Therapy with the gonadotropin-releasing hormone GnRH may potentially reduce cognitive impairment in people with Down syndrome. In mouse models, the researchers found that some of the symptoms of Down syndrome may be due to an abnormal release of this hormone. An already established therapy for people with GnRH deficiency improved cognitive functions in a mouse model and a pilot study with seven Down syndrome patients. There are now larger clinical studies to further evaluate the benefits.
Down syndrome, also known as trisomy 21, occurs in about 1 in 800 live births, making it the most common genetic cause of intellectual disability. The reason is an extra chromosome 21. In addition to various physical symptoms, those affected usually have significantly decreased cognitive abilities. In addition, many adults develop Alzheimer’s-like symptoms in adulthood. Another symptom is a gradual loss of smell, which often begins in puberty. While many women with Down syndrome can have children, most affected men are infertile.
Trisomy 21 disrupts hormone production
A team led by Maria Manfredi-Lozano from the University of Lille in France has now researched a potential therapy for some of the symptoms of Down syndrome. “Loss of the sense of smell, combined with infertility, is also typical of patients with congenital deficiency of gonadotropin-releasing hormone (GnRH), so-called Kallmann syndrome,” explain the authors. GnRH is released by specialized neurons in the hypothalamus and is primarily responsible for triggering the production of certain reproductive hormones. However, new studies also indicate that it may also have an effect on higher brain functions.
The similarity in symptoms of Kallmann syndrome and Down syndrome prompted researchers to look more closely at the role of GnRH in Down syndrome. To do this, they first worked with a mouse model that mimics the changes that result from trisomy 21. In fact, they found a mechanism that explains why GnRH is a problem in people with Down syndrome: the production of the hormone is controlled by so-called microRNAs. At least five of these microRNAs are encoded by regions on human chromosome 21 – and are therefore disrupted in people who have three copies of this chromosome.
Promising results in mice
In Down syndrome rats, Manfredi-Lozano and his team showed that it is actually a deficiency of GnRH that contributes to cognitive impairment, loss of smell, and poor sexual maturation in the animals. If the researchers gave the mice GnRH regularly or transplanted cells that produced the hormone correctly, the symptoms were reduced. After only 15 days of treatment, the rats showed an improvement in cognitive function and regained their sense of smell. However, the animals did not become fertile as a result of the treatment.
“Because of the solid results in rats, we conducted a pilot study in human Down syndrome patients as a next step,” the researchers write. They used a form of therapy already established for the treatment of Kallmann syndrome: a small pump implanted under the skin on patients’ arm, administering a small dose of GnRH every two hours. This so-called pulsatile GnRH therapy mimics the natural release of hormones in the body.
Larger clinical trials needed
Seven men with Down syndrome between the ages of 20 and 50 received this therapy for six months. Before and after, the researchers tested their cognitive abilities and their sense of smell, and also performed MRI scans. RESULTS: After six months of therapy, six out of seven patients were able to understand instructions better, solve reasoning tasks better, were more attentive and had an improvement in their episodic memory. MRI scans also showed that there was increased functional connectivity in the brain. Unlike the rats, however, the treatment had no effect on the patients’ sense of smell.
Han Hoffmann of Michigan State University wrote in a commentary, “The pulsatile administration of GnRH appears to be a promising approach, with few anticipated side effects, to improve cognitive function in a broad spectrum of cognitive decline disorders characterized by impaired function of GnRH neurons. For making.” This study has also been published in the journal Science. “To fully determine the value of vibratory GnRH for improving cognitive function, a randomized controlled trial involving both genders.” Women were not included in the pilot study because GnRH can disrupt their menstrual cycles. Hoffman said, “However, in women who have passed reproductive age or who do not wish to conceive, pulsatile GnRH treatment is likely to be just as beneficial in improving cognitive performance as in men. “
Source: Maria Manfredi-Lozano (Université de Lille, France) et al., Science, doi: 10.1126/science.abq4515
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