GnRH Therapy on Cognition in Down Syndrome

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Ingia / Ingia

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HaliBado kuajiri

Wadhamini

Nelly Pitteloud

JARIBIO LA KLINIKI: NCT04390646

BioSeek: nct04390646

Maneno muhimu

Kikemikali

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.

Tarehe

Imethibitishwa Mwisho:	04/30/2020
Iliyowasilishwa Kwanza:	05/04/2020
Uandikishaji uliokadiriwa Uliwasilishwa:	05/12/2020
Iliyotumwa Kwanza:	05/14/2020
Sasisho la Mwisho Liliwasilishwa:	05/12/2020
Sasisho la Mwisho Lilichapishwa:	05/14/2020
Tarehe halisi ya kuanza kwa masomo:	05/31/2020
Tarehe ya Kukamilisha Msingi iliyokadiriwa:	11/30/2023
Tarehe ya Kukamilisha Utafiti:	02/29/2024

Hali au ugonjwa

Down Syndrome

Cognitive Decline

Alzheimer Disease, Early Onset

Olfaction Disorders

Uingiliaji / matibabu

Drug: Pulsatile GnRH pump treatment

Drug: Pulsatile placebo pump treatment

Awamu

Vikundi vya Arm

Mkono	Uingiliaji / matibabu
Active Comparator: Pulsatile GnRH pump treatment	Drug: Pulsatile GnRH pump treatment Drug administered by a subcutaneous pump during 24 weeks, at a dosage of 75 ng/kg/pulse giving a pulse every 90 minutes in women and every 120 minutes in men.
Placebo Comparator: Pulsatile placebo pump treatment	Drug: Pulsatile placebo pump treatment Drug administered by a subcutaneous pump during 24 weeks, at a dosage of 75 ng/kg/pulse giving a pulse every 90 minutes in women and every 120 minutes in men.

Vigezo vya Kustahiki

Zama zinazostahiki Kujifunza	20 Years Kwa 20 Years
Jinsia Inastahiki Kujifunza	All
Hupokea Wajitolea wa Afya	Ndio
Vigezo	Inclusion Criteria: - Diagnosis of trisomy 21 - Ability to follow the procedures of the study - Olfactory impairment (Sniffin' Sticks, identification score: for men ≤11, for women ≤12) - Consent to a non-hormonal contraception during the whole duration of the study Exclusion Criteria: - Clinical or biochemical findings suggesting acute illness/hospitalization - Chronic alcohol abuse, illicit drug use, or anabolic steroid abuse - Pituitary adenoma and other hormone-dependent tumours - Participation in another clinical study - Intention to become a parent during the course of the study - Pregnant or breastfeeding women - Participant or his/her legal representative do not want to be informed in case of incidental findings

Matokeo

Hatua za Matokeo ya Msingi

1. Cognition [Baseline to end of treatment (Week 24)]

The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) includes 12 subtests that measure 5 indices: Immediate Memory: List Learning (score 0-40), Story Memory (score 0-24) Visuospatial/Construction Index: Figure Copy (score 0-20), Line Orientation (score 0-20) Language: Picture Naming (score 0-10), Semantic Fluency (score in 60 sec) Attention: Digit Span (score 0-16), Coding (score in 90 sec) Delayed Memory: List Recall (score 0-10), Story Recall (score 0-12), List Recognition (score 0-20), Figure Recall (score 0-20) The sum of these 5 Index scores is converted to a Total Scale value via a mapping table. The Total Scale is a norm-based t score based on a distribution with a mean of 100 and standard deviation of 15. Higher scores reflect better performance.

Hatua za Matokeo ya Sekondari

1. Olfaction [baseline to Week 12, and to the end of treatment (Week 24)]

The "Sniffin' Sticks" test is a widely used tool for assessment of olfactory performance consisting of three subtests: olfactory threshold (T), odor discrimination (D) and odor identification (I). Each subtest may be scored 1-16. The sum of the three score, the TDI, gives a score 3-48. Higher scores reflect better performance. Most recent normative data is on an sample of more than 9000 subjects. European Archives of Oto-Rhino-Laryngology (2019) 276:719-728 doi.org/10.1007/s00405-018-5248-1

2. Amyloidosis [baseline to Week 12, and to the end of treatment (Week 24)]

change in amyloidosis biomarkers (Aβ1-40, Aβ1-42, and truncated forms)

3. Brain MRI [baseline to the end of treatment (Week 24)]

change in brain MRI signals

4. Health-related quality of life (HRQoL) [baseline to Week 4, 12, and to the end of treatment (Week 24)]

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. A booklet "SF-12: How to score the SF-12 Physicial and Mental Health Summary Scales" by Ware, Kosinski and Keller contains the algorithm to be used for the scoring of the PCS and MCS components.

Hatua Nyingine za Matokeo

1. Glycemia [baseline to Week 12, and to the end of treatment (Week 24)]

Glucose concentration (mmol/L) is a metabolic parameter.

2. Insulinemia [baseline to Week12, and to the end of treatment (Week 24)]

Insulin concentration (nmol/L) is a metabolic parameter.

3. Leptinemia [baseline to Week 12, and to the end of treatment (Week 24)]

Leptin concentration (µg/L) is a metabolic parameter.

4. Glycated hemoglobin (HbA1c) [baseline to Week 24]

Glycated hemoglobin (mmol/mol and %) is a metabolic parameter.

5. Interleukin-6 (IL-6) [baseline to Week 24]

IL-6 (pg/mL) is an inflammatory mediator.

6. Interferon-alfa (IFN-a) [baseline to Week 24]

IFN-a (pg/mL) is an inflammatory mediator.

7. Tumor necrosis factor- alfa (TNF-a) [baseline to Week 24]

TNF-a (pg/mL) is an inflammatory mediator.

8. Total cholesterol [baseline to Week 24]

Total cholesterol (mmol/L) is a metabolic parameter.

9. High density lipoprotein (HDL)-cholesterol [baseline to Week 24]

HDL-cholesterol (mmol/L) is a metabolic parameter.

10. Low density lipoprotein (LDL)-cholesterol [baseline to Week 24]

LDL-cholesterol (mmol/L) is a metabolic parameter.

11. Triglycerides [baseline to Week 24]

Triglycerides (mmol/L) is a metabolic parameter.