Insulin Resistance in Multiple System Atrophy
- Conditions
- Multiple System Atrophy
- Interventions
- Biological: Homeostasis Model Assessment of insulin resistance (HOMA)Behavioral: MOntreal Cognitive Assessment (MoCA)Behavioral: Clinical characteristics of AMS patientsProcedure: Brain Magnetic Resonance Imaging (MRI)Biological: Blood sampling
- Registration Number
- NCT04250493
- Lead Sponsor
- University Hospital, Bordeaux
- 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.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 124
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
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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description MSA patient Blood sampling Patients will be recruited at the French Reference Center for MSA. Control MOntreal Cognitive Assessment (MoCA) Healthy volunteer matched for age (+/- 5years) and sex with MSA patient. MSA patient Homeostasis Model Assessment of insulin resistance (HOMA) Patients will be recruited at the French Reference Center for MSA. MSA patient Brain Magnetic Resonance Imaging (MRI) Patients will be recruited at the French Reference Center for MSA. Control Brain Magnetic Resonance Imaging (MRI) Healthy volunteer matched for age (+/- 5years) and sex with MSA patient. MSA patient MOntreal Cognitive Assessment (MoCA) Patients will be recruited at the French Reference Center for MSA. Control Homeostasis Model Assessment of insulin resistance (HOMA) Healthy volunteer matched for age (+/- 5years) and sex with MSA patient. MSA patient Clinical characteristics of AMS patients Patients will be recruited at the French Reference Center for MSA. Control Blood sampling Healthy volunteer matched for age (+/- 5years) and sex with MSA patient.
- Primary Outcome Measures
Name Time Method HOMA Index Day 0 Homeostasis Model Assessment of insulin resistance (HOMA) index, calculated from a fasted blood glucose and insulin level between AMS patients and a formula-controlled group (insulinemia x glycemia)/22.5 insulinemia being expressed in mU/l and glucose in mmol/L.
- Secondary Outcome Measures
Name Time Method MOntreal Cognitive Assessment (Moca) score One year Moca evaluates short-term memory, visual spatial skills, executive functions, attention, concentration, working memory, language, abstraction abilities, computing and orientation in time and space. Cognitive impairment is assessed on the score of 30 points (27-30: no cognitive impairment; 21-26: mild)
IRS-1pS312 (Insulin Receptor Substrate-1, Phosphorylated at Serine 312) concentration Day 0 Mean concentration of neuronal IRS-1pS312 in plasma exosomes
COMPosite Autonomic Symptoms Score (COMPASS-31) One year Assessment of dysautonomia. The scale consists of 31 items in 6 domains and provides an autonomic symptom score from 0 to 100. High values represent severe symptoms
AMS-Qol - Quality of life questionnaire One year Quality of life questionnaire to collect the level of difficulty experienced by the patient (from no problem to extreme problem) during the 4 weeks preceding the interview on activities such as : move; walk; maintain balance; talk; feed. It also assesses how the patient feels about his disease
Unified Multiple System Atrophy Rating Scale (UMSARS) score One year UMSARS I (0=no disorder, 48=severe disorders): is an evaluation of activities of daily life via 12 items. It evaluates language, writing, autonomy (diet; dressing; hygiene), walking and the presence of possible urinary, sexual or intestinal disorders.
UMSARS II (0=no disorder, 56=severe disorders): consists of a motor examination on the basis of 14 items that allow to evaluate including facial expression, oculomotricity, oral expression, tremors or walking.
UMSARS III: consists of measurements of blood pressure and heart rate in the lying and standing position for 10 minutes every minute.
UMSARS IV : disability assessment from 1 to 5 (1= completely independent; 5 = totally dependent / dependent)Brain MRI volume One year Imaging data (severity and progression of putamen atrophy, bridge and cerebellum in mm3; magnitude and progression of white substance hypersignals on T2-FLAIR images in mm3
Trial Locations
- Locations (1)
CHU de Bordeaux
🇫🇷Bordeaux, France