MAPPING DISTAL BRAIN ALTERATIONS DURING THE ACUTE PHASE OF ISCHEMIC STROKE

Stroke represents one of the leading causes of disability and mortality worldwide. Stroke diagnosis relies on neuroimaging techniques which allow to quickly characterize the nature (hemorrhagic vs ischemic), size and location of the primary lesion. Beyond the main primary injury, diffuse alterations in secondary regions are known to contribute to patient prognosis, however, the factors driving these distant alterations remain unclear.
To investigate these mechanisms, we used a mouse model of thromboembolic stroke targeting the M2 segment of the middle cerebral artery (MCA). Primary lesion size and location were assessed 24 hours post-ischemia using magnetic resonance imaging (MRI). Blood-brain barrier (BBB) integrity, neuronal activity and connectivity were mapped at the whole-brain using 3D histology (iDISCO+ tissue clearing, light-sheet microscopy, and bioinformatics tools such as IMARIS and ClearMap). Finally, we validated our findings in other stroke models, also targeting the MCA, to confirm that the observed effects were ischemia-induced rather than model-specific.
Our results revealed that MCA occlusion leads to vascular damage beyond the MCA vascular territory, impairing BBB permeability in regions irrigated by the anterior (ACA) and posterior cerebral arteries (PCA). Moreover, functional and connectivity alterations were found beyond the core lesion area, showing only partial overlap with the regions affected by BBB alterations. Our data shows that in the acute phase of ischemia (24 hours), neuronal and vascular mechanisms contribute at least partially independently to distal damage.
Understanding these MRI-silent, widespread effects of focal ischemia may open new avenues to limit lesion expansion and diffuse brain damage after ​stroke.