In vivo vascular hallmarks of diffuse leukoaraiosis

Leukoaraiosis is defined as diffuse white matter lesions that are often visible on computed tomography (CT) or magnetic resonance imaging (MRI) (1). In particular, these regions appear as hyperintense signals on fluid-attenuated inversion-recovery (FLAIR) MRI (2). Unlike white matter lesions associated with known causes such as stroke or brain tumor, the pathogenesis of leukoaraiosis is not well defined. Previous studies report that leukoaraiosis can be associated with various pathologic conditions including vascular dementia (3), Alzheimer's disease (4), hypertension (5–7), small vessel disease (8–10), atherosclerosis (11), and cerebral hemorrhage (12). Another common cause of leukoaraiosis is aging (13,14). A large majority of elderly individuals have a certain degree of leukoaraiosis, which is most pronounced in the periventricular regions (15–19). There is also evidence that the amount of leukoaraiosis is predictive of cognitive function (20,21). Therefore, it is important to characterize the physiologic mechanisms underlying age-related leukoaraiosis. A number of studies have suggested a strong contribution of vascular dysfunction in leukoaraiosis associated with ischemic diseases. Pathologic studies of leukoaraiosis tissue have shown that these regions are characterized by arteriosclerosis and the thickening of the vascular wall as well as a narrowing of the vessel lumen (22,23). Others have postulated that leukoaraiosis is caused by the toxicity of serum protein which leaks into the extravascular tissue when the blood–brain-barrier (BBB) is compromised (24–26). In the present study we aimed to assess whether vascular components also play an important role in age-related leukoaraiosis. The brain vasculature in leukoaraiosis under in vivo conditions has previously been difficult to assess for two possible reasons. First, the perfusion values of white matter are intrinsically lower than that of gray matter (27), thus accurate measurement of white matter perfusion is not trivial. Second, diffuse leukoaraiosis lesions are small and the spatial resolution of the imaging modality needs to be sufficiently high in order to minimize partial volume effects from surrounding normal tissue. Recent advances in high-field MR systems as well as the development of novel MR sequences have allowed the mapping of various physiological parameters in the brain. In the present work we conducted a multiparametric assessment of vascular parameters to gain a better understanding of physiological hallmarks in leukoaraiosis in elderly subjects. Since we are interested in the pathogenesis of diffuse white matter lesions in the absence of clinically defined vascular diseases, we only selected participants who did not have overt cerebral infarction or lacunae. In this cross-sectional study we first tested whether cerebral blood flow (CBF) in leukoaraiosis regions was reduced compared to normal-appearing white matter (NAWM). Considering that CBF reduction may not be specific to vascular damage, we also measured the vasodilatory capacity of the vessels using CO2 inhalation. As a control study, we assessed whether such deficits were also present in subjects who did not have significant leukoaraiosis. In another group of subjects, the leakage of the BBB was assessed using an MR contrast agent. We further assessed the correlation between the extent of BBB leakage and tissue structural integrity as measured by diffusion tensor imaging (DTI).