The image shows the brain region where demyelination is typically induced. The red cells correspond to all of the microglial cells with inflammatory properties when demyelination has just occurred. If the spontaneous regeneration process of myelin is effective, their inflammatory nature then diminishes in favor of an anti-inflammatory and pro-regenerative nature. The green cells are a subpopulation of these microglial cells that become anti-inflammatory.© Zahaf et al.

Multiple sclerosis (MS), an autoimmune disease for which there is no cure as yet, affects three women for every one man. Faced with this observation, scientists are studying the role of the sex hormones in order to better understand the differences between men and women in relation to the disease and its progression. A team led by Inserm researcher Elisabeth Traiffort in Unit U1195 “Diseases and hormones of the nervous system” (Inserm/Université Paris-Saclay) has recently shown that although male hormones – androgens – are present at very low levels in women, their presence is necessary to regenerate the myelin sheath which is destroyed in MS. These findings have been published in Nature Communications.

Multiple sclerosis (MS) is an autoimmune disease. In its most common form, relapsing-remitting MS[1], which accounts for 85% of cases, it manifests as inflammatory flares during which the patient’s immune cells attack and destroy the myelin in the central nervous system (see box). This phenomenon causes lesions that lead to motor, sensory, and visual disorders.

These symptoms are reversible at the beginning of the disease, thanks to the spontaneous repair of the destroyed myelin. However, over time, symptoms gradually become irreversible, reflecting the failure of the repair process, marking entry to the progressive phase of the disease. While current treatments reduce the frequency and severity of the inflammatory flares, thereby improving patient quality of life, they remain ineffective against the progression of the disease.

Current research aims to gain a better understanding of the mechanisms of the disease and develop new therapeutic avenues that would prevent patients from entering the progressive phase, particularly by promoting the regeneration of myelin. Inserm researcher Elisabeth Traiffort and her team at the “Diseases and hormones of the nervous system” unit (Inserm/Université Paris-Saclay) are working for example to better understand the differences between women and men in MS, in order to determine whether it could be beneficial or even necessary to adapt therapeutic management to the patient’s sex. Remember that the disease is predominantly female, since three out of every four patients are women.

Investigating the Role of Androgens in Women

While the hormonal environments of men and women are very different, they cannot be restricted to high androgen levels in men and fluctuating levels of estrogen and progesterone in women. We know that men also produce estrogens, particularly in the brain where an enzyme is found that converts androgens into estrogens, while women produce small amounts of androgens. It was on this last aspect that Inserm researcher Traiffort and her colleagues focused their latest study.

Research has already shown that androgens protect neurons in the central nervous system of men with relapsing-remitting forms of MS and induce the regeneration of myelin sheaths destroyed in males, in animal models of the disease. But what is the role of the small amounts of androgens that are also found in the central nervous system of women? Can these androgens present at much lower levels than in men also impact the progression of the disease in female patients?

The scientists worked with animal models of the disease and also on tissues from patients supplied by organ donation banks. They first showed that in regions where myelin is destroyed, the AR receptor that enables androgens to transmit their signal is strongly expressed in the nervous tissue of women with MS, as it is in the female mouse models of the disease. This observation would suggest the existence of an essential role of androgens in the demyelinated tissue of the affected women.

In accordance with this hypothesis, the scientists have shown that despite only being present in small quantities in female mice, androgens still have a beneficial effect on the optimal regeneration of the destroyed myelin. Indeed, when the signals transmitted by the androgens are completely absent, this regeneration is greatly reduced.

Finally, other findings in animals and in human tissues suggest that these same androgens also have major anti-inflammatory effects on demyelinated nerve tissue in females unlike what is observed in males. The beneficial effects of androgens in women with MS could therefore also be linked to a decrease in the level of local inflammation, in areas where myelin is destroyed. This finding is interesting if we consider the current hypothesis that disease progression could be closely associated with the inflammatory cells residing in nervous tissue.

