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.

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  1. Manfredi-Lozano et al. show the potential of restoring olfactory and cognitive performance with pulsatile GnRH therapy in individuals with DS (and maybe even for the general elderly population). This paper presents very novel findings, in my opinion. First, the role of GnRH in extrahypothalamic areas to understand the olfactory and cognitive deficits in individuals with DS. The 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 (and understand the mechanisms). Second, the focus on understanding the cognitive deficits in DS had traditionally been in the prenatal neurodevelopmental period and in the AD-related cognitive decline much later in adult life. This paper thus emphasizes the need to focus on the postnatal brain maturation in the infantile and, even more surprisingly to me, pubertal and postpubertal periods to fully understand the cognitive deficits associated with DS.

    Despite previous and ongoing efforts, there is no pharmacological therapy to improve cognition in DS. Moreover, and although the bulk of the experiments are performed in Ts65Dn mice, the authors provide a compelling rationale for a potential use of GnRH replacement for other conditions, including AD. The fact that pulsatile GnRH is a safe treatment approved for other indications should accelerate the clinical development and the trials needed to prove the efficacy of this therapy.

    We should, nonetheless, give a word of caution since the data in humans came from a very small pilot study in seven men. Several clinical trials in different age ranges in DS (and other trials in the general population) should be carried out to assess the efficacy of pulsatile GnRH to enhance cognitive function and potentially even prevent AD.

    The MoCA, which is commonly used in the general population, is not well suited to assess cognitive function in DS as most individuals will perform at floor levels. The data in humans in the work comes from a proof-of-concept, very small pilot study in seven men. The (much) larger placebo controlled clinical trials needed to prove the efficacy of this therapy should indeed use adapted cognitive and clinical measures.

    View all comments by Juan Fortea

  2. Secretion of gonadotropin-releasing hormone by the hypothalamus, particularly at high levels during puberty, leads to production of testosterone in boys and estrogen in girls. In children with Down’s syndrome, this pubertal increase never really occurs due to dysregulated GnRH-production and is thought to be the cause of the infertility observed in men and the subfertility in women.

    Manfredi-Lozano et al. show that GnRH-producing neurons also project to the hippocampus and that this connectivity is abnormal in the Ts65dn mouse. They identify five microRNAs encoded on chromosome 21, and therefore have increased expression in DS, which leads to dysregulated GnRH production. Through a meticulous series of experiments, they show that they can rescue this dysregulated neuronal connectivity using pulsatile GnRH and improve memory function in the Ts65dn mouse.   

    Moving into human studies based on the animal model data, they used small minipumps that were placed subdermally in seven adult men with DS to deliver pulsatile (q 2hrs) GnRH for six months. They report finding similar improvements in both brain connectivity on MRI as well as enhancements in cognition.

    The authors should be congratulated on this work. It opens new avenues to pursue as we try to understand the impact of trisomy of chromosome 21 on neurodevelopment while also providing a rational mechanism for testing existing therapeutics to enhance cognition in this population.

    The animal data is well-controlled and is strongly supportive of the potential role of GnRH deficits, subsequent neuroanatomical disruptions and, presumably, the intellectual disability observed in persons with DS.

    Whether this GnRH dysfunction plays a role in the development of AD pathology in DS remains unclear. The results of the pilot study will need to be replicated in a larger number of individuals, perhaps using a modified study design to confirm any cognitive benefit. The Montreal Cognitive Assessment (MoCA), although well-validated in the general population, has not been validated in persons with DS. CSF and plasma biomarkers for AD pathology in older adults could be carefully assessed. Finally, a randomized, placebo-controlled, double-blinded study would help us firmly understand the impact of GnRH on cognition in adults with DS. The participant age range, comorbidities, and concomitant medications would all need to be carefully considered in the study design.

    Whether GnRH could be used in the general population depends upon whether the GnRH dysfunction observed in DS also occurs as part of old age or sporadic AD. That is, if GnRH neurons that project to the hippocampus lose their capacity to release GnRH with age or are deleteriously affected by plaques and tangles.

    View all comments by Michael Rafii

  3. This suggests that GnRH replacement improves cognition in the TsDn65 preclinical models of Down’s syndrome, and that this therapy may have translational value in humans with DS. Even though GnRH has been used to treat other conditions, the proposed use of GnRH as a treatment for cognitive impairment in DS based on findings derived from a genetic preclinical model may lead to a therapeutic dead end, similar to the lack of clinical efficacy of anti-amyloid vaccination therapies based in preclinical model studies of Alzheimer’s disease.

    However, in this study, the authors enrolled seven individuals with DS (20 to 50 years of age) in an open-label pilot study to assess the effect of six-month pulsatile GnRH therapy on cognitive and olfactory function. Cognitive function was assessed using the MoCA test for dementia, which, in my opinion, is not a good test of cognition in people with DS. The authors should have used other tests specifically designed to test cognitive abilities due to the unique cognitive profile found in people with DS. Perhaps a more appropriate battery would have been the Arizona Cognitive Test Battery (ACTB) that includes normative data from individuals whose performance is several standard deviations below average, with a lower floor performance than many traditional cognitive assessments. This factor is essential for a measure to be sensitive to change when administered to individuals who have intellectual deficits such as DS. Moreover, the need to provide GnRH over the life span of an individual with DS would be a daunting task with unknown clinical and physiological consequences.

