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| ID | Type | Description | Link |
|---|---|---|---|
| 700779 | Other Identifier | Swissmedic | |
| 2020-00270 | Other Identifier | Swissethics |
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Down syndrome (DS) is the most common chromosomal disorder; with the increasing life expectancy, about 80% of DS adults reach age 65 years old. Early Alzheimer's disease (AD) is the most common cause of death within this population. DS individuals already show AD neuropathology by the age of 30, while it becomes clinically recognized in their late forties. DS subjects also exhibit olfaction defects in adulthood.
To date, there is no treatment available for the cognitive or olfactory defects in DS. The development of an effective treatment targeting cognitive dysfunction in DS adolescents/adults would be warranted.
GnRH, a decapeptide secreted by hypothalamic neurons is the pilot light of reproduction in all mammals. Pulsatile GnRH acts on the gonadotrophs via the GnRH receptor (GNRHR) in the pituitary gland to stimulate LH and FSH, which themselves will act on the gonads to produce gametes and steroids. However, GNRHR are also expressed in cerebral cortex, hippocampus, amygdala, habenula, olfactory structures, and adrenal gland, suggesting that GnRH may have a role beyond reproduction.
Recently, GnRH has been shown to be involved in the process of ageing and lifespan control. Notably, in murine models, GnRH acts as an anti-ageing factor, independent of sex hormones. While ageing is characterized by hypothalamic inflammation and diminished neurogenesis, particularly in the hypothalamus and the hippocampus, GnRH was able to promote adult neurogenesis.
The regulation of GnRH secretion is complex and involves hormonal, neuronal input, and environmental factors.
Prévot et al. recently explored cognition within the Ts65Dn model and showed an age-dependent loss of the ability to recognize new objects. Also, these mice exhibit defects in olfaction. Given the role of GnRH in anti-aging mice model, pulsatile GnRH or continuous GnRH infusion (leading to desensitization of the GNRHR) were given to the Ts65Dn mice for two weeks. Amazingly, pulsatile but not continuous GnRH therapy was able to recover cognitive and olfaction defects.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Pulsatile GnRH pump treatment | Active Comparator |
| |
| Pulsatile placebo pump treatment | Placebo Comparator |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| GnRH, gonadorelin acetate | Drug | Drug administered by a subcutaneous pump |
|
| Measure | Description | Time Frame |
|---|---|---|
| Cognition | Montreal Cognitive Assessment (MoCA) total score ranges between 0 and 30 (cut-off set at 26 for the healthy population) Higher scores reflect better performance. | Baseline to end of treatment (Week 24) |
| Measure | Description | Time Frame |
|---|---|---|
| Dimensional change card sorting task (DCCS) | change in score of DCCS to assess executive functions | baseline to end of treatment (Week 24) |
| Paired Associated Learning (PAL, part of the CANTAB battery) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Pulse-UP study | Contact | +41 21 314 06 25 | pulseup@chuv.ch | |
| Tommaso Todisco, MD | Contact | +41 79 556 8513 | tommaso.todisco@chuv.ch |
| Name | Affiliation | Role |
|---|---|---|
| Nelly Pitteloud, MD | Endocrinology, Metabolism, Diabetology (CHUV) | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Centre Hospitalier Universitaire Vaudois (CHUV) | Recruiting | Lausanne | Canton of Vaud | 1011 | Switzerland |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 36048943 | Result | Manfredi-Lozano M, Leysen V, Adamo M, Paiva I, Rovera R, Pignat JM, Timzoura FE, Candlish M, Eddarkaoui S, Malone SA, Silva MSB, 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, Buee 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. doi: 10.1126/science.abq4515. Epub 2022 Sep 2. |
| Label | URL |
|---|---|
| CHUV - Etude Pulse-UP | View source |
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| ID | Term |
|---|---|
| D004314 | Down Syndrome |
| D060825 | Cognitive Dysfunction |
| D000544 | Alzheimer Disease |
| D000857 | Olfaction Disorders |
| ID | Term |
|---|---|
| D008607 | Intellectual Disability |
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D007987 | Gonadotropin-Releasing Hormone |
| D000077330 | Saline Solution |
| ID | Term |
|---|---|
| D010906 | Pituitary Hormone-Releasing Hormones |
| D007028 | Hypothalamic Hormones |
| D036361 | Peptide Hormones |
| D006728 | Hormones |
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Multicentric randomized double-blind clinical trial
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| 0.9% NaCl | Drug | Drug administered by a subcutaneous pump |
|
change in score of PAL to assess learning
| baseline to end of treatment (Week 24) |
| Token test | change in score of Token test to assess verbal comprehension | baseline to end of treatment (Week 24) |
| Corsi block tapping task | change in score to assess visuospatial memory | baseline to end of treatment (Week 24) |
| Litmus non-word-repetition test | change in score of Litmus test to assess phonological abilities | baseline to end of treatment (Week 24) |
| Health-related quality of life SF-12 | The health-related quality of life (HRQoL) can be used to measure the effects of healthcare interventions and provide quality-improvement outcomes. The Short Form-12 (SF-12) Health Survey is widely used in measuring HRQoL. SF-12 is a reliable, valid measure in a variety of population groups; it is an equivalent substitute for the SF-36v2 for the summary scales. The response to each of the 12 items is weighted separately by the physical and mental component summary (PCS and MCS) regression coefficients and then calculated to give the SF-12 PCS and MCS scores. | baseline to end of treatment (Week 24) |
| Adaptive behavior (Vineland II) - caregiver questionnaire | change in score of Vineland II (normed assessment tool that assesses adaptive behavior across the areas of communication, activities of daily living, and socialization). | baseline to end of treatment (Week 24) |
| Glycemia | Glucose concentration (mmol/L) is a metabolic parameter. | baseline to end of treatment (Week 24) |
| Insulinemia | Insulin concentration (nmol/L) is a metabolic parameter. | baseline to end of treatment (Week 24) |
| Total cholesterol | Total cholesterol (mmol/L) is a metabolic parameter. | baseline to end of treatment (Week 24) |
| High density lipoprotein (HDL)-cholesterol | HDL-cholesterol (mmol/L) is a metabolic parameter. | baseline to end of treatment (Week 24) |
| Low density lipoprotein (LDL)-cholesterol | LDL-cholesterol (mmol/L) is a metabolic parameter. | baseline to end of treatment (Week 24) |
| Triglycerides | Triglycerides (mmol/L) is a metabolic parameter. | baseline to end of treatment (Week 24) |
| D000015 | Abnormalities, Multiple |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D025063 | Chromosome Disorders |
| D030342 | Genetic Diseases, Inborn |
| D003072 | Cognition Disorders |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D003704 | Dementia |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D024801 | Tauopathies |
| D019636 | Neurodegenerative Diseases |
| D012678 | Sensation Disorders |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D006730 |
| Hormones, Hormone Substitutes, and Hormone Antagonists |
| D009479 | Neuropeptides |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D009842 | Oligopeptides |
| D009419 | Nerve Tissue Proteins |
| D011506 | Proteins |
| D000077324 | Crystalloid Solutions |
| D007552 | Isotonic Solutions |
| D012996 | Solutions |
| D004364 | Pharmaceutical Preparations |