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Diffusion Basis Spectrum Imaging Measures Anti-Inflammatory and Neuroprotective Effects of Fingolimod on Murine Optic Neuritis

Yang, R;Lin, T;Zhan, J;Lai, S;Song, C;Sun, P;Ye, Z;Wallendorf, M;George, A;Cross, A;Song, S;

Background A readily implemented noninvasive imaging modality for evaluating underlying disease
pathology of optic neuritis (ON) and effectiveness of therapeutics in people with CNS demyelinating
diseases is currently lacking. This study aims to prospectively determine whether diffusion basis
spectrum imaging (DBSI) detects, differentiates and quantitates coexisting inammation, demyelination,
axonal injury and axon loss in mice with ON due to experimental autoimmune encephalomyelitis (EAE),
and to determine if DBSI accurately measures effects of ngolimod on underlying pathology.
Methods EAE was induced in 7-week-old C57BL/6 female mice. Visual acuity (VA) was assessed daily to
detect onset of ON (VA ≤ 0.25 cycle/degree of either eye) after which daily oral treatment with either
ngolimod (1 mg/kg) or saline was given for ten weeks. In vivo DBSI scans of optic nerves were
performed at baseline (before immunization), 2-, 6- and 10-weeks post treatment. DBSI-derived metrics
including restricted isotropic diffusion tensor fraction (putatively reecting cellularity), non-restricted
isotropic diffusion tensor fraction (putative reecting vasogenic edema), DBSI-derived axonal volume,
axial diffusivity, λ∥
(putative reecting axonal integrity), and increased radial diffusivity, λ⊥ (putatively
reecting demyelination). Mice were killed immediately after the last DBSI scan for immunohistochemical
assessment.
Results Optic nerves of ngolimod-treated mice exhibited signicantly higher (p < 0.05) VA scores than
saline-treated group at each time point. During ten-week of treatment, DBSI-derived non-restricted and
restricted isotropic diffusion tensor fractions, and axonal volumes were not signicantly different (p >
0.05) from the baseline values in ngolimod-treated mice, suggesting protection in the ngolimod treated
mice. In contrast, in the saline-treated mice, transient DBSI-λ∥ decrease and DBSI-λ⊥ increase were also
detected during Fingolimod treatment. DBSI-derived metrics assessed in vivo signicantly correlated (p <
0.05) with the corresponding histological markers.
Conclusions DBSI was used to assess changes of the underlying optic nerve pathologies in EAE mice
with ON, exhibiting great potential as a noninvasive outcome measure for monitoring disease progression
and therapeutic ecacy for MS.