Experimental treatment improves cognitive abilities of people with Down syndrome

A group of European researchers has discovered that a fundamental hormone used in reproduction also improves the cognitive ability of people with Down syndrome. The scientists have published their research in the journal Science. However, other experts have urged caution, as the testing will need to be replicated among larger groups to achieve more definitive results.

Gonadotropin-releasing hormone (GnRH) activates a complex mechanism in the brain, releasing two other hormones. GnRH is behind the production of testosterone and sperm in males and stimulates the production of estrogen in females – its levels skyrocket at puberty. In children born with an extra copy of chromosome 21 (the other name for Down syndrome is Trisomy 21), the expression of this hormone is comparable to that of children without this genetic alteration. But everything changes when puberty hits. Thereafter, adults with Down syndrome show a deficit in the release of this hormone, which leads to infertility.

But GnRH may have other functions. It has been hypothesized that the neurons that release the hormone do more than just regulate the reproductive system… but exactly what else they do has been difficult to pinpoint.

Vincent Prévot, director of the Laboratory of Development and Plasticity of the Endocrine Brain at the University of Lille (France), has been trying to come up with an answer for several years. Three things about the relationship between GnRH and Down syndrome have intrigued him, he wrote in an email to EL PAÍS:

“One: Down syndrome patients are able to perceive odors during childhood, but lose it during adolescence. Two: Cognitive abilities are fairly comparable between [typical children and children with Down syndrome], but cognitive decline [in those with Down syndrome] accelerates after puberty. And three: five genes that code for microRNAs reside on chromosome 21 (key RNAs in the control of gene expression) and among them we knew that four were enriched in GnRH neurons.”

Cognitive abilities are quite comparable between typical children and those with Down syndrome… but cognitive decline accelerates after puberty

Vincent Prévot, University of Lille (France)

To put some doubts to rest, researchers used mice with Down syndrome (Trisomy 21) in their studies. As in humans, at birth, the pups did not show large differences in GnRH expression when compared to another group of rodents without the extra chromosome. “But, when we looked at GnRH expression during postnatal development, we found that not only did hormone expression decrease in young adult trisomic mice, but also that, in the other [typical] mice, GnRH neurons sent projections to areas other than those involved in the control of reproduction, such as the brain regions involved in cognition and memory. These cortical projections had been lost in trisomic mice,” explains Prévot, senior co-author of the study published in Science.

The Spanish researcher María Manfredi is the first author of the study, which she carried out during her residency at the University of Lille. “Loss of smell with age, infertility and cognitive decline are all part of Down syndrome,” she says. “Prévot was convinced of the connection with the hormone GnRH,” she adds.

Manfredi and the rest of the team verified in the mice that another group of GnRH neurons – different from the ones in charge of reproduction – carried their connections to other areas of the brain. Logic led the way: use the hormone – of which there are synthetic versions on the market – to restore GnRH levels in trisomic rodents. They placed a tiny pump that released the molecule in the form of pulses, as the body itself does. “We saw that the cognition of mice with Down syndrome improved,” says the scientist.

For the first time, it is clear that [the hormone GnHR] has projections in the cerebral cortex and the hippocampus, keys for several cognitive abilities

Manuel Tena-Sempere, researcher at the University of Córdoba

Manuel Tena-Sempere directed Manfredi’s thesis at the University of Córdoba in southern Spain and was the one who encouraged her to go work with Prévot. Also a co-author of the study, Tena-Sempere points out: “GnRH is a very rare type of specialized neuron. It is highly-conserved in different species, with the same function in all mammals. It was suspected that it had some other function. For the first time, it is clear that it has projections in the cerebral cortex and the hippocampus. By reversing the deficit of this hormone, cognitive improvement occurs.”

Having proven the cognitive function of GnRH, the scientists went further: they proposed injecting the hormone into people living with Down syndrome. This part of the study was led by Nelly Pitteloud, an expert in human GnRH neurons at the Lausanne University Hospital (Switzerland). It was not easy to recruit a group with trisomy 21. They had to be adults (when hormonal alteration is greater) and men, since the release of GnRH in women is more complicated and could affect their menstrual cycle and fertility. The team managed to recruit seven individuals, who received pulses of GnRH every two hours for six months.

As a whole, [patients with Down syndrome] improved their cognitive skills by 30%

Nelly Pitteloud, encodrinologist at Lausanne University Hospital (Switzerland)

Six of the seven patients improved their performance in all of the cognitive tests they were given: visual-spatial function (the ability to think in three dimensions), executive function, attention, episodic memory and verbal comprehension. As for the seventh, “we saw an improvement in certain cognitive abilities, mainly driven by improvement in visual-spatial abilities, executive function and attention,” says Pitteloud. Although it is not easy to express the improvement in figures, the Swiss researcher maintains that “as a whole, they improved their cognitive skills by 30%.”

Hanne Hoffmann is a scientist at Michigan State University. Unrelated to the study, she has published a commentary on the results in Science. In Hoffmann’s laboratory, researchers study the release of hormones. When asked about the possible uses of this new therapy by EL PAÍS, she responded via email:

“GnRH is already used to treat certain types of infertility. Based on the findings of the work, the pulsatile release of the hormone could be a new treatment for various types of cognitive impairment that may be associated with a functional reduction of GnRH, such as Alzheimer’s or Down syndrome.”

As hormone release patterns change with age and “abnormal or decreased release of GnRH is often associated with mental decline with age, its administration could serve to delay deterioration,” she adds. But, she concludes, “more research is needed to establish the impact of GnRH on cognitive improvement.”

Mara Dierssen is a researcher in the neurobiology of Down syndrome at the Center for Genomic Regulation in Santander, Spain. She has had the opportunity to read the research and notes that “the authors convincingly show the involvement of GnRH in the function of brain regions related to learning and memory, such as the hippocampus.” But what she values most about the work is “the imbalance that the authors find in a complex network of microRNAs, which regulate the expression of GnRH and the maturation of GnRH neurons.” It seems very relevant to her that “regulatory elements – such as microRNAs – may play a role in the neuropathology of Down syndrome.”

This being said, Dierssen is very cautious when evaluating the results with humans: “The problem is that the clinical study has been carried out with a very small group. There are several examples of very promising clinical trials to improve cognition in people with Down syndrome, which worked well when testing small numbers of individuals, but then failed when the number of participants increased.”