Insulin Resistance in Multiple System Atrophy (IRAMS)

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.

Study Overview

• Status: Recruiting
• Conditions: Multiple System Atrophy
• Intervention / Treatment: Biological: Homeostasis Model Assessment of insulin resistance (HOMA); Behavioral: MOntreal Cognitive Assessment (MoCA); Behavioral: Clinical characteristics of AMS patients; Procedure: Brain Magnetic Resonance Imaging (MRI); Biological: Blood sampling

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.

• Study Type: Interventional
• Enrollment (Anticipated): 124
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Anna DELAMARRE; Phone Number: 05 33 51 47 19; Email: anna.delamarre@u-bordeaux.fr

Study Locations

• France
  • Bordeaux, France, 33 076
    • Recruiting
    • CHU de Bordeaux
    • Contact: Anna DELAMARRE; Phone Number: 05 33 51 47 19; Email: anna.delamarre@u-bordeaux.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Health Services Research
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MSA patient; Patients will be recruited at the French Reference Center for MSA.	Biological: 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; Behavioral: MOntreal Cognitive Assessment (MoCA); Cognitive evaluation with MOntreal Cognitive Assessment (MoCA); Behavioral: 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); Procedure: Brain Magnetic Resonance Imaging (MRI); Brain Magnetic Resonance Imaging (MRI) : putamen imaging, bridge and cerebellum; white substance hypersignals volume; Biological: Blood sampling; Optional blood sampling for the constitution of a biological collection
Other: Control; Healthy volunteer matched for age (+/- 5years) and sex with MSA patient.	Biological: 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; Behavioral: MOntreal Cognitive Assessment (MoCA); Cognitive evaluation with MOntreal Cognitive Assessment (MoCA); Procedure: Brain Magnetic Resonance Imaging (MRI); Brain Magnetic Resonance Imaging (MRI) : putamen imaging, bridge and cerebellum; white substance hypersignals volume; Biological: Blood sampling; Optional blood sampling for the constitution of a biological collection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HOMA Index	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.	Day 0

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
IRS-1pS312 (Insulin Receptor Substrate-1, Phosphorylated at Serine 312) concentration	Mean concentration of neuronal IRS-1pS312 in plasma exosomes	Day 0
Unified Multiple System Atrophy Rating Scale (UMSARS) score	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)	Day 0
Unified Multiple System Atrophy Rating Scale (UMSARS) score	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)	One year
COMPosite Autonomic Symptoms Score (COMPASS-31)	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	Day 0
COMPosite Autonomic Symptoms Score (COMPASS-31)	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	One year
AMS-Qol - Quality of life questionnaire	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	Day 0
AMS-Qol - Quality of life questionnaire	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	One year
MOntreal Cognitive Assessment (Moca) score	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)	Day 0
MOntreal Cognitive Assessment (Moca) score	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)	One year
Brain MRI volume	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	Day 0
Brain MRI volume	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	One year

Collaborators and Investigators

• Sponsor: University Hospital, Bordeaux
• Collaborators: University of Bordeaux; Centre National de la Recherche Scientifique, France; Labex Brain

Study record dates

Study Major Dates

• Study Start (Actual): October 28, 2020
• Primary Completion (Anticipated): October 28, 2023
• Study Completion (Anticipated): October 28, 2023

Study Registration Dates

• First Submitted: January 29, 2020
• First Submitted That Met QC Criteria: January 29, 2020
• First Posted (Actual): January 31, 2020

Study Record Updates

• Last Update Posted (Actual): March 31, 2022
• Last Update Submitted That Met QC Criteria: March 29, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Insulin resistance; Neurodegenerative disease; Multiple system atrophy; Alpha synuclein
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Pathological Conditions, Anatomical; Hyperinsulinism; Autonomic Nervous System Diseases; Primary Dysautonomias; Hypotension; Insulin Resistance; Atrophy; Multiple System Atrophy; Shy-Drager Syndrome; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin
• Other Study ID Numbers: CHUBX 2018/30

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No