, 2011). The ApoE4 allele is associated with increased risk of CAA, whereas both ApoE2 and 4 increase the risk of lobar hemorrhages ( Charidimou et al., 2012). Nevertheless, a strong link between ApoE and sporadic VCI has not

been established ( Lee and Kim, 2013 and Yu et al., 2013). Studies of candidate genes have revealed weak associations with genes involved in the renin-angiotensin system, endothelial nitric oxide synthase, oxidative stress, lipid metabolism and inflammation, but have not been replicated ( Fornage et al., 2011, Lee and Kim, 2013 and Markus, 2008). GWAS of vascular dementia have shown small effect of SNPs in the androgen receptor gene locus ( Schrijvers et al., 2012), a finding not observed in all ethnic groups ( Lee and Kim, 2013). The diversity of pathologies underlying VCI and the overlap Cobimetinib molecular weight with AD complicate the interpretation

of these studies. Linkage studies in patients with white matter lesions on MRI have discovered several loci ( Schmidt et al., 2012), but no specific gene has been identified and the findings await replication and validation ( Lee and Kim, 2013 and Markus, 2008). Although as described in the previous section severe ischemia resulting from arterial occlusion can lead to brain damage and VCI, e.g., multi-infarct dementia, cognitive dysfunction is most often associated with more subtle vascular alterations targeting Vismodegib ic50 predominantly the deep hemispheric white matter (Figure 5). Here we examine the major pathogenic mechanisms leading to white matter damage, inferred either from brain

imaging and postmortem studies in humans, or animal models (Figure 6). Owing to their location at the distal border between different vascular territories (De Reuck, 1971) (Figure 4) and to the susceptibility of their vasculature to risk factors (Brown and Thore, 2011), deep white matter tracts are particularly vulnerable to vascular insufficiency. Even in healthy individuals, hypercapnia, a potent vasodilator, does not increase, but reduces, CBF in the periventricular white matter, suggesting that Calpain vasodilatation of upstream vessels diverts blood flow to other regions (intracerebral steal) (Mandell et al., 2008). This finding highlights the hemodynamic precariousness of the periventricular white matter, even in the absence of vascular damage. Increasing evidence suggests that the white matter cerebral blood supply is compromised in VCI (Figure 6). Resting flow is reduced in areas of leukoaraiosis and vascular reactivity attenuated (Kobari et al., 1990, Makedonov et al., 2013, Markus et al., 2000, Markus et al., 1994, Marstrand et al., 2002, O’Sullivan et al., 2002 and Yao et al., 1992). In patients with VCI risk factors, like hypertension and diabetes, the ability of neural activity to increase blood flow in brain or retina is compromised (Delles et al., 2004, Jennings et al., 2005 and Sorond et al., 2011).