Ischemic Injury to White Matter: An Age-Dependent Process

The risk for ischemic stroke increases drastically with age, although reasons for this remain unexplored. White matter (WM) and gray matter constitute equal proportions of the brain, and WM is injured in most strokes. Axonal injury and dysfunction are responsible for much of the disability associated with clinical deficits observed after stroke. The authors recently reported that central nervous system WM is inherently more vulnerable to ischemic injury in older mice, and the mechanisms of WM injury change as a function of age. Ischemic WM injury in older mice is predominately mediated by a Ca(2+)-independent excitotoxicity involving overactivation of AMPA/kainate receptors. Glutamate release, due to reverse glutamate transport, occurs earlier and is more robust in older mice that show up-regulation of GLT1, the main glutamate transporter. Blockade of NMDA receptors does not improve WM function after ischemia in the young but aggravates ischemic injury in older mice. The main goals of this research update are to summarize the evidence for equivalent brain insults inducing more damage with aging, and to highlight the importance of age in any successful stroke therapy.