Clinical trial NCT04977622: Gray Matter Demyelination in Primary Progressive MS at 7T
Official title: Investigating Cortical Gray Matter Demyelination in Primary Progressive Multiple Sclerosis at 7 Tesla
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Primary Progressive Multiple Sclerosis
Keywords: Magnetic Resonance Imaging
Ultra-high field MRI
Cortex
Multiple Sclerosis
Sensorimotor Function
Myelin
7T
Magnetic Resonance Spectroscopy
Lead sponsor: Danish Research Centre for Magnetic Resonance
Sponsor class: OTHER
Collaborators: name: Scleroseforeningen
name: Danish Multiple Sclerosis Center
First posted: 2021-07-27
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: 30 healthy control volunteers will be recruited from the general population via the departments webpage (www.drcmr.dk), publicly available advertising media 'http://www.forsoegsperson.dk/', links on social media portal: 'facebook' and advertisements in newsstands and communication-boards in public facilities like canteens, educational institutions, sports facilities and hospitals in the Copenhagen area.

Recruitment of 30 patients will be done through the ambulatory care at the Danish Multiple Sclerosis Center (DMSC) at Rigshospitalet in Copenhagen, Denmark.

Brief summary: Progressive-onset multiple sclerosis (PPMS) occurs in about 15% of all people living with MS. PPMS remains understudied, and most disease-modifying treatments are ineffective for PPMS. To date, it is unknown why some people progress immediately from MS onset. The present study will assess the role of gray matter in PPMS by characterizing it with ultra-high field magnetic resonance imaging (MRI). While both white and gray matter are affected in relapsing MS, in PPMS tissue damage is primarily in the cortex. Cortical gray matter consists largely of neuronal cell bodies, which send electrical signals to create a functional response, such as arm or leg movement. While white matter damage slows the signal response, cortical damage inhibits the initial creation of electrical signals. There is a great need to research and develop scientific biomarkers to identify and monitor progression and repair in PPMS. In this project, 7 Tesla MRI is used to investigate the cortical gray matter in people with PPMS. 7 Tesla MRI is the safest and most detailed way to study the brain. Because the cortex is only a few millimeters thick, it has been traditionally difficult to investigate. At 7 Tesla, different layers and lesions within the cortex can be seen. In addition, this project will use myelin-sensitive MRI to determine the biological underpinnings of both cortical lesions and the 'normal appearing' cortical damage in PPMS. This will answer relevant questions about the brain's capacity for repair, the extent of demyelination and the occurrence of inherent cortical remyelination and provides an avenue for the development of novel clinical MR biomarkers tailored to PPMS.

Detailed description: PURPOSE:

PPMS presents very differently from relapsing-remitting MS. Spinal cord involvement is greater and motor impairment significantly outweighs sensory symptoms. Contrast-enhancing lesions are infrequent in PPMS. Instead, gray matter atrophy and cortical demyelination occur at greater rates than in relapsing MS. Cortical involvement is prognostically relevant. MRI at standard clinical field strengths (e.g. 1.5 and 3 Tesla) has clear limitations for visualizing cortical damage. In particular, demyelination at the outer cortical layers is underestimated. Although 7 Tesla MRI is known to be superior to clinical MRI, myelin imaging has not yet been widely explored at 7 Tesla.

STUDY AIMS:

Use anatomical and quantitative MRI at 7 Tesla to identify radiologically visible and invisible features of cortical gray matter damage that contribute to physical and cognitive impairment in PPMS.

The specific project aims are

1. to utilize submillimeter anatomical MRI to map the distribution of the different types of cortical lesions in PPMS and assess cortical lesion volume and burden
2. to characterize and compare cortical lesions, perilesional gray and white matter as well as normal appearing gray matter (NAGM) using quantitative MR sequences
3. to explore the relationship between volumetric and myelin-measures with clinical scores in order to determine the best predictor of progression in PPMS

RESEARCH PLAN:

The investigators will enrol 30 primary-progressive MS subjects and 30 age- and sex-matched healthy controls to participate in two days of MRI experiments.

Whole-brain imaging will be performed on both days at Hvidovre Hospital on a research-only 7 Tesla Philips Achieva (Best, The Netherland) with a dual transmit, 32-channel receive head coil (Nova Medical).

