Longitudinal Assessment of Iron Rims in MS Lesions
ConditionMultiple Sclerosis
Trial statusRecruiting
Trial phaseNot listed
Trial typeObservational
Biological sexAll
Age16+
SponsorNottingham University Hospitals NHS Trust
About this trial
In multiple sclerosis (MS), the presence of white matter lesions surrounded by a rim of iron is suggested to signify a more severe disease course. Iron rim lesions can be detected through their appearance on susceptibility-based brain MRI at either 3-Tesla or 7-Tesla strength. We know that the formation of chronic active lesions is not uniform across MS cohorts so identifying risk factors which predispose individuals to the formation of rim lesions may provide a useful biomarker for clinical progression. One candidate set of risk factors include genetic variants which prevent some MS patients from resolving acute inflammation following their initial wave of inflammatory demyelination at lesion onset.
Additionally, only small longitudinal clinical cohorts have reported the evolution of iron rim lesions many years after their initial formation, as well as their link to clinical disability or disease progression.
NUH hold 7T-MRI scans of over 100 patients who received a research MRI with iron-sensitive sequences between 2008-2012. We will recruit 100 patients that received brain MRI several years ago to provide blood samples. The blood samples along with the previously acquired MRI scan will be sent to Johns Hopkins University in the US where genotyping studies will be performed to explore whether this genetic variation contributes to the accrual of chronic active rim lesions in MS. Patients who consent to provide blood samples will also have the option to consent to receive an additional 7-Tesla MRI scan which will allow us to compare how rim lesions evolve and whether their presence is correlated with disability. 30 MRI scans will initially be performed as funding for this amount is already secured.
Following analysis of the pilot phase 1 data and securing additional funds, we will contact more patients who have already consented to receive the additional MRI to receive the scan
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
Men and women aged above 16 years
Clinical diagnosis of MS as per revised McDonald Criteria 2017
Existing susceptibility-weighted brain MRI scan
Able to provide blood samples
Disqualifiers
Unwilling or unable to comply with the requirements of this protocol including the presence of any condition (physical, mental or social) that, in the opinion of the PI, is likely to affect the participants ability to comply with the study protocol.
Unable to provide informed consent.
Trial population
Participants will be identified through the clinical cohort that previously consented to research participation between 2008 - 2012 where susceptibility based brain MRI scans were obtained. From those who meet the above criteria, 100 participants will provide blood samples, 30 of those participants who consented to also receive an MRI will be invited to have a 7T MRI scan for phase 1 of the longitudinal study, and more participants will be recruited to phase 2 after the analysis of the pilot data.
Trial design
Design model
Cohort
Time perspective
Prospective
Treatments tested in this trial
Blood sample provided
Biological/VaccineIndividuals who consent to provide a blood sample will be included in the cross-sectional genetics study.
7-T MRI scan
Diagnostic testIndividuals who consent to receive an additional 7-T MRI scan will be invited to the Sir Peter Mansfield Imaging Centre. This current MRI will be compared against the baseline 7-T scan performed between 2008 - 2012.
Treatment groups
100 Participants
are divided into 2 treatment groupsGroup A: 1 - Cross sectional genetics study1 intervention
Group B: 2 - Longitudinal cohort MRI study1 intervention
Trial outcomes
Primary outcomes
1
Cross-sectional: To identify gene variants or genetic network predictors of chronic perilesional inflammation in patients classified by the presence of rim lesions on brain MRI.
Primary analyses will evaluate the pre-specified set of known MS-risk variants (both major histocompatibility \[MH\] and non-MH variants) as they relate to rim-lesion formation risk. Secondary unbiased analyses will evaluate novel variants contributing to rim lesion risk.
Time frame
12 months2
Longitudinal: To assess whether the presence and frequency of iron rim lesions in MS patients is associated with a more severe disability or disease course by comparing clinical and cognitive outcomes.
Comparing changes between baseline and current iron rim lesion presence and count with the changes in clinical disability assessed with EDSS and ARMSS.
Time frame
9 monthsSecondary outcomes
1
Cross-sectional: To integrate genetic risk variant information.
This will involve 1) single-nucleus RNA-seq (snRNA-seq) data from human MS lesions and, 2) genetics studies of microglia and other relevant cell types, to identify candidate transcriptional changes in key CNS cell types.We will leverage unique resources available from ongoing snRNA-seq studies (led by Dr. Absinta) that will allow us to correlate genetic risk variants or networks with activity of different cell types hypothesized to be relevant. Taken together, these analyses will integrate transcriptomic and epi-genomic information from studies of microglia and other relevant cell types to understand potential co-localizing biological signals contributing to rim lesions formation.
Time frame
12 months2
Longitudinal: To assess long-term evolution of iron rim presence and frequency from T2* MRI scans of MS patients.
Assess whether iron rim lesions expand or reduce over time.
Time frame
9 monthsSponsors and contacts
Click on the lead sponsor to view all of their trials.
Nottingham University Hospitals NHS Trust
Lead sponsor
Johns Hopkins University
Collaborator
Source ClinicalTrials.gov