Gray Matter Demyelination in Primary Progressive MS at 7T

NCT04977622 | Unknown DMC

• 1 other identifier: A40219
• Study Type: observational
• Target: 60
• Locations: 1 country
• Sites: 1

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.

Conditions

Primary Progressive Multiple Sclerosis

Keywords

Magnetic Resonance Imaging; Ultra-high field MRI; Cortex; Multiple Sclerosis; Sensorimotor Function; Myelin; 7T; Magnetic Resonance Spectroscopy

Outcome Measures

Primary Outcomes (6)

• Distribution of cortical lesions in PPMS

  Three different types of cortical lesions will be quantified across all cortical areas (Leuko- and Intracortical, Subpial). Their number in each area will be compared to existing data of RRMS and SPMS patients. Most patients are expected to show cortical lesions. It will be assessed which areas of the cortex are affected earliest in PPMS.

  Baseline

• Volume of cortical lesions in PPMS

  The volume of the different cortical lesion subtypes \[in cubic mm\] will be quantified and compared to lesion volumes in RRMS and SPMS patients. It will be assessed which type of damage, i.e. which of the three lesion types, drives motor and cognitive impairment using linear regression models. The investigators hypothesize that more extensive cortical demyelination will relate to lower/worse test scores.

  Baseline

• Identify central veins and the presence of paramagnetic rims for cortical lesions

  Susceptibility-sensitive imaging data will be pre-processed as described in literature and co-registered with other anatomical MRI data. It will be assessed whether the location of veins or paramagnetic rims matches areas of already identified lesions. Although central veins have gained large attention in white matter lesions as an additional diagnostic criterium, their presence and role in cortical lesions is less well understood. Paramagnetic rims of MS lesions have been identified as highly relevant predictors of active disease progression. Their prevalence in PPMS \[in %\] will be assessed and relationships to clinical, behavioural and MRI metrics will be explored in mixed effects models that account for other patients specific (age, gender, disease duration, EDSS) or lesion-specific variables (volume, lesion subtype).

  Baseline

• Quantitative assessment of myelin density in cortical lesions, perilesional gray and white matter, and normal appearing cortex using myelin water imaging

  On a group level, the myelin water fraction \[in %\] will be compared between cortical lesion subtypes and the normal appearing cortex. Lesions and normal appearing cortex are expected to have lower myelin density than cortical gray matter in non-neurological individuals. The variance in myelin density among lesions is expected to be high as various degrees of demyelination and remyelination may be present. Remyelination capacity of cortical lesions may be higher than in white matter lesions and thus myelin differences between cortical lesions and normal appearing cortex may be small. Myelin water fraction values will be assessed relative to clinical and behavioural metrics in mixed effects models. The investigators hypothesize that lower myelin densities, in addition to the volume of cortical demyelination, will relate to lower/worse test scores.

  Baseline

• Quantitative assessment of magnetization transfer in cortical lesions, perilesional gray and white matter, and normal appearing cortex

  Similarly, magnetization transfer indices will be assessed between lesion subtypes, normal appearing cortex and compared to cortical gray matter in non-neurological individuals. Instead of assessing directly the relaxation times of different water environments, MT provides an indirect assessment of the interaction of mobile and bound protons. Here, the macromolecular bound pool signal fraction \[in %\] will be assessed relative to clinical and behavioural metrics in mixed effects models. The investigators hypothesize that smaller pool fractions, in addition to the volume of cortical demyelination, will relate to lower/worse test scores.

  Baseline

• Quantitative assessment of fractional anisotropy in cortical lesions, perilesional gray and white matter, and normal appearing cortex using diffusion tensor imaging data

  Fractional anisotropy (FA) is a commonly used diffusion metric for the assessment of tightly packed, myelinated axons in white matter. FA and other diffusion metrics will be compared between the cortical lesion subtypes and the normal appearing cortex. On average, lower microstructural anisotropy is expected in lesions as a reflection of demyelination and partial axonal loss. FA values will be assessed relative to clinical and behavioural metrics in mixed effects models. The investigators hypothesize that lower FA, in addition to the volume of cortical demyelination, will relate to lower/worse test scores.

  Baseline

Secondary Outcomes (7)

• Number of cortical lesions in the primary sensorimotor cortex (SM1)

  Baseline

• Cortical lesion volume in the primary sensorimotor cortex (SM1)

  Baseline

• Motor function

  Baseline

• Sensory acuity

  Baseline

• Regional metabolite concentration of the SM1

  Baseline

Other Outcomes (3)

• Depression

  Baseline

• Fatigue

  Baseline

• Morphometric measures: Whole brain cortical volume and white matter lesion volume (covariate)

  Baseline

Study Arms (2)

Primary Progressive MS (PPMS)

Clinically definite MS patients with identified primary-progressive disease onset, within 10 years of diagnosis

Non-neurological controls (HC)

Age and sex matched to the PPMS patients

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

• 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

You may not qualify if:

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

Sponsors & Collaborators

• Danish Research Centre for Magnetic Resonance: lead
• Scleroseforeningen: collaborator
• Danish Multiple Sclerosis Center: collaborator

Study Sites (1)

Danish Research Centre for Magnetic Resonance

Hvidovre, 2650, Denmark

RECRUITING

Related Publications (11)

• Miller DH, Leary SM. Primary-progressive multiple sclerosis. Lancet Neurol. 2007 Oct;6(10):903-12. doi: 10.1016/S1474-4422(07)70243-0.

  PMID: 17884680 BACKGROUND

• 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.

  PMID: 23864311 BACKGROUND

• 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.

  PMID: 32211962 BACKGROUND

• 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.

  PMID: 26468411 BACKGROUND

• 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.

  PMID: 16230320 BACKGROUND

• 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.

  PMID: 23076662 BACKGROUND

• 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.

  PMID: 27270171 BACKGROUND

• 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.

  PMID: 8057820 BACKGROUND

• 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.

  PMID: 12051469 BACKGROUND

• 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.

  PMID: 27796537 BACKGROUND

• 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.

  PMID: 33118238 BACKGROUND

MeSH Terms

Conditions

Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Vanessa Wiggermann, PhD

  Danish Research Centre for Magnetic Resonance

  PRINCIPAL INVESTIGATOR

• Hartwig R Siebner, Prof

  Danish Research Centre for Magnetic Resonance

  STUDY DIRECTOR

Central Study Contacts

Vanessa Wiggermann, PhD

CONTACT

+4538626446; vanessaw@drcmr.dk

Hartwig R Siebner, Prof

CONTACT

+45 3862 6541; h.siebner@drcmr.dk

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: April 6, 2021
• First Posted: July 27, 2021
• Study Start: November 30, 2021
• Primary Completion: June 1, 2024
• Study Completion: December 1, 2024
• Last Updated: January 29, 2024

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)