Could replenishing a sex hormone improve cognition in Down’s syndrome? If given the right way, gonadotrophin-releasing hormone (GnRH) can do just that, according to researchers led by Vincent Prevot and Paolo Giacobini, University of Lille, France, and Nelly Pitteloud, University of Lausanne, Switzerland. In the September 2 Science, they reported that in a mouse model of DS, GnRH-expressing neurons begin to wither when the animals are pups, causing loss of smell and cognitive trouble during puberty. Pumping pulses of the hormone into adult mice restored olfaction and improved cognition. In a pilot trial, brain connectivity and cognition improved slightly in seven adults with DS who took GnRH for six months. A Phase 2 trial is slated to begin this fall.
- In a mouse model of DS, loss of gonadotrophin-releasing hormone precedes cognitive decline.
- Injecting mice with GnRH improved cognition, restored olfaction.
- In a DS pilot trial, pulses of GnRH improved brain connectivity and cognition.
“This paper is a tour de force with extensive and well-designed experiments in the Ts65Dn mouse model for DS to prove the role of GnRH [in olfactory and cognitive deficits] and understand the mechanisms,” wrote Juan Fortea, Hospital of Sant Pau, Barcelona, Spain (full comment below).
Shahid Zaman, University of Cambridge, U.K., agreed. “This work supports the suspicion that GnRH and its receptor are expressed outside the hypothalamus and have functions beyond reproduction,” he told Alzforum.
People with DS carry three copies of chromosome 21 and experience a wide range of symptoms, including intellectual disability, progressive memory loss, a waning sense of smell, sex hormone deficiency, and fertility issues. The last two stem from a dearth of GnRH. During puberty, neurons in the hypothalamus normally crank out GnRH to stimulate production of luteinizing hormone or follicle-stimulating hormone from the pituitary. In most teens with DS this spike never happens and GnRH levels remain low.
Beyond the sex hormones axis, GnRH is suspected of having other functions in the brain. Prevot and Giacobini previously reported that human GnRH-expressing neurons stretch their processes out from the hypothalamus into the hippocampus and cortex, suggesting a role in learning and memory (Casoni et al., 2016; Skrapits et al., 2021). Others found that, in aged mice, supplementing with the hormone improved cognition and neurogenesis (May 2013 news). Could the withering of GnRH neurons contribute to intellectual disability in DS? And if so, would boosting levels in the brain improve cognition?
To find out, co-first authors Maria Manfredi-Lozano and Valerie Leysen of U Lille and Michela Adamo of U Lausanne first turned to a mouse model of DS. Ts65Dn mice carry three copies of chromosome 16, which includeS regions homologous to human chromosome 21. Like most people with DS, these mice are infertile, have memory problems, and lose their sense of smell.
Newborn Ts65Dn pups sniffed out milk as well as their wild-type counterparts. However, unlike wild-type mice, both 1-month-old prepubescent and 3-month-old adult DS mice had trouble smelling. They could not distinguish novel odors from familiar ones, for example, the smell of orange blossoms versus a citrus scent. As for memory, failure to recognize novel objects began after puberty.
Did these smell and memory problems coincide with GnRH neuron loss? Indeed, immunohistochemistry of brain tissue slices from Ts65Dn mice revealed normal distribution and number of GnRH-positive neurons at birth but a severe decline after puberty. Three-dimensional imaging of whole adult brains showed GnRH-expressing neurons in the hippocampi and cerebral cortices in wild-type, but not Ts65Dn, mice (see image below). The authors believe that a waning sense of smell foretells the loss of neurons that make GnRH, and that a drop in this hormone triggers pubescent cognitive decline.
Missing Neurons. Imaging of the whole brain from 3-month-old wild-type mice (left) showed GnRH-expressing neurons (white) in the hypothalamus (top) and surrounding hippocampal tissue (bottom, arrows). These cells are all but absent from 3-month-old Ts65Dn mice (right). [Courtesy of Manfredi-Lozano et al., Science, 2022.]
Could boosting GnRH levels compensate for this neuron loss? Indeed, a single intraperitoneal injection of the hormone into adult Tsg5Dn mice normalized olfaction two hours later, while three jabs over two days restored cognition.
Because a constant stream of the hormone desensitizes its receptor, ultimately shutting down signaling, the researchers next opted to mimic the pulses of GnRH released by the hypothalamus. They implanted subcutaneous minipumps containing GnRH into 6-month-old mice. These either released the hormone continuously or in 10-minute pulses every three hours. After 15 days of pulsed GnRH, mice could discriminate new smells and objects from known ones, while mice that had continuous GnRH could not. In fact, continuous release worsened olfaction and novel object recognition. These results suggested that restoring pulsatile physiological GnRH signaling, even in adult mice, improves cognition.
