Gray Matter Demyelination in Primary Progressive MS at 7T

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.

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