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Abstract
BackgroundMagnetic resonance imaging markers have been widely used to detect and quantify white matter pathologies in multiple sclerosis. We have recently developed a diffusion basis spectrum imaging (DBSI) to distinguish and quantify co-existing axonal injury, demyelination, and inflammation in multiple sclerosis patients and animal models. It could serve as a longitudinal marker for axonal loss, a primary cause of permanent neurological impairments and disease progression.MethodsEight 10-week-old female C57BL/6 mice underwent optic nerve DBSI, followed by a week-long recuperation prior to active immunization for experimental autoimmune encephalomyelitis (EAE). Visual acuity of all mice was assessed daily. Longitudinal DBSI was performed in mouse optic nerves at baseline (naïve, before immunization), before, during, and after the onset of optic neuritis. Tissues were perfusion fixed after final in vivo scans. The correlation between DBSI detected pathologies and corresponding immunohistochemistry markers was quantitatively assessed.ResultsIn this cohort of EAE mice, monocular vision impairment occurred in all animals. In vivo DBSI detected, differentiated, and quantified optic nerve inflammation, demyelination, and axonal injury/loss, correlating nerve pathologies with visual acuity at different time points of acute optic neuritis. DBSI quantified, in the presence of optic nerve swelling, ~15% axonal loss at the onset of optic neuritis in EAE mice.ConclusionsOur findings support the notion that axonal loss could occur early in EAE mice. DBSI detected pathologies in the posterior visual pathway unreachable by optical coherence tomography and without confounding inflammation induced optic nerve swelling. DBSI could thus decipher the interrelationship among various pathological components and the role each plays in disease progression. Quantification of the rate of axonal loss could potentially serve as the biomarker to predict treatment outcome and to determine when progressive disease starts.
Highlights
Magnetic resonance imaging markers have been widely used to detect and quantify white matter pathologies in multiple sclerosis
When Visual acuity (VA) ≤ 0.25 c/d, defined as onset of optic neuritis (ON) [22], diffusion basis spectrum imaging (DBSI) was performed and the eye was defined as eye 1 at time 1 (12.1 ± 1.9 days post-immunization, mean ± SD, n = 8)
When the VA of eye 2 decreased below 0.25 c/d, DBSI was performed again at the same day (14.4 ± 1.7 days postimmunization, mean ± SD, n = 8, one eye 2 did not develop ON but still included in statistical analyses) defined as time 2 (Fig. 1)
Summary
Magnetic resonance imaging markers have been widely used to detect and quantify white matter pathologies in multiple sclerosis. We have recently developed a diffusion basis spectrum imaging (DBSI) to distinguish and quantify co-existing axonal injury, demyelination, and inflammation in multiple sclerosis patients and animal models. It could serve as a longitudinal marker for axonal loss, a primary cause of permanent neurological impairments and disease progression. Much like MS, is characterized by inflammatory demyelination and varying degrees of axonal injury [10]. Mouse models of optic neuritis present an opportunity to evaluate the connection between imaging, pathology, and function in a disorder like MS
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