2024-03-18 15:34:27
Difficulty concentrating, planning, immediate memory problems… People suffering from long Covid very often complain of cognitive problems, which are added to the many other symptoms from which they suffer. Four years following the first wave of the pandemic, research into the causes of this “brain fog” is progressing.
We now know that the SARS-CoV-2 coronavirus which causes the disease is notably capable of penetrating our brain and destroying certain brain cells. The infection of a small population of neurons particularly worries scientists: these are GnRH neurons, which play an essential role not only in fertility, but also in the neurodevelopment of children.
Research director and head of the Inserm “Development and plasticity of the neuroendocrine brain” laboratory, Vincent Prévot explains to us why their destruction is worrying.
The Conversation: Recent work has shown that infection with the SARS-CoV-2 coronavirus, even when accompanied by only moderate symptoms, is associated with cognitive impairment. Today, there is no longer any doubt that SARS-CoV-2 infection is harmful to the brain?
Vincent Prévot: Several studies have shown that SARS-CoV-2 infection has effects on the brain. One of the most spectacular, published in the journal Nature, shows that it is accompanied by a reduction in brain volume and cognitive loss, which is more significant as people become older. And this, even in people who have not had a severe form.
With our collaborators, we have for our part demonstrated that the coronavirus was the cause of microruptures of cerebral blood vessels, sometimes very numerous. These might lead to the death of certain neurons and have consequences on brain aging.
Various studies have also shown that the latter seems to be accelerated in certain patients. We ourselves have observed the very rapid deterioration, following infection by the coronavirus, of the condition of a patient suffering from vascular dementia at an early stage.
The Conversation: With your collaborators, you were particularly interested in the effects of infection on a very specific category of neurons, GnRH neurons. Could you explain to us what it is?
VP : These neurons produce a hormone called GnRH (Gonadotropin-Releasing Hormone). Scattered throughout our brain, they are very few in number: it is estimated that there are only around 10,000, including 2000 in the hypothalamus. Compared to the 100 billion other neurons, this is extremely few.
However, these neurons, which are found in all vertebrates, are essential. In fact, they control reproductive capacities in particular. GnRH neurons become activated at puberty. The hormone they produce at this time passes into the blood and reaches the pituitary gland, a small gland located under the brain.
This then releases two other hormones, LH and FSH, which will act on the ovaries and testes, causing their growth and triggering the production of sperm and eggs. LH and FSH are also involved in the secretion of estrogen and testosterone.
Therefore, from the hypothalamus, GnRH neurons control all processes associated with reproductive functions: puberty, the acquisition of secondary sexual characteristics and, in adulthood, fertility.
But that’s not all. These neurons also play an essential role in the neurodevelopment of children. Indeed, one week following birth, a first activation of GnRH neurons occurs. Transitory, it is the origin of a “mini-puberty” which lasts approximately six months, before these neurons go into hibernation while awaiting adolescent puberty. However, this first step is fundamental for the development of children’s cognitive abilities.
The Conversation: How did you make the link between these neurons and Covid-19?
Vincent Prévot: At the start of the pandemic, we were troubled by the fact that the majority of victims of severe forms of Covid-19 were men. However, we know that sexual dimorphism is partly controlled by the brain, via the hypothalamus and GnRH neurons.
In addition, many of these patients were overweight, even obese, or diabetic. An observation which, once more, raised suspicion of an involvement of the hypothalamus, because this structure, which is involved in numerous physiological mechanisms (growth, hunger and thirst, circadian rhythm, temperature regulation, metabolism, etc.), also plays a role in obesity and diabetes.
We therefore quickly wondered regarding the possibility that the virus might cross the blood-brain barrier, which protects the brain from invaders. At the time, few people were willing to admit it, because SARS-CoV-2 was mostly considered a lung virus.
However, we have proven that the virus can indeed access the brain, and moreover in various ways.
The Conversation: How does the virus manage to reach these neurons?
VP : The mucosa of the nasal cavity (the olfactory epithelium) is one of its entry points. You should know that GnRH neurons are not born in the brain, but in the nose, during embryonic development. They only migrate into the brain in a second step.
However, we have discovered in recent years that even once installed in the brain, GnRH neurons maintain a physical connection with the olfactory epithelium, via their nerve fibers. This is where the virus goes.