“While the low levels of androgens detected in women could point to a minor role for these hormones in the disease, we show that this is not the case. Our data suggest the use of appropriate doses of androgens in women with MS and the need to consider the patient’s sex when treating this and in all likelihood other conditions involving the destruction of myelin in the central nervous system,” concludes Traiffort.

This research was carried out with the support of the ARSEP Foundation.

[1] There are two active forms of the disease. The most common is the relapsing-remitting form, which accounts for 85% of MS cases at diagnosis. It is characterized by flares, in which symptoms appear within a few hours or days, often associated with the extreme and unusual fatigue suggestive of the diagnosis. Then the symptoms disappear completely or partially within a few weeks. The “primary” progressive form accounts for only 15% of cases. It is characterized by the slow and continuous worsening of the neurological symptoms, with no flares or remission.

Images showing the human brain anatomy in two axial slices obtained by MRI (left), then the corresponding molecular images showing a larger number of mGluR5 receptors in the brain of an adult subject with ASD (right) compared to a control subject (middle). © Laurent Galineau

While great progress has been made in recent years in the understanding of autism spectrum disorder (ASD), its underlying molecular mechanisms remain fairly poorly documented. Several hypotheses have been put forward regarding the possible dysfunction of certain neurotransmitters in the brain, but rigorous scientific studies are still lacking in order to validate them. In a new publication, researchers from Inserm and Université de Tours at the Imaging & Brain unit have shown that specific receptors of glutamate, one of the most important neurotransmitters in the nervous system, are expressed in large quantities in the brains of adults with ASD. However, this overexpression of the receptors does not occur at earlier stages of development. The study, sponsored by Tours university hospital and published in Molecular Psychiatry, paves the way for a better understanding of ASD to help refine therapeutic research.

Autism spectrum disorder (ASD) is caused by neurodevelopmental particularities and affects around 700 000 people in France. This term brings together a large variety of clinical realities and as such a large variety of specific individual needs. The development of treatments that specifically target severe autism-related disorders has long been hampered by a piecemeal understanding of the underlying molecular and genetic mechanisms.

At present, those affected may therefore use treatments for potential comorbidities such as sleep disorders or epilepsy, but there is no therapeutic solution to improve behavioral disorders or the associated alterations in social interactions.

One avenue put forward to explain the development of ASD is dysfunction of glutamate – the main excitatory neurotransmitter of the central nervous system. Studies have recently suggested that glutamate receptors called mGluR5 (see inset) are expressed in increased quantities in certain brain regions in people with ASD.

Compensatory mechanism

In order to further understand the molecular mechanisms of ASD, Frédérique Bonnet-Brilhault’s team at the Imaging & Brain unit (unit 1253 Inserm/Université de Tours) sought to better characterize glutamate dysfunction in the brains of adults with ASD.

They started by quantifying the glutamate levels in the cingulate cortex of 12 adults with ASD and 14 adults without ASD (referred to as “control” participants), using several methodological approaches. Next, they looked at the expression of the mGluR5 receptors in the participants’ brains.

The scientists observed that the glutamate levels varied widely in the adults with ASD. However, they found that the quantity of mGluR5 receptors expressed was particularly high in the brains of all these individuals, compared to the controls.

Then, to better understand how the quantity of mGluR5 varies at different stages of development, the team also quantified these receptors in the brains of young rats, grouped into animal models of ASD and “control” animals.

Their analyses show that the quantities of mGluR5 in the “ASD rats” and the “control rats” did not differ during childhood. However, in adolescence, larger quantities of these receptors were present in certain brain regions of the “ASD rats”.

The fact that mGluR5 receptors are expressed in large quantities in the adult human participants with ASD, but not at the earliest stages of development in the animal models, suggests that the overexpression of these receptors is not a cause of this disorder, but rather a consequence that emerges progressively throughout life.

“Our findings suggest that the changes in the quantity of mGluR5 receptors expressed during development could be a compensatory mechanism for the early dysfunction in the brain communication systems, rather than a primary element that causes the development of ASD,” explains Bonnet-Brilhault.

