Epigallocatechin-3-gallate combined with cognitive training in young adults with down syndrome phase ii clinical trial: important considerations for treatment- efficacy evaluation on cognitive and functional improvement
- Autores: Laura del Hoyo Soriano
- Directores de la Tesis: Rafael de la Torre Fornell (codir. tes.), Magí Farré Albaladejo (codir. tes.)
- Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2016
- Idioma: inglés
- Tribunal Calificador de la Tesis: Óscar García Algar (presid.), Jorge Pérez Sánchez (secret.), Nina Gramunt Fombuena (voc.)
- Programa de doctorado: Programa de Doctorado en Farmacología por la Universidad Autónoma de Barcelona
- Materias:
- Enlaces
- Tesis en acceso abierto en: TESEO
- Resumen
Down syndrome is a neurodevelopmental disorder caused by trisomy 21, which leads to cognitive and functional deficits, high risk for Alzheimer's disease and cognitive impairment at early ages. Due to the increased life expectancy and the existing large cognitive and functional variability in Down syndrome, it is essential to assess possible factors explaining these differences. This knowledge will contribute to a more efficient design of those clinical trials that aim to evaluate the efficacy of new therapies for cognitive and functional improvement in Down syndrome.
Objectives and methods: In order to detect possible confounding factors in the assessment of cognitive and functional improvements in treatment-efficacy clinical trials in Down syndrome, four original research cross-sectional studies were performed. We evaluate the interaction between biomarkers (biochemical and genetic) and sleep factors (sleep quality, apnea and snoring disorders), cognitive performance (psychomotor speed, attention, memory, executive function, and language) and functional state (adaptive behavior, quality of life, early symptoms of dementia). The following biomarkers were evaluated: Study 1: amyloidosis biomarkers (Aβ40 and Aβ42), Study2: thyroid function biomarkers (Thyroid Stimulating Hormone, free thyroxine and T-thyroxine dosage), Study 3: COMTVal158Met, VNTR-DAT1 polymorphisms and Study 4: 5-HTTLPR polymorphism.
Results: In Study 1, poorer semantic verbal fluency strategies, communication skills and a higher rate of early symptoms of dementia were associated with higher plasma Aβ42 concentrations. In Study 2 we observed that higher concentrations of free thyroxine (controlling for L-thyroxine dosage) were partially correlated with a better performance in memory, executive function and attentional span. Hypothyroidism diagnosis was associated to a poorer visuospatial memory. Study 3 showed that COMTVal158Met Met allele carriers and VNTR-DAT1 10-repeat allele homozygotes displayed an improved mental flexibility. Met allele carriers showed poorer adaptive behavior and a higher rate in early social symptoms of dementia than Val allele homozygotes. Finally in Study 4, we observed that a poorer quality of sleep was associated to 5-HTTLPR Short-allele homozygotes. Regarding cognitive performance, poor sleep quality and apnea were both associated to worse visual memory skills. Furthermore apnea and snoring were associated to a lower performance in adaptive behavior, while only snoring was associated to a higher rate of early dementia symptoms and a higher Aβ42/ Aβ40 ratio in plasma. The 5-HTTLPR was neither associated to cognition, adaptive behavior nor early dementia symptoms.
Conclusions: Plasma Aβ concentrations, plasma free thyroxine concentrations, L-thyroxine dosage, sleep quality, apnea and snoring diagnosis and genetic polymorphisms of the dopamine (COMTVal158Met and VNTR-DAT) neurotransmission system are factors of interference with the cognitive, behavioral and functional DS phenotype. Finally, the genetic polymorphism of the serotonin (5-HTTLPR) neurotransmission system does not interfere with cognitive or behavioral aspects, but it does with sleep quality in this population. Thus, these factors, which explain part of the phenotype variability, need to be assessed in the screening visit in the context of a drug-efficacy clinical trial for cognitive, behavioral and/or functional enhancement. This knowledge will allow us to balance those factors associated with phenotype variability across groups of treatment, leading to a proper efficacy assessment.
