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Diffusion MRI quantifies early axonal loss in the presence of nerve swelling

View Article: PubMed Central - PubMed

ABSTRACT

Background: 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.

Methods: Eight 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.

Results: In 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.

Conclusions: Our 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.

No MeSH data available.


Related in: MedlinePlus

Visual acuity (VA) of EAE mice (n = 8) from baseline, pre-onset (time 1 of eye 2), onset (time 1 of eye 1 and time 2 of eye 2), and post-onset (time 2 of eye 1). Eye 1 = filled symbols; eye 2 = open symbols. The dotted line indicates VA = 0.25 c/d, which was the threshold of defined onset of optic neuritis. The results indicated that there was no visual acuity difference between eye 1 and eye 2 at time 2 (p = 0.15)
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Fig1: Visual acuity (VA) of EAE mice (n = 8) from baseline, pre-onset (time 1 of eye 2), onset (time 1 of eye 1 and time 2 of eye 2), and post-onset (time 2 of eye 1). Eye 1 = filled symbols; eye 2 = open symbols. The dotted line indicates VA = 0.25 c/d, which was the threshold of defined onset of optic neuritis. The results indicated that there was no visual acuity difference between eye 1 and eye 2 at time 2 (p = 0.15)

Mentions: For each mouse in our cohort, onset of optic neuritis, as indicated by impairment of visual function defined by VA, did not occur simultaneously for both eyes. We therefore defined time 1 as the day in which the first eye had a VA ≤0.25 c/d and time 2 as the day in which the second eye had a VA ≤0.25 c/d. Concordantly, for each mouse, eye 1 is the eye affected at time 1 and eye 2 is the eye affected at time 2. VA for each eye is presented in Fig. 1. Based on this experimental paradigm, time 1 and time 2 corresponded to onset and post-onset of optic neuritis for eye 1 and pre-onset and onset of optic neuritis for eye 2, respectively.Fig. 1


Diffusion MRI quantifies early axonal loss in the presence of nerve swelling
Visual acuity (VA) of EAE mice (n = 8) from baseline, pre-onset (time 1 of eye 2), onset (time 1 of eye 1 and time 2 of eye 2), and post-onset (time 2 of eye 1). Eye 1 = filled symbols; eye 2 = open symbols. The dotted line indicates VA = 0.25 c/d, which was the threshold of defined onset of optic neuritis. The results indicated that there was no visual acuity difference between eye 1 and eye 2 at time 2 (p = 0.15)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5384143&req=5

Fig1: Visual acuity (VA) of EAE mice (n = 8) from baseline, pre-onset (time 1 of eye 2), onset (time 1 of eye 1 and time 2 of eye 2), and post-onset (time 2 of eye 1). Eye 1 = filled symbols; eye 2 = open symbols. The dotted line indicates VA = 0.25 c/d, which was the threshold of defined onset of optic neuritis. The results indicated that there was no visual acuity difference between eye 1 and eye 2 at time 2 (p = 0.15)
Mentions: For each mouse in our cohort, onset of optic neuritis, as indicated by impairment of visual function defined by VA, did not occur simultaneously for both eyes. We therefore defined time 1 as the day in which the first eye had a VA ≤0.25 c/d and time 2 as the day in which the second eye had a VA ≤0.25 c/d. Concordantly, for each mouse, eye 1 is the eye affected at time 1 and eye 2 is the eye affected at time 2. VA for each eye is presented in Fig. 1. Based on this experimental paradigm, time 1 and time 2 corresponded to onset and post-onset of optic neuritis for eye 1 and pre-onset and onset of optic neuritis for eye 2, respectively.Fig. 1

View Article: PubMed Central - PubMed

ABSTRACT

Background: 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.

Methods: Eight 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.

Results: In 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.

Conclusions: Our 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.

No MeSH data available.


Related in: MedlinePlus