Imaging the Interplay Between Axonal Damage and Repair in Multiple Sclerosis

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system characterized by multifocal inflammatory infiltrates, microglial activation and degradation of oligodendrocytes, myelin and axons. Clinical MS categories exhibit variable amount of central nervous system (CNS) damage and repair, depending on numerous variables including genetic, immunological, pathological and environmental factors.

Therefore, understanding the interplay between axonal damage (i.e. axonal demyelination/degeneration/loss/disorganization) and (ii) axonal repair (i.e. axonal remyelination/reorganization) in living MS patients may be the key to understand disease progression, to establish accurate disease monitoring criteria and to predict disease response to future reparative therapies. New in-vivo methods are necessary to elucidate the interplay between axonal damage and repair in the brain of living patients with MS. Advanced MRI (aMRI) permits a multifaced quantification of the various components of the axons and their organization. Neurite Orientation Dispersion and Density Imaging (NODDI) and Diffusion Kurtosis (DK) are new approaches in clinical research This study is to identify in vivo the specific neuropathological pattern of axonal damage and repair exhibited by active MS (aMS) and non-active progressive MS (naPMS) patient by leveraging the information provided by model-based diffusion metrics (NODDI, DK), Magnetization Transfer Imaging (MTI), Multi-echo Susceptibility-Based imaging (SBI), Myelin Water Imaging (MWI) and quantitative T1 relaxometry (qT1). These advanced MRI contrasts provide complementary and partially redundant information about the axonal structure and its organization (i.e. density and orientation of axons and dendrites in the brain tissue, axonal integrity and myelination, presence of myelin and iron, and brain tissue architecture). Therefore, their combination may prove high sensitivity and specificity to axonal damage and repair.

This project has 3 main aims:

Aim 1. Quantify differences in axonal integrity and organization in aMS versus naPMS patients.

Aim 2. Quantify changes in axonal integrity and organization in aMS versus naPMS patients over a two-year period.

Aim 3. Validate the combination of imaging parameters that best differentiate aMS versus naPMS patients using histopathology.

Inclusion criteria

for patients:

• Patients may be diagnosed with:

• active RRMS (n=100): Relapsing-remitting course and > 1 clinical relapse and/or signs of MRI activity (> 1 Gd enhancing lesion) during the last year before study enrollment.
• non-active PMS (n=100): Progressive course (PPMS or SPMS) and no clinical relapses and/or signs of MRI activity during the last year before study enrollment.
• Age 18-80 years old
• No other neurological or psychiatric disorder

Inclusion criteria

for healthy controls:

• Age 18-80 years old
• No other neurological or psychiatric disorder

Exclusion criteria

for patients and healthy controls:

• Pregnancy
• Contraindication to MRI (eg, claustrophobia, metallic implants, pacemaker etc).
• Inability to give consent