Investigating potentially salvageable penumbra tissue in an in vivo model of transient ischemic stroke using sodium, diffusion, and perfusion magnetic resonance imaging

Abstract

Background Diffusion magnetic resonance imaging (MRI) is the current-state-of-the-art technique to clinically investigate acute (0–24 h) ischemic stroke tissue. However, reduced apparent diffusion coefficient (ADC)—considered a marker of tissue damage—was observed to reverse spontaneously during the subacute stroke phase (24–72 h) which means that low ADC cannot be used to reflect the damaged tissue after 24 h in experimental and clinical studies. One reason for the change in ADC is that ADC values drop with cytotoxic edema (acute phase) and rise when vasogenic edema begins (subacute phase). Recently, combined 1H- and 23Na-MRI was proposed as a more accurate approach to improve delineation between reversible (penumbra) and irreversible ischemic injury (core). The aim of this study was to investigate the effects of reperfusion on the ADC and the sodium MRI signal after experimental ischemic stroke in rats in well-defined areas of different viability levels of the cerebral lesion, i.e. core and penumbra as defined via perfusion and histology. Transient middle cerebral artery occlusion was induced in male rats by using the intraluminal filament technique. MRI sodium, perfusion and diffusion measurement was recorded before reperfusion, shortly after reperfusion and 24 h after reperfusion. The animals were reperfused after 90 min of ischemia.ResultsSodium signal in core did not change before reperfusion, increased after reperfusion while sodium signal in penumbra was significantly reduced before reperfusion, but showed no changes after reperfusion compared to control. The ADC was significantly decreased in core tissue at all three time points compared to contralateral side. This decrease recovered above commonly applied viability thresholds in the core after 24 h.ConclusionsReduced sodium-MRI signal in conjunction with reduced ADC can serve as a viability marker for penumbra detection and complement hydrogen diffusion- and perfusion-MRI in order to facilitate time-independent assessment of tissue fate and cellular bioenergetics failure in stroke patients.

Ischemia-Triggered Glutamate Excitotoxicity From the Perspective of Glial Cells

“…The infarction core is characterized by a lack of adenosine triphosphate (ATP), pathological concentrations of ions, high concentrations of glutamate and tissue acidosis. Cell death occurs within the first minutes after the onset of ischemic injury (Wetterling et al, 2016), partially due to the inability of compromised astrocytes to deliver nutrients to neurons (Chisholm and Sohrabji, 2016). Nevertheless, it is necessary to mention that in the ischemic core, also surviving and even newly formed viable neurons have been detected (Zhang et al, 2017).…”

“…Moreover, microglial cells are least vulnerable to ischemia because they express glutamate receptors only after the onset of pathological conditions when they become reactive (Gottlieb and Matute, 1997). During the subacute phase (24-72 h after the stroke onset), vasogenic edema begins (Wetterling et al, 2016). However, weeks after the onset of ischemia, the chronic phase leads to additional tissue damage and may be the result of delayed neurodegeneration triggered by oxidative stress and immune activation.…”

Structural and Functional Remodeling of the Brain Vasculature Following Stroke

“…This is followed by reperfusion when the effects of ET-1 wear off after several hours (Biernaskie et al, 2001). The reperfusion creates an ischemic penumbra (Weinstein et al, 2004;Gauberti et al, 2016), largely absent in PT stroke, corresponding to a region where neurons remain at risk but are salvageable (Heiss, 2012;Wetterling et al, 2016). PT strokes are induced by cortical photoactivation of a light-sensitive dye that is administered peripherally, resulting in singlet oxygen production, endothelial damage, platelet activation and aggregation, causing permanent occlusion of vessels in the irradiated region of the brain (Uzdensky, 2018).…”

Astrocyte‐induced synapse formation and ischemic stroke

“…Ischemic stroke is categorized as major stroke, where blood flow cannot be supplied to the brain, oxygen and glucose are deficient, and nerve cell death is strongly induced (Blanco‐Suarez et al, 2017; Marsh & Keyrouz, 2010). Magnetic resonance imaging analysis indicates that neuronal cell death due to ischemic stroke occurs within the first minutes of ischemic injury (Wetterling et al., 2016). Oxygen deficiency interferes with mitochondrial oxidative phosphorylation and induces extensive neuronal and glial cell death (Erecinska & Silver, 2001).…”