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

Abstract

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 inflammation, 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 fingolimod 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 fingolimod (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 reflecting cellularity), non-restricted isotropic diffusion tensor fraction (putative reflecting vasogenic edema), DBSI-derived axonal volume, axial diffusivity, λ∥ (putative reflecting axonal integrity), and increased radial diffusivity, λ⊥ (putatively reflecting demyelination). Mice were killed immediately after the last DBSI scan for immunohistochemical assessment.Results Optic nerves of fingolimod-treated mice exhibited significantly 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 significantly different (p > 0.05) from the baseline values in fingolimod-treated mice, suggesting protection in the fingolimod 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 significantly 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 efficacy for MS.

Childhood obesity is linked to putative neuroinflammation in brain white matter, hypothalamus, and striatum

“…Finally, the largest limitation of the current study is the limited interpretation of diffusionweighted MRI neuroinflammation metrics. While DBSI-assessed neuroinflammation metrics have been histopathologically validated in some inflammatory neurological diseases including human multiple sclerosis (Wang et al, 2015), rodent models of multiple sclerosis (Chiang et al, 2014;Wang et al, 2011), and rodent optic neuritis (Lin et al, 2017;Yang et al, 2021), this is not the case for obesity. The validity of DBSI and RSI neuroinflammation metrics as true reflections of obesity-related cellularity and/or gliosis remains to be proven using histopathology in post-mortem brains of individuals that, ideally, were recently neuroimaged, or in animal models of obesity.…”

“…Investigating obesity-related neuroinflammation in living humans, however, requires noninvasive methods, such as brain magnetic resonance imaging (MRI)-based assessments. Diffusion basis spectrum imaging (DBSI) , a diffusion MRI-based technique applied to diffusionweighted images to model anisotropic and isotropic water diffusivities separately within tissue microstructure (Wang et al, 2011;White et al, 2013), has been histopathologically validated as neuroinflammation-sensitive using rodent and human neural tissue in multiple sclerosis (Chiang et al, 2014;Wang et al, 2014;Wang et al, 2011Wang et al, , 2015, epilepsy (Zhan et al, 2018), and optic neuritis (Lin et al, 2017;Yang et al, 2021). DBSI-assessed putative neuroinflammation in white matter (WM) correlates with cerebrospinal fluid biomarkers in Alzheimer's disease (Wang et al, 2019).…”