Illustration of SARS-CoV-2 infection (immunoreactivity for the S-protein in white) in the olfactory neurons expressing the olfactory marker protein (OMP, in red) in the human nasal epithelium. © Vincent Prévot/Inserm

The brain impacts of infection with SARS-CoV-2, responsible for COVID-19, are increasingly well documented in the scientific literature. Researchers from Inserm, Lille University Hospital and Université de Lille, at the Lille Neuroscience & Cognition unit, in collaboration with their colleagues at Imperial College London, focused more specifically on the impacts of this infection on a population of neurons known for regulating sexual reproduction via the hypothalamus (the neurons that express the GnRH hormone). Their findings suggest that SARS-CoV-2 infection can lead to the death of these neurons and cause certain symptoms that persist over time. The findings of this study have been published in eBioMedicine.

Numerous scientific studies have documented the brain impacts of SARS-CoV-2 infection. One such effect is that a significant proportion of men have low testosterone levels that persist over time. Persistence beyond a period of four weeks is referred to as “long COVID”.

For many years, a research team from Inserm, Lille University Hospital and Université de Lille has been studying the role of certain neurons that express gonadotropin-releasing hormone (GnRH). From the hypothalamus, these neurons control all the processes associated with reproductive function: puberty, acquisition of secondary sexual characteristics, and fertility in adulthood.

These are the same scientists who had, for example, previously revealed that GnRH neuron dysfunction in an animal model of Down syndrome could affect the cognitive function impairment associated with this condition.

In this latest study, the scientists wanted to test the hypothesis that SARS-CoV-2 infection may have harmful consequences on this population of neurons that regulate reproduction.

The Virus Penetrates GnRH Neurons and Alters Their Functions

Following hormone measurements (testosterone and luteinizing hormone) performed three months and then one year after infection in a small group of 47 men[1], the scientists observed that contact with the virus could alter the functions of GnRH neurons, leading to a fall in testosterone levels in certain patients some time after the infectious episode.

The scientists then wanted to verify whether the infection of the GnRH neurons and the subsequently observed hormone abnormalities could be associated with cognitive deficits. To do this, they listed the cognitive symptoms reported by the cohort patients, who underwent extensive testing three months and then one year after the infection.

The outcome was that the proportion of patients reporting memory or attention disorders, regardless of frequency or severity, and also concentration difficulties, tended to be slightly higher in the patients with abnormal hormone measurements, characterized by a decrease in testosterone levels.

“Although these were measurements made on a small sample of only male patients, these findings are very interesting and warrant further exploration in other larger-scale studies,” explains Waljit Dhillo, professor at Imperial College London and co-last author of this study.

To supplement their analyses, the researchers went on to study the cortexes of patients who died as a result of COVID-19. They identified the presence of the virus in the hypothalamus and the death of part of the GnRH neuron population.

“These findings may be worrying on several levels in terms of the role of these neurons in reproduction and their involvement in certain cognitive functions. They point to the necessity to optimize and generalize the medical follow-up of people with persistent symptoms following COVID-19 infection,” concludes Vincent Prévot, Inserm research director and co-last author of this study.

The study also encourages further research into the neurological impacts of long COVID.

[1]These data were collected as part of a larger study evaluating adrenal and thyroid function following Sars-CoV-2 infection: https://pubmed.ncbi.nlm.nih.gov/34008009/

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