Assessing Fingolimod Axonal Protection Efficacy in Mouse Optic Neuritis Using Diffusion Basis Spectrum Imaging (DBSI) Tsen-Hsuan (Abby) Lin 1 , Rui-Meng Yang 1 , Jie Zhan 1 , Chunyu Song 2 , Peng Sun 1 , Michael Wallendorf 3 , Anne H Cross 4,5 , and Sheng-Kwei Song 1,2,5 1 Radiology, 3 Biostatistics, 4 Neurology, 5 The Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO , USA 2 Biomedical Engineering, Washington University in St. Louis, St. Louis, MO , USA Feb. 1 st , 2018 ACTRIM, San Diego NAIMS Symposium on Therapeutics
Declaration of Financial Interests or Relationships Speaker Name: Tsen-Hsuan (Abby) Lin I have no financial interests or relationships to disclose with regard to the subject matter of this presentation.
Introduction • Fingolimod is an approved disease-modifying treatment for relapsing MS. • Optic neuritis (ON) is often the first clinical sign of MS. • We employed diffusion basis spectrum imaging (DBSI) to noninvasively assess the treatment efficacy of fingolimod on EAE mice with ON. • In vivo DBSI was followed by histological validation.
Fingolimod Treatment Timeline Onset of optic neuritis (10 – 18 days post-immunization) 3 months post- 2 months post- 1 month post- Day 0 immunization immunization immunization ….. ….. Immunization DBSI DBSI DBSI DBSI 2 weeks Baseline 1 month 2 months MOG 35-55 EAE post-treatment post-treatment post-treatment Saline (n=9) Fingolimod Mice were perfusion fixed after in vivo MRI (1 mg/kg, n=8) Four DBSI scan time points Baseline, one, two, and three months post-immunization
Diffusion Basis Spectrum Imaging (DBSI)* Diffusion Basis Spectrum Imaging (DBSI) Isotropic Components Anisotropic Components MR Imaging Voxel Cross and Song, Journal of Neuroimmunology 2016; 304: 81-85
Isotropic Components Non-Restricted (Edema) Restricted (Cellularity) Saline Saline Fingolimod Fingolimod Baseline 1 Month 2 Months 3 Months 0.4 0 fraction
Anisotropic/Fiber Components DBSI λ ǁ (axonal injury) DBSI λ ⊥ (demyelination) Fiber Fraction (axonal loss) Saline Fingolimod Saline Fingolimod Saline Fingolimod Baseline 1 Month 2 Months 3 Months 0.8 1.0 2.5 0 0 0 µm 2 /ms µm 2 /ms
Immunohistochemisty (IHC) Saline Fingolimod 100x Zoom-in 100x Zoom-in SMI312 (total axons) MBP (myelin) SMI31 (Phosphorylated /intact axons) White bar: 50 μ m DAPI Yellow bar: 5 μm (cell nuclei)
Histology: Axon Preservation with Fingolimod Treatment Axonal Volume Myelination ⋆ ⋆ Saline (n=18 nerves) Fingolimod Axonal Integrity Cellularity (n=16 nerves) ⋆
DBSI Agrees with Histology Axonal Volume Myelination Saline (n=18 nerves) Fingolimod Axonal Integrity Cellularity (n=16 nerves)
Conclusions • Fingolimod reduced axonal loss in EAE mouse optic nerve (direct axonal protection, or indirect protection from its anti-inflammatory effects). • DBSI could be a non-invasive biomarker to monitor disease progression assess treatment efficacy serve as an outcome measure for MS clinical trials
Acknowledgments Prof. Victor Song Prof. Anne H Cross Prof. Peng Sun Dr. Karen Yang Prof. William M Spees Dr. Jenny Zhan Mr. Bob Mikesell Mr. Rob Massa Dr. Ajit George This work was supported in part by NIH P01-NS059560 (A.H.C.), U01-EY025500(S.- K.S.), Department of Defense Idea Award W81XWH-12-1-0457(S.-K.S.), and National Multiple Sclerosis Society (NMSS) RG 4549A4/1(S.-K.S.), RG 1507-05315 (T.-H.L.). Poster Session 1 (P117): Thursday (2/1) 6 – 8 PM
DBSI Agrees with Histology Saline (n=18 nerves) Fingolimod (n=16 nerves) Myelination Axonal Volume Axonal Integrity Cellularity
Onset of Optic Neuritis in MOG 35-55 EAE Mice • Visual acuity (VA) for normal C57BL/6 mice: 0.37 ± 0.02 c/d (n = 30) • Operational definition of onset of optic neuritis: VA ≤ 0.25 c/d (mean – 3 SD) Onset of optic neuritis 9 – 14 days Visual Acuity (c/d) 0.5 Mean ± SD 0.4 0.3 Sham (n = 20) 0.2 EAE (n = 20) 0.1 0 0 10 20 30 40 50 60 Lin et al., NeuroImage (2014) 100:244-253 Days post-immunization Lin et al., Neurobiology of Disease (2014) 67:1 -8 Chiang et al. NeuroImage (2014) 101:390-398 Lin et al. J of Neuroinflammation (2017) 14(1):78
Visual Acuity Profile
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