Clinical trial NCT05177523: Imaging the Interplay Between Axonal Damage and Repair in Multiple Sclerosis
Official title: INsIDER: Imaging the Interplay Between Axonal Damage and Repair in Multiple Sclerosis
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Multiple Sclerosis (MS)
Relapsing-remitting Multiple Sclerosis (RRMS)
Secondary-progressive Multiple Sclerosis (SPMS)
Primary Progressive Multiple Sclerosis (PPMS)
Keywords: axonal damage
axonal demyelination
axonal degeneration
axonal loss
axonal disorganization
axonal repair
axonal remyelination
axonal reorganization
Advanced MRI (aMRI)
Neurite Orientation Dispersion and Density Imaging (NODDI)
Diffusion Kurtosis (DK)
Magnetization Transfer Imaging (MTI)
Multi-echo Susceptibility-Based imaging (SBI)
Myelin Water Imaging (MWI)
T1 relaxometry (quantitative T1, qT1)
machine learning technique
Lead sponsor: University Hospital, Basel, Switzerland
Sponsor class: OTHER
Collaborators: name: Swiss National Science Foundation
First posted: 2022-01-04
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: The recruitment of MS patients will take place at the MS Clinic of the Department of Neurology (Neurologische Klinik und Poliklinik), University Hospital Basel (Universitätsspital Basel). Healthy subjects will be recruited by public announcements (i.e. advertisement/flyer) on the University Hospital's and the University's notice board.

Brief summary: This project is to:

1. Quantify differences in axonal integrity and organization in aMS versus naPMS patients.
2. Quantify changes in axonal integrity and organization in aMS versus naPMS patients over a two-year period.
3. Validate the combination of imaging parameters that best differentiate aMS versus naPMS patients using histopathology.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria for patients:

* Patients may be diagnosed with:

  1. 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.
  2. 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

Primary outcomes:
measure: MRI- change in axonal integrity and organization over 2 years in aMS, naPMS and HC, by using machine learning techniques
timeFrame: at baseline and 2 years (+/- 3 months) after baseline
Secondary outcomes:
measure: Change in MUSIC Test
timeFrame: at baseline and 2 years (+/- 3 months) after baseline
measure: Change in auditory verbal learning and memory test/ Verbaler Lern- und Merkfähigkeitstest (VLMT)
timeFrame: at baseline and 2 years (+/- 3 months) after baseline
measure: Change in Symbol Digital Modalities Test (SDMT)
timeFrame: at baseline and 2 years (+/- 3 months) after baseline
measure: Change in Brief Visuospatial Memory Test (BVMT)
timeFrame: at baseline and 2 years (+/- 3 months) after baseline
measure: Change in Hospital Anxiety and Depression Scale (HADS)
timeFrame: at baseline and 2 years (+/- 3 months) after baseline
Other outcomes:
Locations:
city: Basel
country: Switzerland
facility: University Hospital Basel, Department of Neurology
Study officials:
affiliation: Department of Neurology, University Hospital Basel
name: Cristina Granziera, Prof. Dr. med.
role: PRINCIPAL_INVESTIGATOR
References: