Does the white matter matter in Alzheimer disease and cerebral amyloid angiopathy?

White matter hyperintensities on MRI are frequently observed in the elderly. These may be punctuate or more confluent, the latter referred to as leukoaraiosis, and characterized by bilateral diffuse or patchy signal changes primarily in the centrum semiovale. Though previously thought to be incidental and of little clinical significance, there is now substantial evidence that these white matter lesions represent pathologic changes. White matter abnormalities are associated with increased risk of stroke, myocardial infarction, and cognitive impairment.1,2 Confluent white matter hyperintensities (but not periventricular caps) are also associated with microvascular changes on pathologic correlation.3 The precise etiology of white matter lesions is unknown, but clues from pathologic findings, anatomic characteristics, and risk factors suggest ischemic origins. The white matter is populated exclusively by oligodendrocytes, astrocytes, and axons traversing through to distant sites. Histopathologic analysis of white matter lesions reveals diffuse pallor of the white matter, which is attributed to rarefaction of myelin sheaths with evidence of demyelination,4 and is associated with reactive gliosis.5 Furthermore, a variety of microvascular abnormalities have also been described in association with white matter lesions, including …