Natural History and Disease Progression Biomarkers of Multiple System Atrophy

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

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.

Eligibility Criteria:
INCLUSION CRITERIA:

Applicable to MSA patients:

* Patients with possible or probable MSA according to consensus diagnosis criteria \[Gilman et al., 2008\]
* Patients aged between 30 and 80 years
* Patients at the early stages of the disease, defined as maximum 5 years since the onset of one of the following symptoms associated to MSA:

Parkinsonism Ataxia Orthostatic hypotension and/or urinary dysfunction - Patients with an anticipated survival of at least 3 years on the basis of Investigators' clinical judgment

Applicable to healthy controls:

* Participants with a similar age (+/- 5 years) and gender distribution compared to MSA patients
* Participants with absence of neurological pathology
* Patients aged between 25 and \< 80 years

Applicable to both patients and healthy controls:

- Participants who voluntarily sign the written informed consent form, indicating that they understand the purpose of and procedures required for the study and are willing to participate in it Participants affiliated to the French social security health system

EXCLUSION CRITERIA:

Applicable to MSA patients:

* Speech impairment (score of ≥3 on UMSARS (Unified Multiple System Atrophy Rating Scale) question 1);
* Impairment in ambulation (score of ≥3 on UMSARS (Unified Multiple System Atrophy Rating Scale) question 7)
* Falling more frequently than once per week (score of ≥3 on UMSARS (Unified Multiple System Atrophy Rating Scale) question 8)

Applicable to both MSA patients and healthy controls:

* Participants with significant cognitive impairment (MoCA score \<21)
* Any major medical or psychiatric condition which may compromise participation in the study or the safety, at the discretion of the Investigator
* Contraindications for MRI imaging, including claustrophobia and presence of metallic implants such as cardiac or auditory prostheses, pacemakers or cerebral clips
* Contraindications to obtain a FP-CIT SPECT(Single Photon Emission Computed Tomography) (i.e. known hypersensitivity to the active substance or to any of the excipients, or to iodine)
* Current pharmacological treatments that may alter the DAT(dopamine transporter ) SPECT (Single Photon Emission Computed Tomography) reading, including amphetamines, benzatropine, buproprion (amfebutamone), cocaine, mazindol, methylphenidate, phentermine or sertraline
* Females who are pregnant, breast feeding or of child bearing age without effective contraception
* Participants who lack the capacity to give informed consent
* Participants taking any investigational products within 3 months before baseline assessment
* Participant under adult autonomy protection system, legal guardianship or incapacitation.

Additional exclusion criteria concerning only patients consenting to the lumbar puncture:

* Coagulopathy and/or anticoagulant treatment
* Thrombocytopenia
* Intracranial hypertension
* Severe degenerative arthritis of the lumbar spine Patients failing to meet these criteria can still participate in the study and all other study assessments (with the exception of lumbar puncture) as appropriate.