Age-Dependent Exacerbation of White Matter Stroke Outcomes

Abstract

Subcortical white matter stroke (WMS) constitutes up to 30% of all stroke subtypes. Mechanisms of oligodendrocyte and axon injury and repair play a central role in the damage and recovery after this type of stroke, and a comprehensive study of these processes requires a specialized experimental model that is different from common large artery, gray matter stroke models. Diminished recovery from stroke in aged patients implies that damage and repair processes are affected by advanced age, but such effects have not been studied in WMS. WMS was produced with focal microinjection of the vasoconstrictor N5-(1-iminoethyl)-L-ornithine into the subcortical white matter ventral to the mouse forelimb motor cortex in young adult (2 months), middle-aged (15 months), and aged mice (24 months). WMS produced localized oligodendrocyte cell death with higher numbers of apoptotic cells and greater oxidative damage in aged brains than in young-adult brains. Increased expression of monocyte chemotactic protein-1 and tumor necrosis factor-α in motor cortex neurons correlated with a more distributed microglial activation in aged brains 7 days after WMS. At 2 months, aged mice displayed increased white matter atrophy and greater loss of corticostriatal connections compared with young-adult mice. Behavioral testing revealed an age-dependent exacerbation of forelimb motor deficits caused by the stroke, with decreased long-term functional recovery in aged animals. Age has a profound effect on the outcome of WMS, with more prolonged cell death and oxidative damage, increased inflammation, greater secondary white matter atrophy, and a worse behavioral effect in aged versus young-adult mice.