Longitudinal Assessments of Normal and Perilesional Tissues in Focal Brain Ischemia and Partial Optic Nerve Injury with Manganese-enhanced MRI

Abstract

Although manganese (Mn) can enhance brain tissues for improving magnetic resonance imaging (MRI) assessments, the underlying neural mechanisms of Mn detection remain unclear. In this study, we used Mn-enhanced MRI to test the hypothesis that different Mn entry routes and spatiotemporal Mn distributions can reflect different mechanisms of neural circuitry and neurodegeneration in normal and injured brains. Upon systemic administration, exogenous Mn exhibited varying transport rates and continuous redistribution across healthy rodent brain nuclei over a 2-week timeframe, whereas in rodents following photothrombotic cortical injury, transient middle cerebral artery occlusion, or neonatal hypoxic-ischemic brain injury, Mn preferentially accumulated in perilesional tissues expressing gliosis or oxidative stress within days. Intravitreal Mn administration to healthy rodents not only allowed tracing of primary visual pathways, but also enhanced the hippocampus and medial amygdala within a day, whereas partial transection of the optic nerve led to MRI detection of degrading anterograde Mn transport at the primary injury site and the perilesional tissues secondarily over 6 weeks. Taken together, our results indicate the different Mn transport dynamics across widespread projections in normal and diseased brains. Particularly, perilesional brain tissues may attract abnormal Mn accumulation and gradually reduce anterograde Mn transport via specific Mn entry routes.

Matrix-bound nanovesicles prevent ischemia-induced retinal ganglion cell axon degeneration and death and preserve visual function

“…In MBV, but not untreated or PBS treated IOP-injured animals, Mn transport was visible from the posterior globe to both the LGN and the SC in the visual cortex. Since Mn transport requires active transport by intact RGC axons 35 , these data show that functional RGC axons remain terminated within their appropriate visual nuclei 14-days post-injury. Though additional time points and optokinetic testing are required, the combined histology, MRI, and ERG data suggest MBV injections preserved visual function in IOP-injured animals.…”

“…Each animal (n = 4 per group) received a 1.5 µl bilateral injection of 100 mM MnCl 2 . T1-weighted MEMRI was done immediately before and then 8 hrs post injection with a fast spin echo imaging sequence as described 35 . Briefly, slices were oriented orthogonal to the pre-chiasmatic ON.…”

Manganese Enhanced MRI for Use in Studying Neurodegenerative Diseases

“…Animal models of ischemic stroke includes the middle cerebral artery occlusion (MCAO) and photothrombotic cortical injury (PCI). Systemic administration of manganese in rats and mice that undergo unilateral MCAO and PCI showed increased manganese accumulation in the perilesional tissue and reduced Mn 2+ transport in the first few days after stroke was induced (Aoki et al, 2003; Hao et al, 2016; Chan et al, 2017). The increased Mn 2+ uptake was attributed to inflammatory processes in the perilesional tissue (Kawai et al, 2010; Hao et al, 2016).…”

Age-related Changes in Eye, Brain and Visuomotor Behavior in the DBA/2J Mouse Model of Chronic Glaucoma

“…Apart from probing structural integrity by diffusion-based MRI measures, Mn-enhanced MRI allows in vivo evaluation of the physiological anterograde Mn transport between the retina and the brain’s visual pathway without depth limitation 18 , 48 – 51 . The observed anterograde Mn transport reduction during increasing IOP elevation in the D2 mice generally concurred with the increasing severity of neurofilament loss, tauopathy and inflammation in the glaucomatous visual pathway across age 38 , 39 , 52 , all of which may affect active anterograde axonal transport 53 , 54 .…”