Pathophysiology of Ischemic White Matter Injury

Cerebral ischemia is a complex injury process that results in damage to both gray matter and white matter. White matter accounts for up to half of the stroke lesion volume in the central nervous system (CNS), with 20% of strokes being purely in the white matter . White matter is sensitive to ischemia across all developmental ages: perinatal hypoxia causing periventricular leukomalacia, stroke in adults, and vascular dementia in the elderly. Clinically, ischemic white matter damage brings with it a host of motor, sensory, behavioral, and cognitive consequences due to primary or secondary axonal disruption. Cerebrovascular injury that includes white matter is associated with worse functional outcomes . Magnetic resonance imaging (MRI) shows that the extent of post-stroke disability is related to specific deep white matter damage, and improvement after recanalization therapy is associated with the degree of salvage of these white matter areas .

Prior studies of ischemic pathophysiology have focused on injury mechanisms of the neuronal soma and dendrites in gray matter, and have tended to minimize the significance of white matter injury. In part this is due to an inherent deficit of rodent models commonly used to study experimental stroke. About half of the human forebrain is comprised of white matter, while this proportion is only 10–14% in mouse and rat brains . Injury or preservation of cerebral white matter in the rodent would have minimal impact on total infarct volume, a common outcome measure. Compared to gray matter, white matter has lower metabolic rates for glucose and oxygen, and requires relatively less cerebral perfusion; however, this does not provide protection during vascular occlusion. Much of the deep white matter is perfused by direct penetrating arterioles. These areas, lacking collateral supply, are especially vulnerable to focal ischemia (lacunar stroke). Recognition of the prominent role played by the white matter in stroke highlights the importance of identifying distinct molecular mechanisms in white matter ischemia, and provides avenues for new therapeutic exploration.