The brain possesses a system to get rid of unwanted substances, named Glymphatic System (GS). When this system is faulty, these accumulate, there is local inflammation, and progressive death of the cells. This occurs in neurological diseases including Parkinson's, or Alzheimer's. Inflammation and progressive death of the cells are also present in another neurological disorder, named Multiple Sclerosis (MS).

Doctors think that GS dysfunction plays a role in MS too. In this research therefore, the aim is to study whether it drives inflammation, and disease progression in MS patients.

The researchers have developed a new way to find signs of alteration of the GS using a scan named Magnetic Resonance Imaging (MRI) and will use it in a pilot study on patients with a condition named Clinically Isolated Syndrome (CIS), which often represents the very beginning of MS. It would therefore be demonstrated that the GS is a new mechanism of disease in CIS, which may associate with the symptoms, or the alterations in the levels of some substances in the blood suggestive of brain cells damage.

Should this study be successful, this would provide preliminary evidence to perform a larger research study to assess if GS dysfunction drives the progression of MS.

This is a cross-sectional case-control study on patients with a diagnosis of Clinically Isolated Syndrome (CIS) and a group of age- and gender-matched healthy controls.

In this study all participants will undergo two visits. In the first visit, all participants will sign the informed consent form and perform a detailed neurological examination, with administration of a few questionnaires for assessment of symptoms related to CIS/Multiple Sclerosis. Participants will also donate a sample of blood for safety analysis, analysis of biomarkers related to CIS and the glymphatic system, as well as for storage in a biobank. Participants will donate a sample of urine for urinalysis and pregnancy test in females of childbearing potential.

In the second visit, all participants will visit the Mireille Gillings Neuroimaging Centre of the University of Exeter for an MRI scan, that will last about 60 minutes.

Inclusion Criteria:

1. Male or female, aged 18 or over
2. Suitable physically and psychologically to undertake the assessments, as judged by the Investigator
3. Have voluntarily provided informed consent and have signed an ICF indicating that the purpose of the study has been explained and are willing and able to adhere to the study procedures described in the ICF.
4. (For CIS group): A diagnosis of CIS or MS at first presentation
5. Subjects must not have taken corticosteroids or IVIg or plasma-exchange within the 30 days prior to consent
6. Adequate vision and hearing to perform the study procedures
7. Medically healthy with no clinically significant findings on physical examination, laboratory profiles, vital signs at screening (with the exception of the signs of the condition under investigation)
8. Women of child-bearing potential must practice a medically acceptable method of birth control. Acceptable methods include oral contraceptive, contraceptive patch, long-acting injectable contraceptive, or double-barrier method (condom or intrauterine device with spermicide).
9. If on immunomodulatory medication, patients must have started it at least 30 days from screening and should not change their medication dose for the duration of the study.

Exclusion Criteria:

1. Have a diagnosis of clinically definite Multiple Sclerosis according to the 2017 McDonald's Criteria (Thompson et al., 2018)
2. Have a CIS limited to the spinal cord (transverse myelitis)
3. Present psychiatric disorders or severe cognitive deficit
4. Past or present history of drug or alcohol abuse
5. Are pregnant or breastfeeding, if females of childbearing potential
6. Have any other medical, neurological, or psychiatric condition or clinically significant laboratory abnormality excluding CIS which, in the opinion of the Investigator, might preclude participation
7. Are taking benzodiazepines on a regular basis or are unable to suspend intake of benzodiazepines
8. Have received any investigational product within a time-period equal to five half-lives of the product, if known, or minimum of 60 days before consent
9. Are unable to lie down for MRI scanning
10. Have any finding on the brain MRI that would compromise subject safety or the scientific integrity of the study
11. Have implants, such as implanted cardiac pacemakers or defibrillators, insulin pumps, cochlear implants, metallic ocular foreign body, implanted neural stimulators, aneurysm clips, or other medical implants that have not been deemed safe for MRI
12. Have a history of claustrophobia
13. Have any other contraindication to MRI scanning
14. Have a relapse occurred after consent but before the MRI scan
15. It is preferable the following laboratory tests are part of the subject's medical history for differential diagnosis of clinically isolated syndrome (CIS): erythrocyte sedimentation rate (ESR), antinuclear antibody (ANA), complement (C3, C4) and anticardiolipin IgG - IgM

Group 1: Patients with a diagnosis of Clinically Isolated Syndrome Group 2: Healthy controls