Improving the Assessment of Myelin and Axonal Integrity in Early Multiple Sclerosis

PROJECT SUMMARY
Neurodegeneration, characterized by myelin and axonal injury, is a key driver in multiple sclerosis (MS) pathology and
a major determinant of patients’ disability and outcome. Currently, it is not possible to assess neurodegeneration in vivo
because there are no magnetic resonance imaging (MRI) biomarkers sensitive and specific to myelin and axonal injury.
Finding this biometric is set as a major priority by an MS International Panel of Experts, as a path toward halting
neurodegeneration and promoting neuroprotection in MS. Accordingly, the long-term goal of the current lines of
investigations is to identify MRI biomarkers of neurodegeneration and repair that can be used to monitor disease and predict
likelihood of progression. The overall objective of this work is to establish the sensitivity to disease, neurological
dysfunction and outcome, of two novel MRI methods in patients at the time of diagnosis.
The central hypothesis of this proposal is that metrics derived from selective inversion recovery quantitative
magnetization transfer imaging (SIR-qMT) and multi-compartment microscopic diffusion imaging using the spherical mean
technique (SMT) are sensitive hallmarks of myelin and axonal neurodegenerative tissue injury early in the disease course,
and relate to and predict disease progression more accurately than currently favored MRI measures. The central hypothesis
will be tested by pursuing three specific aims: 1) Establish that metrics derived from SIR-qMT (Aim 1) and SMT (Aim 2)
are sensitive hallmarks of neurodegenerative injury and reflect neurological dysfunction cross-sectionally, early in the
disease course; 2) and explore if metrics derived from SIR-qMT and SMT predict clinical outcome and radiological
progression, longitudinally, more accurately than currently favored MRI measures (Aim 3). Longitudinal data will also be
used for sample size computations for proof of concept clinical trials on neuroprotection and repair (corollary analysis).
The research proposed in this application is innovative because, through the use of two advanced and novel MRI
techniques, this project 1) assesses and measures progression of neurodegeneration in Veterans with MS; and 2) delivers
sample computations for proof of concept clinical trials on neuroprotection. The proposed research is significant because
1) it will lay the foundation for future larger studies providing a more accurate understanding of MS progression in Veterans;
2) it will help untangle the effects of modifiable and non-modifiable Veteran-related risk factors on disease progression and
mortality; and 3) it has the potential to support new interventions and treatments.

Grant Number: 5I01CX002160-05
NIH Institute/Center: VA
Principal Investigator: Francesca Bagnato