    View all comments by Elliott Mufson

  4. Although this is an interesting approach, which may open up new avenues for investigating the cognitive impairments associated with Down’s syndrome, I see several issues with this paper.

    First, the animal model experiments are at best preliminary, as they are based on very small groups (n=4 in some cases), and thus do not allow for exploration of sex differences, which are important in understanding the effects of GnRH. Furthermore, the experiments make use of an older mouse model (Ts65Dn). It includes triplicated genes that are not on human chromosome 21, and focuses on phenotypes not universally recognized in Down’s syndrome, such as olfactory deficits. Much more preclinical work needs to be done before the findings can be applied in human studies.

    Although the authors included data from a small study in young men with Down's syndrome (n = 7), the participants (and possibly also raters) were not blinded, and a control group is not included. The cognitive measure (MoCA) used to show supposed cognitive improvement on treatment with pulsatile GnRH therapy was designed for neurotypical older adults, and is not used to determine cognitive abilities in individuals with Down’s syndrome. People with Down's syndrome typically have significant floor effects on such tools unless adapted for this population and then validated (which is not the case for the MoCA). In addition, the treatment was short-term. In summary, the result of the human experiment is not meaningful.  

    It is important not to confuse the neurodevelopmental aspects of Down's syndrome (in this case, lifelong cognitive impairment) from the later effects of Alzheimer's pathology, which leads to cognitive decline from a neurodevelopmental baseline. This study does not include experimental data on Alzheimer's disease in Down's syndrome. 

    View all comments by Andre Strydom

  5. This paper is obviously the culmination of an enormous amount of work. However, the mouse results come from a single model, Ts65Dn, which was extremely important when published in 1995 (Reeves et al., 1995), but we have known for over a decade that:

    (i) of critical importance, Ts65Dn carries a duplicated region without homology to human chromosome 21, and thus of no relevance to Down’s syndrome, which includes 50 genes; these genes are expressed in the nervous system and at least some of those genes are dosage-sensitive and give rise to phenotypes, mechanistically unrelated to DS (Reinholdt et al., 2011; Duchon et al., 2011); 

    (ii) male infertility in Ts65Dn is almost certainly due to the well-known meiotic block that occurs in spermatogenesis in aneuploidy (Davisson et al., 2007); 

    (iii) recent seminal work by the Haydar lab has demonstrated phenotypic drift in key Ts65Dn colonies (Shaw et al., 2020). Thus, the high variability in the Ts65Dn model means that in the small, underpowered, non-randomized preclinical studies of this report, inadvertent experimental subject selection bias can lead to erroneous interpretation of results.

    Since 2010, several DS models have been freely available that have construct validity and carry duplicated regions with homology to human chromosome 21 only (for example, Yu et al., 2010). 

    Given that the 50 triplicated extra genes in Ts65Dn were published over a decade ago, and that previous preclinical work in Ts65Dn has failed to translate in the clinic, and the weaknesses in the study design, I am surprised that the clinical study was undertaken prior to data being collected to corroborate the change in LH and FSH hormones in adults who have Down’s syndrome. 

    References:

    Reeves RH, Irving NG, Moran TH, Wohn A, Kitt C, Sisodia SS, Schmidt C, Bronson RT, Davisson MT. A mouse model for Down syndrome exhibits learning and behaviour deficits. Nat Genet. 1995 Oct;11(2):177-84. PubMed.

    Reinholdt LG, Ding Y, Gilbert GJ, Czechanski A, Solzak JP, Roper RJ, Johnson MT, Donahue LR, Lutz C, Davisson MT. Molecular characterization of the translocation breakpoints in the Down syndrome mouse model Ts65Dn. Mamm Genome. 2011 Dec;22(11-12):685-91. Epub 2011 Sep 28 PubMed.

    Duchon A, Raveau M, Chevalier C, Nalesso V, Sharp AJ, Herault Y. Identification of the translocation breakpoints in the Ts65Dn and Ts1Cje mouse lines: relevance for modeling Down syndrome. Mamm Genome. 2011 Dec;22(11-12):674-84. Epub 2011 Sep 28 PubMed.

    Davisson M, Akeson E, Schmidt C, Harris B, Farley J, Handel MA. Impact of trisomy on fertility and meiosis in male mice. Hum Reprod. 2007 Feb;22(2):468-76. Epub 2006 Oct 17 PubMed.

    Shaw PR, Klein JA, Aziz NM, Haydar TF. Longitudinal neuroanatomical and behavioral analyses show phenotypic drift and variability in the Ts65Dn mouse model of Down syndrome. Dis Model Mech. 2020 Sep 25;13(9) PubMed.

    Yu T, Li Z, Jia Z, Clapcote SJ, Liu C, Li S, Asrar S, Pao A, Chen R, Fan N, Carattini-Rivera S, Bechard AR, Spring S, Henkelman RM, Stoica G, Matsui S, Nowak NJ, Roder JC, Chen C, Bradley A, Yu YE. A mouse model of Down syndrome trisomic for all human chromosome 21 syntenic regions. Hum Mol Genet. 2010 Jul 15;19(14):2780-91. Epub 2010 May 4 PubMed.

    View all comments by Elizabeth Fisher

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