Disease stage-dependent relationship between diffusion tensor imaging and electrophysiology of the visual system in a murine model of multiple sclerosis

Abstract

Purpose: Diffusion tensor imaging (DTI) is commonly used to evaluate white matter integrity in multiple sclerosis (MS), but the relationship between DTI measures and functional changes during disease remains ambiguous. Using a mouse model of MS, we tested the hypothesis that DTI measures would correlate to the visual evoked potential (VEPs) dynamically at different disease stages.

Methods: In vivo DTI, gadolinium-enhanced T1WI (Gd-T1WI) and VEPs were performed in 5 control and 25 mice after 2-12 weeks of experimental autoimmune encephalomyelitis (EAE). DTI indices, including fractional anisotropy (FA), axial and radial diffusivities (AD and RD), and Gd-T1WI enhancement, were measured in the optic nerve and tract (ON and OT), which were compared with measured VEPs.

Results: Gd-T1WI showed a 3- to 4-fold enhancement over controls beginning after 2 weeks of EAE. Across the time course, we found progressive reductions in FA and increases in RD with increases in VEP latency and reductions in amplitude. Significant correlations between DTI (FA and RD) and VEP evolved; in control/early asymptomatic EAE mice, both FA and RD were highly correlated with VEP latency (but not amplitude), while in late EAE, both DTI indices were highly correlated with VEP amplitude (but not latency).

Conclusion: DTI measures FA and RD are associated to VEP latency in early stages of EAE but associated to VEP amplitude in later stages, suggesting that the patterns of DTI related to the functional decline may depend on the stage of disease progression.

Keywords: Diffusion tensor imaging (DTI); Experimental autoimmune encephalomyelitis (EAE); Gd-enhanced T1WI (Gd-T1WI); Multiple sclerosis (MS); Visual evoked potential (VEP).

Figure 1.

DTI maps from the Optic Nerve and Optic Tract. FA maps show the location of the ON and OT (left), with individual diffusion index maps show on the right. Diffusion maps are pseudocolored to show changes in each metric, with ON and OT regions of interests outlined in white. After 12 weeks of EAE, the ON has reductions in FA and increases in RD vs. controls. Alterations in the OT are less obvious, with only small reductions in anisotropy and increases in RD.

Figure 2.

Clinical scores of mice affected by EAE. Mice began to show symptoms 2–3 weeks after EAE induction.

Figure 3.

DTI measurements from the Optic Nerve and Tract. With increasing durations of EAE, the ON and OT have reductions in FA, increases in RD, and inconsistent changes in AD. “*” indicates a p<0.05 compared to controls.

Figure 4.

Averaged VEP waveforms from each experimental cohort. VEPs are increased in latency and reduced in amplitude with longer durations of EAE. “*” indicates a p<0.05 compared to controls.

Figure 5.. Gadolinium Enhancement reveals potential BBB leakage in the ON.

Top left, RARE image shows coronal slice with optic nerves outlined in white (right). Bottom left, T1 images show signal enhancement after gadolinium. Quantification (right) of enhancement in the ON and OT after Gd-injection shows selective increases above control levels in the ON but not OT. “*” indicates a p<0.05 compared to controls.

Figure 6.

Significant relationships between VEP and DTI data. VEP latency and amplitude are correlated with DTI data at different stages of disease severity. A. VEP latency is closely correlated to FA and RD measures in control and 2wk EAE mice, without any significant linear relationship at later stages of EAE (8 and 12 weeks). B. In contrast, VEP amplitude shows little relation to DTI measures during early stages of disease, but correlates well after 8 and 12 weeks of EAE. Each mouse includes two independent datapoints (ex. N=5 mice, 10 optic nerves/tracts). The 2wk time-point includes N=4 mice due to early death of one mouse.

Figure 7.

Relationships between VEP measurements and ON-Gd enhancement. A. Blood-brain barrier permeability within the ON did not correlate with VEP latency in Control / 2wk EAE groups or 8 / 12wk EAE groups. B. Gd-enhancement did show significant relation to VEP amplitude at several stages of EAE, in 2 wk and 8 wk EAE groups.