Tracking elemental changes in an ischemic stroke model with X-ray fluorescence imaging

Abstract

Stroke is a leading cause of long-term disability in adults and a leading cause of death in developed nations. The cascade of cellular events and signalling that occur after cerebral ischemia are complex, however, analyzing global element markers of metabolic state affords the means to monitor stroke severity, status of injury, and recovery. These markers provide a multi-parameter method for assessing changes through the post-stroke time course. We employ synchrotron-based elemental mapping to follow elemental changes in the brain at 1 h, 1-, 2-, and 3-days, and at 1-, 2-, 3-, and 4-weeks post-stroke in a photothrombotic stroke model in mice. Our analysis reveals a highly consistent metabolic penumbra that can be readily identified based on the level of dysregulated potassium and other key elements. Maps of elemental distributions are also useful to demarcate events in the cellular response to the inflammatory cascade, including ion dysregulation, recruitment of cells to the lesion, and glial scar formation.

Sex differences in the mouse photothrombotic stroke model investigated with X-ray fluorescence microscopy and Fourier transform infrared spectroscopic imaging

“…3 A and summarized in Table S3 ). Additional metabolites, such as lactate, glutamate, ATP+ADP, aggregated protein content, S, Cl, K, and Zn also followed this general trend of deviations from normal levels through the penumbra and continuing into the infarct core, but not all reach statistically significant changes at 24-hours post-stroke ( Pushie et al, 2020 ). Nevertheless, the infarct and penumbra ROIs generally demonstrated the same trends in metabolite concentrations across all 3 animal groups ( Table S3 ).…”

“…Glycogen was increased nearly 1.4 x in the female post-stroke penumbra compared to levels in the penumbra of post-stroke males. At 24-hours post-stroke, the glial response following ischemia peaks resulting in astrocyte activity and glial scar formation ( Pushie et al, 2020 , Hackett et al, 2016 ). Sex differences have been reported in astrocyte estrogen receptors in the hippocampus leading to an increase in glycogen metabolism ( Ibrahim et al, 2020 ).…”

“…Coronal brain sections on glass slides were fixed in 4% buffered paraformaldehyde, washed with 0.1 M phosphate buffered saline (PBS), and then stained with H&E as previously described ( Caine et al, 2016 , Pushie et al, 2020 ). Leica Aperio virtual microscope was used to image the H&E-stained tissues with a 20 x objective lens and images were extracted using Aperio ImageScope (Leica Biosystems Inc., CA).…”

Is Mini Beam Ready for Human Trials? Results of Randomized Study of Treating De-Novo Brain Tumors in Canines Using Linear Accelerator Generated Mini Beams

“…From ref. 29, using this collimator results in dose peaks with full width at half maximum (FWHM) of 1.0 mm at isocenter. The FWHM is relevant because megavoltage mini beams take a profile with a sharp peak widening towards the base, as opposed to synchrotron beams which are quasi-parallel.…”

Quantification of human plasma metalloproteins in multiple sclerosis, ischemic stroke and healthy controls reveals an association of haptoglobin-hemoglobin complexes with age

“…In the last two decades it has indeed been established that certain neurodegenerative diseases are associated with the dyshomeostasis of essential metals, such as Fe, Cu and Zn [ 23 ], which are present in gray matter at concentrations between 0.1–0.5 mM [ 24 , 25 ]. Several studies have demonstrated that these metal ions are directly implicated in the pathophysiology and pathogenesis of Alzheimer’s disease [ 26 – 28 ], multiple sclerosis (MS) [ 29 – 31 ] and stroke [ 32 ]. To evaluate the potential that the quantification of plasma metalloproteins may offer in terms of disease diagnosis, progression, or severity, we conducted a pilot study in which we quantified Fe, Cu and Zn-containing metalloproteins in plasma collected from AIS and MS participants (disease control) as well as healthy controls.…”