, 2013). As reviewed above, VCI can stem from a wide variety of cardiovascular and cerebrovascular pathologies, but it has been difficult to pin IWR-1 ic50 down the contribution of each condition to cognitive dysfunction because of the coexistence of the different lesions and overlap with neurodegenerative pathology (Gorelick et al., 2011). Reductions

in global cerebral perfusion, such as those caused by heart diseases or carotid artery stenosis/occlusion, if below a critical threshold, can impair cognition independently of brain lesions (Marshall et al., 2012). Reductions in CBF by 40%–50% are associated with suppression of brain activity and cognitive dysfunction, which are reversible upon re-establishing normal CBF levels (Marshall et al., 1999, Marshall, 2012 and Tatemichi et al., 1995). As for the other pathologies underlying VCI, there is a general correlation between the total burden of vascular pathology and cognitive deficits (Gelber et al., 2012, Gorelick et al., 2011 and Inzitari Selleck SB203580 et al., 2009). A caveat is that, due to confounding factors, such as overlap

with AD, differences in educational level (see below), and microscopic pathology not seen by in vivo imaging, the exact parameters of the relationship have been hard to define (Black et al., 2009 and Brickman et al., 2011). However, there is general consensus that cognitive impairment results from the brain dysfunction caused by cumulative tissue damage (Gorelick et al., 2011), as originally proposed by Tomlinson et al. for large cerebral infarcts

(Tomlinson et al., 1970). In addition to gray matter damage, disruption of the white matter can have profound effects on the precision and fidelity of the information transfer underlying brain function and cognitive health (Nave, 2010a). Fast-conducting myelinated white matter tracts are responsible for long-range connectivity, interhemispheric synchronization, and neurotrophic effects through spike-timing-dependent plasticity and axonal transport (Dan and Poo, 2004, Nave, 2010a and Stone and Tesche, 2013). Indeed, white matter lesions affect brain structure and function broadly and are associated with reductions in frontal lobe glucose utilization (DeCarli et al., 1995, Haight not et al., 2013 and Tullberg et al., 2004), global reduction in cortical blood flow (Appelman et al., 2008, Chen et al., 2013a, ten Dam et al., 2007 and Kobari et al., 1990), disruption of brain connectivity (Lawrence et al., 2013 and Sun et al., 2011), and cerebral atrophy (Appelman et al., 2009). In addition, since myelination of previously naked fibers participates in neuroplasticity and skilled motor learning (Fields, 2010 and Richardson et al., 2011), myelin damage could also compromise these important functions and contribute to cognitive impairment.