Day 1: Submillimeter resolution anatomical images are collected for tissue segmentation, lesion identification, the assessment of central veins and paramagnetic rims.

In addition, a battery of physical and cognitive testing with a focus in sensorimotor hand function and cognitive processing speed will be performed, assessing two prominent symptoms of PPMS.

Day 2: Quantitative, spectroscopic (MRS) and functional MRI (fMRI) for the assessment of myelin.

ANALYSIS:

The main analysis will consist of cortical lesion identification, segmentation of both lesions and cortex and the assessment of the MRI myelin measures in both the lesions and NAGM. Control data will be used to establish a baseline measure of myelination. Myelin content in the different types of lesions and NAGM will be compared.

All statistical analysis will be performed in R. Linear and mixed effects modelling will determine how clinical, structural and MRI measures contribute to physical and cognitive performance, and will allow to extract the most relevant MR predictors of the clinical scores.

In part, the analysis will merge the acquired data with data from an ongoing study on structural and functional assessments for sensorimotor function in relapsing-remitting (RRMS) and secondary progressive MS (SPMS) (NCT03653585). This will allow to place the PPMS cohort directly in the context of other subtypes of MS.

The present study will significantly enhance the understanding of cortical damage in PPMS, the main contributor to chronic impairment. The non-invasive characterization of cortical lesions, structurally and in terms of myelin, will answer relevant questions about the brain's capacity for repair, the extent of demyelination and the occurrence of inherent cortical remyelination.

Eligibility criteria: PATIENTS

Inclusion Criteria:

* Diagnosed with primary progressive multiple sclerosis
* Expanded Disability Status Scale of ≤ 6.5
* No clinical relapse within last three months
* Have the ability to comply with all requirements of the study protocol, as determined by the investigator

Exclusion Criteria:

* Pregnancy
* Pacemaker or other implanted electronic devices
* Claustrophobia
* Psychiatric disorder
* Administration of acute cortisol
* Changes in pharmacological treatment within the last 3 months
* Any contraindication to MRI
* Persons who do not wish to be informed about abnormal findings as part of the investigations

HEALTHY CONTROLS

Inclusion Criteria:

* Able bodied
* Have the ability to comply with all requirements of the study protocol, as determined by the investigator

Exclusion Criteria:

* Pregnancy
* Under medication at the time of the experiment (with the exception of contraceptive drugs)
* History of neurologic disease
* Pacemaker or other implanted electronic devices
* History of cerebral hemorrhage or brain damage
* Claustrophobia
* Psychiatric disorder
* Any contraindication to MRI
* Persons who do not wish to be informed about abnormal findings as part of the investigations