At a time when research in adults with ASD is a real priority, this work points to the need to understand the development trajectory of each individual with ASD to distinguish the causes of the adaptation mechanisms.

Fluorescent marking of the Tau protein in a human cell hNT; the Tau protein, has a role in Alzheimer’s disease, particularly in its familial forms ©Inserm/U837

An international consortium has identified rare variants in two new genes that markedly increase the risk of developing Alzheimer’s disease (AD). The work was led by two research groups in France (headed respectively by Gaël Nicolas, Rouen and Jean-Charles Lambert, Lille) and a group in the Netherlands (headed by Henne Holstege, Amsterdam). The new results provide a better understanding of the genetics of AD and open up new research themes on more relevant in vitro and in vivo models. The consortium’s findings are also likely to catalyze the development of new strategies for treating AD. The results were published in the journal Nature Genetics in November 2022.

As the most prevalent neurodegenerative disease, AD affects about 55 million people across the world – 4% of whom are under the age of 65. It is a complex, multifactorial disease caused by interactions between many genetic and non-genetic predisposing factors. Given that AD has a large genetic component, the characterization of these factors is a major challenge for basic research and therapeutic development.

Our knowledge of the involvement of common gene variants (those present in more than 1% of the general population) in AD has improved enormously over recent last years, through the discovery of 75 chromosomal/gene regions associated with the risk of developing the disease. However, the role of rare or even very rare variants has not been extensively studied. In fact, these variants might contribute significantly to genetic predisposition to AD as a result of their direct biological effects and their great diversity.

Two new genes identified

It is in this context that a large international consortium has identified a number of rare mutations in two genes that markedly increase the risk of developing AD. Along with their European and American colleagues, researchers from the INSERM, the Pasteur Institute in Lille, Lille University Medical Centre, the University of the Lille, the University of Rouen Normandy, and the French National Reference Centre for Patients with Early-Onset Alzheimer’s Disease (Centre national de référence pour les malades Alzheimer jeunes (CNRMAJ)) at Rouen University Medical Centre and from the Amsterdam University Medical Center performed a high-throughput sequencing study of 16,032 AD patients and 16,522 controls. This sequencing approach provides the most precise possible picture of an individual’s genetic variants.

By specifically studying the DNA regions that code for the proteins in our body (the exons), the researchers were able to map deleterious, rare variants that might change the corresponding proteins’ biological functions. The researchers confirmed the pathological role of rare variants in the SORL1, TREM2 and ABCA7 genes and, for the first time, highlighted potentially pathological variants in two other genes (ATP8B4 and ABCA1). The potentially pathological role of variants in one other gene (ADAM10) remains to be confirmed.

Better understanding the mechanisms of AD

The identification of the effects of these rare variants should provide a better understanding of the mechanisms that underlie AD.

In fact, two disease pathways have already been well documented in the AD brain: the accumulation of beta-amyloid peptides, and changes in and the accumulation of Tau protein. Importantly, some of the genes studied by the researchers are involved in the production or aggregation of beta-amyloid peptides – confirming the latter’s central role in the development of AD. Furthermore, the present research confirmed previous reports of the importance of microglial cells (cells that help to remove waste from the brain) in AD.

These results from the largest yet sequencing study in this field constitute a major step forward in our understanding of the genetics of AD and the underlying biological mechanisms. Furthermore, these results will open up new research themes on more relevant in vitro and in vivo models in which the newly identified genes are knocked out. By continuing this work, the consortium’s scientists’ also hope to foster the development of new strategies for treating AD.

©AdobeStock

Meditation as a tool to prevent dementia and improve the mental health and well-being of elderly people is one of the avenues explored by the European Medit-Ageing research program, coordinated by Inserm. As part of this program, researchers from Inserm and Université de Caen Normandie, in collaboration with French and European teams, observed the impact of 18 months of meditation training on certain brain structures involved in regulating attention and emotions in healthy people over 65. While their findings, to be published in JAMA Neurology, show a positive impact on attentional and socio-emotional regulation capacities, they do not show any significant benefits of meditation on the volume and functioning of the brain structures studied, in comparison to control groups. However, they do call for further research to study the brain as a whole, over longer time periods, and with more participants.

