesions typical of Alzheimer’s disease, in particular amyloid plaques and neuroinflammation. Reduced cognitive impairment was also observed in the same mice. Importantly, the team has shown that suppression of the IGF receptor leads to a series of neuroprotective effects. This confirms their previous results concerning prolonged lifespan.

This new study reveals a self-defense system used by the neurons when they suffer the kind of harmful attack typical of Alzheimer’s disease. In fact, the gene families activated in Alzheimer neurons and in the neurons deprived of the IGF-1 receptor are essentially the same. This suggests that, in the early stages of the disorder, a neuron faced with an Alzheimer-type disease is able to instigate a process of self-defense of its own accord (this is called an endogenous response). This endogenous response is not however sufficient over the long-term in a brain affected by Alzheimer’s, and effective protection against the disease requires total suppression of IGF-1 receptors in the neurons. It is not yet known at what point this neuronal response ceases to be effective against the disease.

These results enable a better understanding of the mechanisms of Alzheimer-type neurodegeneration, a disease that affects nearly one million people in France. This work is crucial, suggesting a paradigm shift concerning the role of IGF-1 in the progression of age-related neurodegenerative diseases: it is not stimulation, but rather long-term blocking of IGF signaling that would improve neuronal function and neuroprotection.

Ultimately, this work will lead to the development of new therapeutic and preventive targets in the fight against Alzheimer’s disease. However, the researchers emphasize that there is still a long way to go. “We cannot inhibit the IGF-1 receptor throughout the entire body because this hormone is essential for other cells. However, specifically targeting the neurons is a possibility. In any case, we have to better understand how to benefit from the good effects of IGF while preventing its less beneficial effects. “, concludes Martin Holzenberger.

11 childhood vaccines soon to be mandatory?

On Friday, June 16, 2017, the French Minister of Solidarity and Health said, in an interview with French daily Le Parisien, that she was considering “making the eleven vaccines intended for children mandatory, for a limited period of time”. Today, only childhood vaccinations against diphtheria, tetanus and poliomyelitis are mandatory and eight others (against whooping cough, hepatitis B and measles, among others) are recommended.

Vaccination involves protecting an individual against a disease by stimulating his or her immune system. It is the most effective means of preventing and even eradicating many infectious diseases. However, in France, skepticism is gaining ground and we see certain diseases reappearing that up until now had virtually disappeared. This is particularly the case for measles, of which 189 cases were reported between January 1 and April 30, 2017, according to French health surveillance institute InVS.

Should we get vaccinated? Should we get our children vaccinated? How does a vaccine work? Does vaccination really protect us?

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The book “Vaccination : agression ou protection ? [Vaccination: aggression or protection?]” (published in French), as part of the “Choc Santé” collection, answers these questions and many others. It is written by Annick Guimenazes, Inserm researcher at the Marseille-Luminy Immunology Center (CIML) and Marion Mathieu, PhD in biology and ESPCI-ParisTech engineer.

Let There be Healing Light!

Vitesse lumière

© Copyright Inserm/Decrouy, Xavier

Numerous light-related technological innovations were presented at the Onlylight trade fair, which took place in Lyon from June 13 to 15. This year a number of public health issues were discussed, including “illuminating for health”, how to implement “good light habits”, and how to “illuminate for learning without risking myopia”.

Claude Gronfier, an Inserm chronobiologist who participated in the exhibition, carries out research into light as a regulator of biological rhythms. He emphasized the need to control “poor light exposure habits”, like the light generated by screens, in particular, and that can upset the biological clock.

Read the press release “Dimly lit working environments : correcting your body clock is possible!

Another topic discussed during the exhibition was “illuminating for learning”. At a time when the number of nearsighted people aged 12 to 54 is doubling in Europe, and tripling among young people in some Asian countries, Vincent Daien, an Inserm researcher (Inserm Unit 1061) and ophthalmologist at the University Hospital of Montpellier, is investigating the risk factors associated with myopia. Beyond the genetic factors associated with myopia, the environment—more precisely, prolonged exposure to natural light—may also play a role. It is thought to activate the retina’s production of dopamine, a neurotransmitter that controls eye growth.

Read the article [in French] “Myopia: how to stop the epidemic ” published in Science&Santé no. 25.

Finally, as part of the “healing with light” topic, optogenetics, which first emerged in the 2000s, appears to be a promising method for restoring vision in patients with retinal degeneration. This technique consists of inserting a gene into the neurons to make them more sensitive to light.

Eric Burguière, an Inserm researcher (Inserm Unit 1127, Brain and Spinal Cord Institute), also uses this technique for treating OCD.

See [in French]: “Optogenetics, from algae to the retina“.

Also read the press release “Optogenetics is proving to be highly promising in the treatment of OCD“.

Let There be Healing Light!

Vitesse lumière

© Copyright Inserm/Decrouy, Xavier

Numerous light-related technological innovations were presented at the Onlylight trade fair, which took place in Lyon from June 13 to 15. This year a number of public health issues were discussed, including “illuminating for health”, how to implement “good light habits”, and how to “illuminate for learning without risking myopia”.

Claude Gronfier, an Inserm chronobiologist who participated in the exhibition, carries out research into light as a regulator of biological rhythms. He emphasized the need to control “poor light exposure habits”, like the light generated by screens, in particular, and that can upset the biological clock.

Read the press release “Dimly lit working environments : correcting your body clock is possible!

Another topic discussed during the exhibition was “illuminating for learning”. At a time when the number of nearsighted people aged 12 to 54 is doubling in Europe, and tripling among young people in some Asian countries, Vincent Daien, an Inserm researcher (Inserm Unit 1061) and ophthalmologist at the University Hospital of Montpellier, is investigating the risk factors associated with myopia. Beyond the genetic factors associated with myopia, the environment—more precisely, prolonged exposure to natural light—may also play a role. It is thought to activate the retina’s production of dopamine, a neurotransmitter that controls eye growth.

Read the article [in French] “Myopia: how to stop the epidemic ” published in Science&Santé no. 25.

Finally, as part of the “healing with light” topic, optogenetics, which first emerged in the 2000s, appears to be a promising method for restoring vision in patients with retinal degeneration. This technique consists of inserting a gene into the neurons to make them more sensitive to light.

Eric Burguière, an Inserm researcher (Inserm Unit 1127, Brain and Spinal Cord Institute), also uses this technique for treating OCD.

See [in French]: “Optogenetics, from algae to the retina“.

Also read the press release “Optogenetics is proving to be highly promising in the treatment of OCD“.

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