Insulin Resistance in Multiple System Atrophy

Обзор

Multiple system atrophy (MSA) is a rare and fatal neurodegenerative disorder. The pathologic hallmark is the accumulation of aggregated alpha-synuclein in oligodendrocytes forming glial cytoplasmic inclusions. Some symptomatic treatments are available while disease-modification remains an unmet treatment need. Post-mortem findings suggest insulin resistance, i.e. reduced insulin signaling, in the brains of MSA patients. The aim of this study is to complete the target validation of insulin resistance for future treatment trials.

Подробное описание

Multiple system atrophy (MSA) patients have a poor prognosis with a median survival ranging between 6 and 10 years. MSA belongs to the synucleinopathies, which are characterized by the abnormal accumulation of alpha-synuclein. We have recently shown brain insulin resistance (i.e. reduced insulin signaling) in post-mortem brain tissue of MSA patients and transgenic MSA mice, as illustrated by increased protein levels of insulin receptor substrate-1 phosphorylated at serine 312 (IRS-1pS312). Additionally, exendin-4, an approved anti-diabetic drug targeting glucagon-like peptide-1 (GLP-1) receptors, was capable of decreasing brain levels of IRS-1pS312 and preserving dopamine neurons in transgenic MSA mice. We further observed an inverse correlation between plasma neural-derived exosomal IRS-1pS312 levels and survival of dopamine neurons in transgenic MSA mice.

The aim of this study is to further characterize peripheral and central insulin resistance in MSA patients, thereby validating this target for future treatment trials. For this purpose, fasting blood glucose and insulin levels will be determined in samples of MSA patients and healthy controls for a homeostatic model assessment of insulin resistance (HOMA). Additionally, IRS-1pS312 will be measured in neural-derived plasma exosomes of MSA patients and healthy controls.

Вмешательства

• Биопрепарат Homeostasis Model Assessment of insulin resistance (HOMA)
  Fasting blood sample for : glucose, insulinemia, hemoglobin and lipid test to determine the Homeostasis Model Assessment of insulin resistance (HOMA) index
• Поведенческое MOntreal Cognitive Assessment (MoCA)
  Cognitive evaluation with MOntreal Cognitive Assessment (MoCA)
• Поведенческое Clinical characteristics of AMS patients
  Severity and progression of motor disorders assessed by the UMSARS scale, severity of dysautonomia assessed by the COMPASS31 scale ; quality of life questionnaire (AMS-Qol) for the level of difficulty experienced by the patient (on activities such as : move; walk; maintain balance; talk; feed)
• Процедура Brain Magnetic Resonance Imaging (MRI)
  Brain Magnetic Resonance Imaging (MRI) : putamen imaging, bridge and cerebellum; white substance hypersignals volume
• Биопрепарат Blood sampling
  Optional blood sampling for the constitution of a biological collection

Первичные конечные точки

• HOMA Index [Срок оценки: Day 0]

Вторичные конечные точки (11)

• IRS-1pS312 (Insulin Receptor Substrate-1, Phosphorylated at Serine 312) concentration [Срок оценки: Day 0]
• Unified Multiple System Atrophy Rating Scale (UMSARS) score [Срок оценки: Day 0]
• Unified Multiple System Atrophy Rating Scale (UMSARS) score [Срок оценки: One year]
• COMPosite Autonomic Symptoms Score (COMPASS-31) [Срок оценки: Day 0]
• COMPosite Autonomic Symptoms Score (COMPASS-31) [Срок оценки: One year]
• AMS-Qol - Quality of life questionnaire [Срок оценки: Day 0]
• AMS-Qol - Quality of life questionnaire [Срок оценки: One year]
• MOntreal Cognitive Assessment (Moca) score [Срок оценки: Day 0]
• MOntreal Cognitive Assessment (Moca) score [Срок оценки: One year]
• Brain MRI volume [Срок оценки: Day 0]
• Brain MRI volume [Срок оценки: One year]

Критерии участия

Критерии включения

Patients :

• Patients suffering from "possible" or "probable" MSA according to clinical consensus criteria (Gilman et al., 2008).
• Age > 30
• Written informed consent
• Patient covered by the national health system

Controls:

• Patients not suffering from a neurologic disorder
• Age > 30
• Written informed consent
• Patient covered by the national health system

Критерии исключения

For patients and controls:

• Presence of a diabetes
• Treatment with corticosteroids, estrogen, atypical antipsychotics, and anti-retroviral agents
• Patient under tutelage
• Patient unable to give consent
• Any other neurologic disorder
• Pregnancy and breastfeeding
• MOCA ≤21
• Contraindication to perform an MRI

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Распределение

Нерандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Организация здравоохранения

Центры проведения

Франция · 1 центр

• CHU de Bordeaux — Bordeaux

Идентификаторы

NCT: NCT04250493 · CHUBX 2018/30

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