In order to prevent the onset of dementia in elderly people, recent intervention strategies have been multidisciplinary and focused on lifestyle improvements. These include cognitive stimulation, physical activity, a healthy diet, and cardiovascular recommendations. However, there are no dedicated preventive interventions for psycho-affective factors such as depression, stress, and anxiety.

Mental training aimed at regulating stress and attention, such as mindful meditation, has proven to be beneficial in managing the cognitive and emotional aspects of aging, particularly to reduce stress, anxiety, and depression.

Recent research has reported that the insula and anterior cingulate cortex are brain regions particularly sensitive to meditation training. These interconnected regions are involved in self-awareness and in the processing and regulation of attention, emotions, and empathy. In young adults, meditation has already shown its capacity to structurally (e.g. in terms of volume) and functionally modify these structures, particularly in the brain of meditation experts with several thousand hours of practice under their belts.

The insula and anterior cingulate cortex are particularly sensitive to aging. It has been shown that in elderly people who are experts in meditation, gray matter volume and glucose metabolism (a physiological process essential for good brain function) were higher than in people who do not meditate.

Meditation could therefore be an interesting approach to preserve brain structures, functions, and cognitive capacities, and by extension, prevent dementia.

A team of researchers from the European Medit-Ageing research group, led by Inserm Research Director Gaël Chételat from the Physiopathology and Imaging of Neurological Disorders laboratory (Inserm/Université de Caen Normandy), in collaboration with teams from Lyon Neuroscience Research Center (Inserm/CNRS/Université Claude Bernard Lyon 1/Université Jean-Monnet-Saint-Etienne), University College London, University of Liège and University of Geneva, looked at the potential physiological, cognitive, and emotional benefit of meditation in elderly individuals.

In the Age-Well clinical trial involving 136 participants aged 65 or older with no known diseases, the researchers measured the impact of an 18-month meditation intervention on tissue volume and perfusion (physiological process of supplying an organ with nutrients and oxygen necessary for its metabolism) of the insula and anterior cingulate cortex. They also looked at specific cognitive and socio-affective parameters.

The participants were assigned to three groups in order to compare the potential benefit of meditation with different types of interventions. The first group followed the meditation intervention protocol (mindfulness meditation and loving kindness and compassion meditation), the second group (the “active control” group) followed a period of English-language training, and the third group (the “passive control” group) did not follow any intervention.

After 18 months of intervention, the researchers saw no significant changes in volume or perfusion of the cingulate cortex or insula in the meditation group compared to the control groups.

“The fact that no anatomical differences were observed between these two groups could indicate that while meditation can modify the volume of younger and more plastic brains, 18 months of meditation training are not enough to modify the effects of aging,” analyzes Chételat. “In addition, while the results of the volume measurement are strictly negative, those of the perfusion show a trend in favor of meditation that could be interesting to explore over a longer intervention time and/or with a larger population sample,” specifies the researcher.

The research team will therefore conduct a 4-year follow-up of the participants, to investigate potential long-term effects.

In contrast, significant differences were observed in behavioral measures between the meditation group and the English-learning group, with improved regulation of attention and socio-emotional capacities in the meditation group participants. “Here the practice of meditation is showing its real benefit on the mental health of elderly people, with a significant improvement in parameters specific to well-being and fulfilment, but also to the maintenance of attentional and socio-emotional capacities, as reported by participants,” adds Antoine Lutz, responsible for the study’s meditation component.

More specific measurements and analyses will be conducted within the Age-Well trial to improve the understanding of these mechanisms. These analyses could be used to identify the measures which are most sensitive to meditation and to study the mechanisms behind its effects.

