Natural History and Disease Progression Biomarkers of Multiple System Atrophy

Not Applicable

Completed

• Conditions: Multiple System Atrophy
• Interventions: Diagnostic Test: MRI acquisition; Behavioral: Evaluation about depression cognition; Diagnostic Test: DAT-SPECT; Diagnostic Test: blood sample, cerebrospinal fluid (optional); Behavioral: Evaluations about motor abilities, depression, cognition and lifestyle

• Registration Number: NCT04229173
• Lead Sponsor: University Hospital, Toulouse

Brief Summary

Multiple system atrophy (MSA) is a rare and fatal neurodegenerative disease characterised by a variable combination of parkinsonism, cerebellar impairment and autonomic dysfunction. The neuropathological hallmark is the accumulation of alpha-synuclein in oligodendrocytes. While some symptomatic treatments exist, neuroprotective treatments for MSA remain an urgent, unmet need. Moreover, at present there is not a single surrogate biomarker of MSA which could be used to inform clinical trials.

This study seeks to characterise the natural history of MSA on a panel of candidate biomarkers, pre-selected for being putative surrogates of the underlying neurodegenerative process

Detailed Description

Surrogate biomarkers are objectively measured characteristics of a disease which act as indicators of the underlying pathophysiological processes responsible for disease progression. Reduced grey matter volume in putamen, cerebellum and brainstem as measured with MRI have been consistently reported to differentiate MSA from other parkinsonian disorders. However, to date, there are no longitudinal studies examining the natural history of MSA on these structural neuroimaging markers over time. The magnitude of the abnormalities observed cross-sectionally in MSA compared to other parkinsonian disorders and the fast clinical progression of the disease make it very likely that structural changes can be observed even over short periods of time. There is also a strong scientific rationale for the potential of measures reflecting white matter integrity, cerebral iron deposition and presynaptic dopaminergic dysfunction, as well as levels of neurofilament light chain (NfL), alpha-synuclein and other proteins involved in the neurodegenerative process in MSA, to serve as progression biomarkers of the disease, although supporting evidence remains limited. A better understanding of the natural history of MSA over 6 and 12 months on a panel of candidate surrogate biomarkers is needed to better understand the disease, help optimise future trial designs in terms of patient selection, sample size and trial duration, and improve the ability to measure the therapeutic effects of novel treatments.

In evaluating potential progression markers of a neurodegenerative disease such as MSA, it is important to control for the normal effects of aging. Studies in healthy volunteers have shown regionally distinct effects of aging on both brain volume and dopamine transporter density, justifying the inclusion of healthy controls with a similar age and gender distribution than patients.

Study Timeline

• Study First Submitted: 2019-11-28
• Study First Submitted QC: 2020-01-10
• Study First Posted: 2020-01-18
• Study Start: 2020-05-26
• Primary Completion: 2022-05-30
• Study Completion: 2022-10-28
• Status Verified: 2023-06
• Last Update Submitted: 2023-06-19
• Last Update Posted: 2023-06-22

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 61

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
MSA patients	blood sample, cerebrospinal fluid (optional)	Patients with multiple system atrophy will be examined at baseline, 6 months and 12 months via the following procedures performed at all 3 visits: * a clinical examination; * blood and cerebrospinal fluid (CSF) (optional) sampling for the assessment of selected fluid biomarkers; * MRI for the assessment of brain volume, white matter integrity and cerebral iron deposition; DAT-SPECT (Dopamine Transporter, Single Photon Emission Computed Tomography) for the assessment of presynaptic dopaminergic function
MSA patients	MRI acquisition	Patients with multiple system atrophy will be examined at baseline, 6 months and 12 months via the following procedures performed at all 3 visits: * a clinical examination; * blood and cerebrospinal fluid (CSF) (optional) sampling for the assessment of selected fluid biomarkers; * MRI for the assessment of brain volume, white matter integrity and cerebral iron deposition; DAT-SPECT (Dopamine Transporter, Single Photon Emission Computed Tomography) for the assessment of presynaptic dopaminergic function
MSA patients	Evaluations about motor abilities, depression, cognition and lifestyle	Patients with multiple system atrophy will be examined at baseline, 6 months and 12 months via the following procedures performed at all 3 visits: * a clinical examination; * blood and cerebrospinal fluid (CSF) (optional) sampling for the assessment of selected fluid biomarkers; * MRI for the assessment of brain volume, white matter integrity and cerebral iron deposition; DAT-SPECT (Dopamine Transporter, Single Photon Emission Computed Tomography) for the assessment of presynaptic dopaminergic function
Healthy volunteers	MRI acquisition	healthy. Controls will undergo an MRI scan at baseline, 6 months and 12 months, and a DAT-SPECT(Dopamine Transporter, Single Photon Emission Computed Tomography) scan at baseline and 12 months.
Healthy volunteers	Evaluation about depression cognition	healthy. Controls will undergo an MRI scan at baseline, 6 months and 12 months, and a DAT-SPECT(Dopamine Transporter, Single Photon Emission Computed Tomography) scan at baseline and 12 months.
MSA patients	DAT-SPECT	Patients with multiple system atrophy will be examined at baseline, 6 months and 12 months via the following procedures performed at all 3 visits: * a clinical examination; * blood and cerebrospinal fluid (CSF) (optional) sampling for the assessment of selected fluid biomarkers; * MRI for the assessment of brain volume, white matter integrity and cerebral iron deposition; DAT-SPECT (Dopamine Transporter, Single Photon Emission Computed Tomography) for the assessment of presynaptic dopaminergic function

Primary Outcome Measures

Name	Time	Method
Change putamen, cerebellum and brainstem volume measured on MRI	at 12 month	volume measured with T1-3D MRI, unit : Volume (mm3), Fer: R2\* (s-1), diffusion: mean diffusivity (mm2s-1)

Secondary Outcome Measures

Name	Time	Method
Effect of disease progression on other measures of brain structural integrity and iron accumulation	6 month and 12 month	volume measured with T1-3D MRI, unit : Volume (mm3), Fer: R2\* (s-1), diffusion: mean diffusivity (mm2s-1)
Effect of disease progression on axonal damage as evidenced in biofluids	6 month and 12 month	biomarkers dosages in blood and Cerebral Spinal Fluid total Concentration unit : pg/ml.
Effect of disease progression on the loss of presynaptic dopaminergic terminals in the striatum integrity and iron accumulation	6 month and 12 month	volume measured with DAT SPECT (Single Photon Emission Computed Tomography), unit : binding potential (e.g ratio striatum/brain activity)

Trial Locations

Locations (10)

CHU de Bordeaux; 🇫🇷 Bordeaux, France

Hôpital Neurologique Pierre Wertheimer; 🇫🇷 Bron, France

CHU Lille; 🇫🇷 Lille, France

CHU de Nancy; 🇫🇷 Nancy, France

Hôpital Pitié-Salpêtrière; 🇫🇷 Paris, France

Hôpital de La Timone; 🇫🇷 Marseille, France

Clinique neurologique - Hôpital Laennec; 🇫🇷 Nantes, France

CHU; 🇫🇷 Toulouse, France

Chu Clermont Ferrand; 🇫🇷 Clermont Ferrand, France

Hôpital de Hautepierre; 🇫🇷 Strasbourg, France