Primary outcomes:
measure: Distribution of cortical lesions in PPMS
timeFrame: Baseline
measure: Volume of cortical lesions in PPMS
timeFrame: Baseline
measure: Identify central veins and the presence of paramagnetic rims for cortical lesions
timeFrame: Baseline
measure: Quantitative assessment of myelin density in cortical lesions, perilesional gray and white matter, and normal appearing cortex using myelin water imaging
timeFrame: Baseline
measure: Quantitative assessment of magnetization transfer in cortical lesions, perilesional gray and white matter, and normal appearing cortex
timeFrame: Baseline
measure: Quantitative assessment of fractional anisotropy in cortical lesions, perilesional gray and white matter, and normal appearing cortex using diffusion tensor imaging data
timeFrame: Baseline
Secondary outcomes:
measure: Number of cortical lesions in the primary sensorimotor cortex (SM1)
timeFrame: Baseline
measure: Cortical lesion volume in the primary sensorimotor cortex (SM1)
timeFrame: Baseline
measure: Motor function
timeFrame: Baseline
measure: Sensory acuity
timeFrame: Baseline
measure: Regional metabolite concentration of the SM1
timeFrame: Baseline
measure: Functional MRI data for the assessment of temporal synchronization
timeFrame: Baseline
measure: Cognitive performance and relationship to MRI measures (Exploratory)
timeFrame: Baseline
Other outcomes:
measure: Depression
timeFrame: Baseline
measure: Fatigue
timeFrame: Baseline
measure: Morphometric measures: Whole brain cortical volume and white matter lesion volume (covariate)
timeFrame: Baseline
Locations:
city: Hvidovre
country: Denmark
facility: Danish Research Centre for Magnetic Resonance
Study officials:
affiliation: Danish Research Centre for Magnetic Resonance
name: Vanessa Wiggermann, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Danish Research Centre for Magnetic Resonance
name: Hartwig R Siebner, Prof
role: STUDY_DIRECTOR
References:
citation: Miller DH, Leary SM. Primary-progressive multiple sclerosis. Lancet Neurol. 2007 Oct;6(10):903-12. doi: 10.1016/S1474-4422(07)70243-0.
citation: Nielsen AS, Kinkel RP, Madigan N, Tinelli E, Benner T, Mainero C. Contribution of cortical lesion subtypes at 7T MRI to physical and cognitive performance in MS. Neurology. 2013 Aug 13;81(7):641-9. doi: 10.1212/WNL.0b013e3182a08ce8. Epub 2013 Jul 17.
citation: Cocozza S, Cosottini M, Signori A, Fleysher L, El Mendili MM, Lublin F, Inglese M, Roccatagliata L. A clinically feasible 7-Tesla protocol for the identification of cortical lesions in Multiple Sclerosis. Eur Radiol. 2020 Aug;30(8):4586-4594. doi: 10.1007/s00330-020-06803-y. Epub 2020 Mar 24.
citation: Louapre C, Govindarajan ST, Gianni C, Langkammer C, Sloane JA, Kinkel RP, Mainero C. Beyond focal cortical lesions in MS: An in vivo quantitative and spatial imaging study at 7T. Neurology. 2015 Nov 10;85(19):1702-9. doi: 10.1212/WNL.0000000000002106. Epub 2015 Oct 14.
citation: Kutzelnigg A, Lucchinetti CF, Stadelmann C, Bruck W, Rauschka H, Bergmann M, Schmidbauer M, Parisi JE, Lassmann H. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain. 2005 Nov;128(Pt 11):2705-12. doi: 10.1093/brain/awh641. Epub 2005 Oct 17.
citation: Chang A, Staugaitis SM, Dutta R, Batt CE, Easley KE, Chomyk AM, Yong VW, Fox RJ, Kidd GJ, Trapp BD. Cortical remyelination: a new target for repair therapies in multiple sclerosis. Ann Neurol. 2012 Dec;72(6):918-26. doi: 10.1002/ana.23693. Epub 2012 Oct 17.
citation: Absinta M, Sati P, Schindler M, Leibovitch EC, Ohayon J, Wu T, Meani A, Filippi M, Jacobson S, Cortese IC, Reich DS. Persistent 7-tesla phase rim predicts poor outcome in new multiple sclerosis patient lesions. J Clin Invest. 2016 Jul 1;126(7):2597-609. doi: 10.1172/JCI86198. Epub 2016 Jun 6.
citation: MacKay A, Whittall K, Adler J, Li D, Paty D, Graeb D. In vivo visualization of myelin water in brain by magnetic resonance. Magn Reson Med. 1994 Jun;31(6):673-7. doi: 10.1002/mrm.1910310614.
citation: Ingle GT, Thompson AJ, Miller DH. Magnetic resonance imaging in primary progressive multiple sclerosis. J Rehabil Res Dev. 2002 Mar-Apr;39(2):261-71.
citation: Dal-Bianco A, Grabner G, Kronnerwetter C, Weber M, Hoftberger R, Berger T, Auff E, Leutmezer F, Trattnig S, Lassmann H, Bagnato F, Hametner S. Slow expansion of multiple sclerosis iron rim lesions: pathology and 7 T magnetic resonance imaging. Acta Neuropathol. 2017 Jan;133(1):25-42. doi: 10.1007/s00401-016-1636-z. Epub 2016 Oct 27.
citation: Wiggermann V, MacKay AL, Rauscher A, Helms G. In vivo investigation of the multi-exponential T2 decay in human white matter at 7 T: Implications for myelin water imaging at UHF. NMR Biomed. 2021 Feb;34(2):e4429. doi: 10.1002/nbm.4429. Epub 2020 Oct 28.