Insulin Resistance in Multiple System Atrophy

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Sponzori

University Hospital, Bordeaux

Suradnici

Université de Bordeaux

Labex Brain

Centre National de la Recherche Scientifique, France

KLINIČKO ISPITIVANJE: NCT04250493

BioSeek: nct04250493

Ključne riječi

Sažetak

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.

Opis

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.

Datumi

Posljednja provjera:	02/29/2020
Prvo podneseno:	01/28/2020
Predviđena prijava poslana:	01/28/2020
Prvo objavljeno:	01/30/2020
Posljednje ažuriranje poslano:	03/28/2020
Posljednje ažuriranje objavljeno:	03/30/2020
Stvarni datum početka studija:	06/14/2020
Procijenjeni datum primarnog završetka:	06/14/2022
Procijenjeni datum završetka studije:	06/14/2023

Stanje ili bolest

Multiple System Atrophy

Intervencija / liječenje

Biological: Homeostasis Model Assessment of insulin resistance (HOMA)

Behavioral: MOntreal Cognitive Assessment (MoCA)

Behavioral: MSA patient

Procedure: Brain Magnetic Resonance Imaging (MRI)

Biological: Blood sampling

Faza

Grupe ruku

Ruka	Intervencija / liječenje
Experimental: MSA patient Patients will be recruited at the French Reference Center for MSA.	Behavioral: MSA patient 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)
Other: Control Healthy volunteer matched for age (+/- 5years) and sex with MSA patient.

Kriterij prihvatljivosti

Dobni uvjeti za studiranje	30 Years Do 30 Years
Spolovi koji ispunjavaju uvjete za studij	All
Prihvaća zdrave volontere	Da
Kriteriji	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

Ishod

Primarne mjere ishoda

1. 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.

Sekundarne mjere ishoda

1. IRS-1pS312 (Insulin Receptor Substrate-1, Phosphorylated at Serine 312) concentration [Day 0]

Mean concentration of neuronal IRS-1pS312 in plasma exosomes

2. Unified Multiple System Atrophy Rating Scale (UMSARS) score [Day 0]

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)

3. Unified Multiple System Atrophy Rating Scale (UMSARS) score [One year]

4. COMPosite Autonomic Symptoms Score (COMPASS-31) [Day 0]

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

5. 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

6. AMS-Qol - Quality of life questionnaire [Day 0]

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

7. AMS-Qol - Quality of life questionnaire [One year]

8. MOntreal Cognitive Assessment (Moca) score [Day 0]

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)

9. MOntreal Cognitive Assessment (Moca) score [One year]

10. Brain MRI volume [Day 0]

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

11. 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

Insulin Resistance in Multiple System Atrophy

Ključne riječi

atrophy

neurodegenerative diseases

synucleinopathies

insulin resistance

dopamine

antidijabetik