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| Name | Class |
|---|---|
| University of Bordeaux | OTHER |
| Labex Brain | OTHER |
| Centre National de la Recherche Scientifique, France | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| MSA patient | Experimental | Patients will be recruited at the French Reference Center for MSA. |
|
| Control | Other | Healthy volunteer matched for age (+/- 5years) and sex with MSA patient. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Homeostasis Model Assessment of insulin resistance (HOMA) | Biological | Fasting blood sample for : glucose, insulinemia, hemoglobin and lipid test to determine the Homeostasis Model Assessment of insulin resistance (HOMA) index |
| 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 |
| 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 |
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Inclusion Criteria:
Patients :
Controls:
Exclusion Criteria:
For patients and controls:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Wassilios MEISSNER | Contact | 05 57 82 14 20 | wassilios.meissner@chu-bordeaux.fr |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| CHU de Bordeaux | Recruiting | Bordeaux | 33 076 | France |
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| ID | Term |
|---|---|
| D019578 | Multiple System Atrophy |
| D019636 | Neurodegenerative Diseases |
| C565324 | Parkinson Disease 4, Autosomal Dominant Lewy Body |
| D007333 | Insulin Resistance |
| ID | Term |
|---|---|
| D054969 | Primary Dysautonomias |
| D001342 | Autonomic Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D001480 | Basal Ganglia Diseases |
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| ID | Term |
|---|---|
| D000073216 | Mental Status and Dementia Tests |
| D001800 | Blood Specimen Collection |
| ID | Term |
|---|---|
| D009483 | Neuropsychological Tests |
| D011581 | Psychological Tests |
| D004191 | Behavioral Disciplines and Activities |
| D013048 | Specimen Handling |
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| MOntreal Cognitive Assessment (MoCA) | Behavioral | Cognitive evaluation with MOntreal Cognitive Assessment (MoCA) |
|
| Clinical characteristics of AMS patients | Behavioral | 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) |
|
| Brain Magnetic Resonance Imaging (MRI) | Procedure | Brain Magnetic Resonance Imaging (MRI) : putamen imaging, bridge and cerebellum; white substance hypersignals volume |
|
| Blood sampling | Biological | Optional blood sampling for the constitution of a biological collection |
|
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 |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009069 | Movement Disorders |
| D000080874 | Synucleinopathies |
| D006946 | Hyperinsulinism |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D019411 | Clinical Laboratory Techniques |
| D019937 | Diagnostic Techniques and Procedures |
| D003933 | Diagnosis |
| D011677 | Punctures |
| D013514 | Surgical Procedures, Operative |
| D008919 | Investigative Techniques |