Quantifying Optic Nerve Inflammation and Axon Loss by Diffusion MRI

Abstract

Purpose : Axon loss is the substrate of irreversible visual impairment. Herein, we applied diffusion basis spectrum imaging (DBSI) to longitudinally quantify the extent of optic nerve axon loss and inflammation after crush injury. Results revealed co-existing axon loss and inflammation up to one month after crush injury.

Methods : Four C57BL/6 mice underwent optic nerve crush (left eye) using a pair of 45-degree-bent micro-forceps at the location approximately 1-3 mm from the eyeball for 20s. Right eye underwent the same procedure without crush as the sham control. Visual acuity (VA) was assessed before DBSI at baseline, 7- and 28-day after injury. Scans were performed on a 4.7-T Agilent small-animal MR scanner. A 25-direction diffusion scheme was employed. All images were obtained with the following acquisition parameters: TR = 1.5s, TE = 35ms, Δ = 18ms, δ = 6ms, maximal b-value = 2,200 s/mm², slice thickness = 1.0 mm, in-plane resolution = 117 × 117 µm². A lab-developed code was used to estimate λ_∥, λ_⊥, and FA derived by DBSI and DTI. DBSI derived restricted (~cellularity) and non-restricted (~edema) isotropic diffusion tensor fractions were also computed.

Results : All ONC eyes were blind (VA=0) and sham eyes maintained normal vision prior to 7- and 28-day DBSI. Axon and myelin injury was overestimated by DTI due to confounding inflammation and axon loss (Fig. 1). In addition to axon/myelin injury, DBSI further quantified the extent of edema and cell infiltration over the time (Fig. 2), approximately 37% and 55% axonal loss was detected in ONC nerves at 7- and 28-day after injury, respectively (Fig. 2).

Conclusions : DBSI quantitatively assessed optic nerve injury, the extent of axon loss, and the severity of inflammation. DBSI assessed axon loss, an irreversible pathology, could prove to be an effective biomarker of irreversible degeneration of optic nerve that can be used to assess therapeutic efficacy. Varying ONC severity is currently being pursued, in conjunction with visual function measurement and quantitative histology, to determine the threshold of axon loss leading to blindness.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

 

Figure 1 DTI measurements showed exaggerated changes as comparing to DBSI, reflecting the effect of confounding co-existing pathologies.

 

Figure 2 DBSI quantified edema, cell infiltratin, and axon loss progressed over time.