Many researchers praised the mouse data. “It strongly supports the potential role of GnRH deficits [in] subsequent neuroanatomical disruptions and, presumably, the intellectual disability observed in persons with DS,” Michael Rafii, University of Southern California, San Diego, wrote (full comment below).
Could replenishing GnRH improve cognition in people with DS? The scientists recruited seven men who had DS, and a poor sense of smell, from Lausanne University Hospital for an open-label pilot study. They ranged from 20 to 50 years old. For six months, a subdermal pump infused GnRH once every two hours to mimic pulse frequency in healthy men. This hormone pump is used to treat GnRH deficiency, a disease called Kallmann syndrome (Raivio et al., 2007). Participants received structural and functional MRI scans and took the Montreal Cognitive Assessment before and after treatment. The researchers chose the MoCA because it is short and manageable for people with DS.
At baseline, structural MRI showed less myelin in the thalamus and corticospinal tract than in age-matched controls and a smaller than normal thalamus, cerebellum, and cingulate gyrus. Resting-state fMRI revealed altered default mode network (DMN) connectivity. All participants had impaired cognition on the MoCA, with baseline scores ranging widely from 4 to 22 out of 30.
After GnRH treatment, the visual and sensorimotor portions of the DMN became better connected (see image below). MoCA scores improved by a few points in six participants, particularly in visuospatial, executive function, and attention subscores. Memory scores, olfaction, and brain structure remained unchanged. Overall, the authors concluded that the pulsed GnRH therapy might improve cognition in people with DS.
Boosting Connectivity, Cognition. In seven people with DS, brain connectivity after six months of treatment with GnRH was better (top, right) than at baseline (top, left). Scores on the MoCA and its visuospatial, executive, and attention, but not memory, indices also improved slightly (bottom). [Courtesy of Manfredi-Lozano et al., Science, 2022.]
“This work opens new avenues to pursue as we try to understand the impact of chromosome 21 trisomy on neurodevelopment while also providing a rational mechanism for testing existing therapeutics to enhance cognition in this population,” wrote Rafii. Zaman thought this work offered a unique approach to improving cognition. “GnRH replacement puts a different spin on cognitive remediation by evoking compensatory mechanisms rather than reversing a disease pathway,” he noted.
However, other researchers interpreted the clinical results cautiously. “This pilot study shows that the GnRH pump is feasible to use in people with DS, but you cannot determine treatment efficacy without a placebo control,” Elizabeth Head, University of California, Irvine, told Alzforum. Zaman agreed, wondering if the modest MoCA improvements were due to the practice effects of repeated testing. Prevot said they used two different versions of the MoCA before and after treatment to avoid practice effects.
Still, the MoCA was not designed for people with intellectual disabilities and has not been validated in DS. “This was evident as most participants scored in the mild cognitive impairment range or below,” Head noted. Fortea agreed. “Most individuals [with DS] will perform at floor levels,” he wrote. Mark Mapstone, also at UC Irvine, noted that the MoCA is a global cognitive screening measure, not a comprehensive evaluation of cognitive domains. Scientists are developing cognitive tests tailored to DS or confirmed to be sensitive in this population (May 2021 news).
“This study was not powered to determine GnRH’s effect on memory and other domains,” said Mapstone. Pitteloud said they are planning a placebo-controlled Phase 2 trial, aiming to enroll 60 to 80 adults with DS and poor senses of smell. All will wear a subdermal pump—half will get GnRH, half saline—for six months. The primary outcome is a change in MoCA score, though Pitteloud said they are open to also using DS-specific tests. Secondaries include the change in functional MRI, sense of smell, and fluid markers of amyloidosis. The trial is slated to begin in November in Lausanne.—Chelsea Weidman Burke
Research Models Citations
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- Raivio T, Falardeau J, Dwyer A, Quinton R, Hayes FJ, Hughes VA, Cole LW, Pearce SH, Lee H, Boepple P, Crowley WF Jr, Pitteloud N. Reversal of idiopathic hypogonadotropic hypogonadism. N Engl J Med. 2007 Aug 30;357(9):863-73. PubMed.
- Manfredi-Lozano M, Leysen V, Adamo M, Paiva I, Rovera R, Pignat JM, Timzoura FE, Candlish M, Eddarkaoui S, Malone SA, Silva MS, Trova S, Imbernon M, Decoster L, Cotellessa L, Tena-Sempere M, Claret M, Paoloni-Giacobino A, Plassard D, Paccou E, Vionnet N, Acierno J, Maceski AM, Lutti A, Pfrieger F, Rasika S, Santoni F, Boehm U, Ciofi P, Buée L, Haddjeri N, Boutillier AL, Kuhle J, Messina A, Draganski B, Giacobini P, Pitteloud N, Prevot V. GnRH replacement rescues cognition in Down syndrome. Science. 2022 Sep 2;377(6610):eabq4515. PubMed.