Clinical trial NCT04250493: Insulin Resistance in Multiple System Atrophy
Official title: Insulin Resistance in Multiple System Atrophy
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Multiple System Atrophy
Keywords: Multiple system atrophy
Neurodegenerative disease
Alpha synuclein
Insulin resistance
Lead sponsor: University Hospital, Bordeaux
Sponsor class: OTHER
Collaborators: name: University of Bordeaux
name: Labex Brain
name: Centre National de la Recherche Scientifique, France
First posted: 2020-01-31
Enrollment: 124
Sex: ALL
Minimum age (years): 30
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: HEALTH_SERVICES_RESEARCH

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

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

Exclusion Criteria:

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

Primary outcomes:
measure: HOMA Index
timeFrame: Day 0
Secondary outcomes:
measure: IRS-1pS312 (Insulin Receptor Substrate-1, Phosphorylated at Serine 312) concentration
timeFrame: Day 0
measure: Unified Multiple System Atrophy Rating Scale (UMSARS) score
timeFrame: Day 0
measure: Unified Multiple System Atrophy Rating Scale (UMSARS) score
timeFrame: One year
measure: COMPosite Autonomic Symptoms Score (COMPASS-31)
timeFrame: Day 0
measure: COMPosite Autonomic Symptoms Score (COMPASS-31)
timeFrame: One year
measure: AMS-Qol - Quality of life questionnaire
timeFrame: Day 0
measure: AMS-Qol - Quality of life questionnaire
timeFrame: One year
measure: MOntreal Cognitive Assessment (Moca) score
timeFrame: Day 0
measure: MOntreal Cognitive Assessment (Moca) score
timeFrame: One year
measure: Brain MRI volume
timeFrame: Day 0
measure: Brain MRI volume
timeFrame: One year
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: CHU de Bordeaux
Study officials:
References: