A therapy improves intellectual capacity in people with Down syndrome

An experimental therapy improves the cognitive ability of people with Down syndrome. It is based on an injection of gonadotropin-releasing hormone (GnRH) which, in a small study conducted on seven people with Down syndrome, has shown its potential on cognition. The first results are published in ‘science’.

Down syndrome or trisomy 21 affects one in 800 births and causes various clinical manifestations, including impaired cognitive ability. With age, 77% of sufferers experience symptoms similar to those of Alzheimer’s disease. The gradual loss of olfactory capacity, typical of neurodegenerative diseases, is also frequent from the prepubertal period, with possible deficits in sexual maturation in men.

Before the pilot study in patients, researchers at the Inserm of the University Hospital of Lille and of University Hospital of Lausanne (France), identified a dysfunction of GnRH neurons in an animal model of Down syndrome, as well as its repercussions on the deterioration of cognitive function associated with the disease.

Recent research has suggested that neurons expressing GnRH, known to regulate reproduction through the hypothalamus, could also act in other brain regions with a potential role in other functions, such as cognition.

With this idea, Vincent Prévot’s group studied the mechanism that regulates GnRH in mouse models of Down syndrome.

The laboratory showed that five microRNA chains that regulate the production of this hormone – found on chromosome 21 – are dysfunctional. This supernumerary chromosome causes abnormalities in neurons that secrete GnRH. These results were confirmed both at the genetic and cellular level.

After 15 days, the team was able to demonstrate the restoration of the olfactory and cognitive functions of the mice

Furthermore, the scientists showed that restoring the physiological function of the GnRH system restores cognitive and olfactory functions in trisomic mice.

With this information, the Inserm group contacted Nelly Pitteloud, from the University of Lausanne, whose research focuses on congenital GnRH deficiency, a rare disease manifested by the absence of spontaneous puberty. These patients are given pulsatile GnRH therapy to reproduce the natural rhythm of GnRH secretion, in order to induce puberty.

Therefore, they 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 the olfactory and cognitive functions of the mice.

The next step was the design of a pilot clinical trial in patients to evaluate the effects of this treatment.

Seven men with Down syndrome, ages 20 to 50, received a subcutaneous dose of GnRH every two hours for 6 months through a device placed in their arm. Cognitive and olfactory tests as well as MRI examinations were performed before and after treatment.

And the results, from the clinical point of view, were positive. As detailed in the study, cognitive performance improved in 6 of the 7 patients with better three-dimensional representation, better understanding of instructions, improved reasoning, attention and episodic memory.

However, the treatment had no impact on olfactory ability.

This improvement in cognitive function was confirmed by brain imaging, which revealed a significant increase in functional connectivity.

The experts explain that these data suggest that the treatment acts in the brain by reinforcing communication between certain regions of the cortex. “The maintenance of the GnRH system seems to play a key role in the maturation of the brain and cognitive functions,” explains Prévot.

For Pittelou, this is a promising therapy, especially “because it is an existing treatment without significant side effects.”


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