Some GnRH neurons (green) express NOS1 (red) during their migration from the nose to the brain during fetal life. The GnRH + NOS1 double-labeled cells appear in yellow. © Vincent Prévot/Inserm

Children born prematurely have a higher risk of not just cognitive and sensory disorders, but also infertility in adulthood. In a new study, a team of researchers from Inserm, University Hospital Lille and Université de Lille at the Lille Neuroscience and Cognition laboratory has opened up interesting avenues for improving their prognosis. By conducting research into a rare disease known as congenital hypogonadotropic hypogonadism, the scientists have discovered the key role of an enzyme and the therapeutic potential of the neurotransmitter that it synthesizes – nitric oxide – in reducing the risk of long-term complications in the event of prematurity. Their findings are described in Science Translational Medicine.

Congenital hypogonadotropic hypogonadism is a rare disease characterized by delayed puberty or the complete absence of puberty in adolescence, leading to infertility. Some forms of the disease are caused by a lack of production of GnRH, a hormone produced in the brain that remotely controls the development and functioning of male and female gonads through various intermediaries.

The team of Vincent Prévot, Inserm Research Director, specializes in the dialogues between the brain and the rest of the body.

Here the scientists looked at nitric oxide, a neurotransmitter that regulates the activity of GnRH neurons, and more specifically NOS1, the enzyme that synthesizes it.

“Nitric oxide suppresses the electrical activity of the GnRH neurons and modulates the release of this hormone, so NOS1 dysfunction was not ruled out as being the cause of congenital hypogonadotropic hypogonadism,” explains Prévot, the principal coordinator of the study.

To go further, his team collaborated with a laboratory in Lausanne (Switzerland) which has a cohort of 341 patients with this disease. Using DNA samples, they looked for the presence of rare mutations on the gene encoding the NOS1 enzyme and found five different mutations that could explain the disease. Some of the individuals concerned had, in addition to fertility problems, sensory and cognitive disorders (intellectual disability or loss of hearing or smell).

An application in the context of preterm birth?

The next stage of the study consisted of developing a NOS1-deficient mouse model[1] in order to better understand the role of this enzyme. The researchers encountered puberty problems, as well as sensory and neurological alterations, as observed in humans with congenital hypogonadotropic hypogonadism. They also saw an exacerbation of minipuberty in these animals. Minipuberty occurs in all mammals just after birth (between one and three months of age in humans) and triggers an initial brain activation of the axis controlling reproduction prior to the “real” puberty in adolescence.

Here the researchers observed that the peak of the sex hormone associated with this minipuberty was twice as high in NOS1-deficient mice.

“This caught our attention because premature infants also tend to present a more intense minipuberty than usual. And the greater the prematurity, the greater the risk of neurosensory and mental complications in adulthood,” reiterates Konstantina Chachlaki, Inserm researcher and first author of the study.

Based on these observations, the researchers tested the administration of nitric oxide in NOS1-deficient mice just after their birth, during the minipuberty period. What they saw was the reversal of all the symptoms they had developed: the puberty problems and sensory and neurological disorders disappeared, and this was over the long term, for the remainder of their lives.

An ongoing clinical trial

These promising findings could help to improve the care of preterm infants. Nitric oxide is also given to some children born prematurely, to facilitate the opening of the bronchi in the event of breathing difficulties.

“In light of this consistency of observations and practices, we decided to set up a clinical trial to test the effect of nitric oxide in preterm infants by studying reproductive and neurosensory parameters,” explain Prévot and Chachlaki, who are coordinating a European project dedicated to…“Administering nitric oxide at birth could reduce the risk of reproductive, sensory and intellectual complications in children born prematurely. This is what we are going to try to verify in the wake of these astonishing discoveries in mice,” they continue.

The miniNO trial was launched at University Hospital Lille in partnership with a hospital in Athens (Greece). The objective is to verify whether children receiving this treatment go on to experience normal minipuberty and puberty, and whether they develop fewer sensory and neurological complications compared to premature infants who were not administered nitric oxide at birth.

[1] In which the gene encoding the NOS1 enzyme was disactivated.

