.. Correlates of white matter hyperintensities Despite the ubiquity of WMH among older adults,

they are a uniquely radiological phenomenon. That is, when examining grossly the brain regions underlying WMH, there is no obvious pigmentation abnormality. Our current understanding of the nature, clinical importance, and cognitive consequences of WMH has come from a number of careful clinicopathological correlates and observational studies among clinical and epidemiological samples. A prevailing view is that WMH Inhibitors,research,lifescience,medical are a surrogate marker of small-vessel vascular disease19 resulting from ischemic damage due to chronic hypoperfusion. White matter hyperintensities tend to develop in regions that are considered “watershed” areas, which extend up to 13 mm beyond the ventricular walls.20-22 Indeed, most of the major risk factors for ischemia have been shown to be associated with the severity of WMH distribution.23-27 Further evidence for an ischemic origin comes from postmortem pathological examination of Inhibitors,research,lifescience,medical tissue that appears as WMH during life. Areas most vulnerable to development of WMH receive blood supply primarily from ventriculofugal vessels, which originate from the subependymal Inhibitors,research,lifescience,medical arteries.28,29 These vessels have relatively few anastomoses and are particularly vulnerable

to injurydue to systemic hypoperfusion.29-30 Clinico-pathological correlate studies have shown that smooth periventricular WMH are associated with subependymal gliosis and disruption of the ependymal lining, whereas deep white matter punctate WMH or irregularly Inhibitors,research,lifescience,medical shaped periventricular WMH are associated with disruption in fibers secondary to ischemic/arteriosclerotic changes.31,32 In general, WMH are related to diminished pallor or rarefaction and gliosis33 and myelin or axonal loss.34 By combining structural neuroimaging data with measures of cerebral blood flow, as measured by arterial spin labeling (ASL), we showed that areas appearing as WMH on FLAIR images had diminished blood flow relative to normal appearing white matter and grey matter.35 The finding complements recent observations Inhibitors,research,lifescience,medical that the spatial frequency of WMH among

healthy older adults is greater in regions with lower normative perfusion values.36 We also showed that, among an epidemiological cohort of phosphatase inhibitor nondemented older adults, WMH were associated with chronological age and vascular risk factors37 Drug_discovery and were most severe among adults with the highest absolute blood pressure and blood pressure fluctuation over a 3-year period (Brickman et al, unpublished). These observations lend further support that diminished perfusion and perhaps compromised cerebral autoregulation increase the risk for WMH development. The role of white matter hyperintensities in cognitive aging Consistent observations of increasing WMH severity and variability with aging supports ongoing interest in their clinical or cognitive correlates (see ref 13).