Photomicrograph illustrating SARS-CoV-2 infection (the S protein of the virus is detected in white) in olfactory neurons expressing the olfactory marker protein (OMP, in red), in the human nasal mucosa. Florent Sauvé – DR, Author provided (no reuse)
What’s more, in the nasal mucosa there is another type of neurons, the olfactory neurons, whose role is to detect odorous molecules. Their nerve fibers are in contact with the olfactory bulb located in the brain (the structure that processes information related to smells). We demonstrated that the SARS-CoV-2 coronavirus was capable of infecting these neurons (this is why one of the symptoms is the loss of smell, or anosmia), which therefore constitute a second gateway to entrance.
But the virus also has a third route of access to the brain. Our German colleagues have indeed discovered that the coronavirus destroys the cells that line the inside of cerebral blood vessels. These then lose their tightness, damaging the blood-brain barrier supposed to insulate the brain, and allowing the virus to “leak”.
Finally, in certain places in the hypothalamus, the blood-brain barrier is interrupted, to allow the neurohormones produced by this brain structure, such as GnRH, to pass freely into the blood. We can therefore imagine that the virus, present in the blood, might also pass through there. We have also shown that it also infects cells called “tanycytes”, which regulate in particular the frequency of GnRH secretion in the blood…
The entry of the virus into the brain is not without consequences: when we performed autopsies on patients who died from the disease, we discovered that their GnRH neurons had been killed or were dying. GnRH was therefore no longer produced at sufficient levels. However, in the current state of knowledge, we consider that these neurons do not regenerate.
The Conversation: What are the consequences for patients?
VP : Various scientific reports have reported very low testosterone levels in patients with Covid-19. Furthermore, many men with long Covid complain of a drop in libido or erectile problems.
We also observed this in the cohort of 47 men that we analyzed during our latest work. The dosages that we carried out also indicate that this drop in testosterone is not due to a problem with the sexual organs, but rather to a deficit in GnRH production in the hypothalamus (this is what we called hypogonadotropic hypogonadism.
Photomicrograph illustrating infection by SARS-CoV-2 (the S proteins, which allow the virus to enter cells, are detected in green) of a neuron producing the reproductive neurohormone (GnRH, in red), and which expresses the virus receptor (ACE2 receptor with which the virus S protein interacts, in white) in the human hypothalamus. Scale bar: 50 micrometers. Florent Sauvé – DR, Author provided (no reuse)
But the problems posed might be bigger than just a drop in libido. In this same study, we had already noted a higher mortality rate in people in intensive care whose gonadotropic axis was altered. But we also know that a GnRH deficiency can result in cognitive disorders.
Thus, certain treatments for prostate cancer or endometriosis, which consist of suppressing the GnRH axis, are accompanied by cognitive loss in certain people, as well as an increased risk of developing Alzheimer’s disease. later.
However, in our cohort, patients who presented abnormal hormonal dosages resulting in a drop in testosterone were more likely to report memory or attention problems, or difficulty concentrating. These results must still be confirmed in larger cohorts also including women.
The Conversation: Should we fear that the effect of the virus will be felt in the long term?
VP : We can legitimately ask the question of the consequences of SARS-CoV-2 infection on the human brain. How will the brains of infected people age? Will the cognitive disorders that patients complain of persist? Will we see an increase in cases of dementia in the decades to come?
This is all the more worrying as effects on the brain have been observed, including in people suffering only moderate symptoms.
This is not to be alarmist, of course. But the case of the Spanish flu epidemic of 1917 should make us think: a large part of the survivors had developed Parkinson’s disease, for reasons that remain to be elucidated.
Furthermore, we can wonder if the infection of very young children, long considered to be of little concern, might not also have longer-term consequences. If the mini-puberty stage has been altered in certain infants, their neurological development might be affected, and require support to try to mitigate the impact of this situation.
Answering these questions will require further research in the years to come.
The Conversation: What will be the continuation of this work?
VP : So far, our results have been obtained on small cohorts. We will now change scale, by analyzing samples from men and women participating in the French Coper cohort.
These include 300 people who had “mild” Covid without long-term consequences, and 300 people who had similar Covid, but developed long-term Covid.
We will test the state of the gonadotropic axis and compare it between the two groups, in order to verify whether a deficient gonadotropic axis is indeed associated with neurological disorders.
While waiting to know more, it is better to avoid being contaminated by this virus, which is obviously not a simple respiratory virus.
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