Abstract
Magnetic resonance imaging (MRI) is a clinically relevant non-invasive imaging tool commonly utilized to assess stroke progression in real time. This study investigated the utility of MRI as a predictive measure of clinical and functional outcomes when a stroke intervention is withheld or provided, in order to identify biomarkers for stroke functional outcome under these conditions. Fifteen MRI and ninety functional parameters were measured in a middle cerebral artery occlusion (MCAO) porcine ischemic stroke model. Multiparametric analysis of correlations between MRI measurements and functional outcome was conducted. Acute axial and coronal midline shift (MLS) at 24 h post-stroke were associated with decreased survival and recovery measured by modified Rankin scale (mRS) and were significantly correlated with 52 measured acute (day 1 post) and chronic (day 84 post) gait and behavior impairments in non-treated stroked animals. These results suggest that MLS may be an important non-invasive biomarker that can be used to predict patient outcomes and prognosis as well as guide therapeutic intervention and rehabilitation in non-treated animals and potentially human patients that do not receive interventional treatments. Neural stem cell–derived extracellular vesicle (NSC EV) was a disruptive therapy because NSC EV administration post-stroke disrupted MLS correlations observed in non-treated stroked animals. MLS was not associated with survival and functional outcomes in NSC EV–treated animals. In contrast to untreated animals, NSC EVs improved stroked animal outcomes regardless of MLS severity.
Highlights
Therapeutic development for ischemic stroke has previously focused on small molecules, with anti-thrombotic, thrombolytic, and anti-inflammatory mechanisms of action [1]
Multivariate analysis was conducted for all measured Magnetic resonance imaging (MRI) parameters at day 1 post-middle cerebral artery occlusion (MCAO) versus 90 recorded gait and behavior parameters at day 1 and day 84 post-MCAO, in order to determine which MRI parameters were most predictive of functional outcome at acute and chronic time points
When comparing average modified Rankin scale (mRS) scores at day 6 post-MCAO, there was a significant difference in mRS scores of non-treated animals with high midline shift (HMLS) and LMLS, while there was no significant difference in mRS scores of Neural stem cell–derived extracellular vesicle (NSC EV) treatment animals with HMLS and LMSL (NSC EVS p = 0.9999; Fig. 3l). These results suggest HMLS significantly correlates with decreased recovery speed as measured by mRS in nontreated animals, while NSC EV treatment eliminates the difference in speed of recovery between LMLS and HMLS animals
Summary
Therapeutic development for ischemic stroke has previously focused on small molecules, with anti-thrombotic, thrombolytic, and anti-inflammatory mechanisms of action [1]. Markets [2], ischemic stroke continues to remain a leading cause of death and long-term disability worldwide [3] This translational disconnect, from promising preclinical studies to late-stage clinical trial failure, has originated from a number of factors including (1) an absence of predictive functional outcome biomarkers [4], (2) a limited pipeline of cell-based neurorestorative and neuroprotective therapeutics [5,6,7,8], and (3) a lack of models more representative of the human stroke condition [8,9,10,11,12].
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