Here, the pump, which is similar in aspect to a band aid, is being placed on a patient’s arm. This medical device allows for a pulsatile delivery of GnRH, under the skin. © 2022 CHUV Eric Deroze

An Inserm team at the Lille Neuroscience & Cognition laboratory (Inserm/Université de Lille, Lille University Hospital) has joined forces with its counterparts at Lausanne University Hospital (CHUV) to test the efficacy of GnRH injection therapy in order to improve the cognitive functions of a small group of patients with Down syndrome. First the scientists revealed a dysfunction of the GnRH neurons in an animal model of Down syndrome and its impacts on the cognitive function impairment associated with the condition. Then a pilot study testing GnRH pulsatile injection therapy was conducted in seven patients. The results were promising : the therapy led to improved cognitive function and brain connectivity. This study has been published in Science.

Down syndrome, also known as trisomy 21, affects around one in 800 births and results in a variety of clinical manifestations, including decline in cognitive capacity. With age, 77% of people with the condition experience symptoms similar to those of Alzheimer’s disease. Gradual loss of the ability to smell, typical of neurodegenerative diseases, is also commonly encountered from the prepubertal period, with potential sexual maturation deficits occurring in men.

GnRH-secreting neuron dysfunction identified in Down syndrome

Recent discoveries have suggested that the neurons expressing gonadotropin-releasing hormone (GnRH) – which is known for regulating reproduction via the hypothalamus – could also act on other brain regions with a potential role in other functions, such as cognition.

With this idea in mind, the Lille Neuroscience & Cognition laboratory team led by Inserm Research Director Vincent Prévot studied the mechanism which regulates GnRH in mouse models of Down syndrome.

The laboratory demonstrated that five strands of microRNA regulating the production of this hormone – which are found on chromosome 21 – are dysfunctional. This supernumerary chromosome then leads to abnormalities in the neurons that secrete GnRH. These findings were confirmed at both genetic and cellular levels. The Inserm scientists were able to demonstrate that the progressive cognitive and olfactory deficiencies seen in the mice were closely linked to dysfunctional GnRH secretion.

Restoring GnRH production to restore cognitive function

The Inserm scientists were then able to demonstrate that restoring physiological GnRH system function restores cognitive and olfactory functions in trisomic mice.

These findings in mice were discussed with Nelly Pitteloud, professor at the Faculty of Biology and Medicine of the University of Lausanne and head of the Endocrinology, Diabetology, and Metabolism Department at CHUV. Her research focuses on congenital GnRH deficiency, a rare disease which manifests by the absence of spontaneous puberty. These patients are given pulsatile GnRH therapy in order to reproduce the natural pulsatile rhythm of this hormone’s secretion, in order to induce puberty.

The researchers therefore decided to test the efficacy of pulsatile GnRH therapy on cognitive and olfactory deficits in trisomic mice, following a protocol identical to that used in humans. After 15 days, the team was able to demonstrate the restoration of olfactory and cognitive functions in mice.

Pulsatile GnRH therapy improves cognitive function and neural connectivity in a small patient group

The next stage for the scientists and doctors involved a pilot clinical trial in patients to evaluate the effects of this treatment. Seven men with Down syndrome, between 20 and 50 years of age, received one subcutaneous dose of GnRH every two hours for 6 months via a pump placed on the arm. Cognition and olfactory tests as well as MRI exams were performed before and after the treatment.

From the clinical viewpoint, cognitive performance increased in 6 of the 7 patients with better three-dimensional representation, better understanding of instructions, improved reasoning, attention, and episodic memory.

One of the most significant examples concerns the change in the representation of 3D objects shown by the drawing above. On the left, a cube drawn before the start of treatment. On the right, a bed drawn 6 months later by one of the participants.

These data suggest that the treatment acts on the brain by strengthening the communication between certain regions of the cortex.

“Maintaining the GnRH system appears to play a key role in brain maturation and cognitive functions,” explains Prévot. “In Down syndrome, pulsatile GnRH therapy is looking promising, especially as it is an existing treatment with no significant side effects,” adds Pitteloud.

These promising findings now justify the launch of a larger study – with the inclusion of women – to confirm the efficacy of this treatment in people with Down syndrome, but also for other neurodegenerative conditions such as Alzheimer’s disease.