White matter hyperintensities (WMH) are areas of hyperintense signal on T2-weighted magnetic resonance images (MRI) of the brain and are thought to be due to ischemic demylination, neuronal loss, and gliosis (Fazekas et al., 1993 and Pantoni, 2002). WMH burden increases in healthy aging but is also related to risk factors such as hypertension, heart disease, and diabetes (Breteler et al., 1994, Debette et al., 2010 and DeCarli et al., 1995). WMHs are typically greater in older adults with mild cognitive impairment (MCI) and dementia than in healthy older adults (Wolf et al., 2000 and Wu et al., 2002), and have been related to cognition in all three groups (DeCarli et al., 2005a, Elias et al., 2004, Gunning-Dixon and Raz, 2000, Lopez et al., 2003 and Wu et al., 2002). Longitudinal data have supported the cross-sectional findings and have indicated a relationship between WMH burden and cognitive performance, with increasing WMH burden associated with decreasing cognitive functioning, particularly with regard to executive function and processing speed (de Groot et al., 2001, Gunning-Dixon and Raz, 2000, Kramer et al., 2002, Prins et al., 2005 and Vannorsdall et al., 2009). Longitudinal reports have also shown that WMH can predict declines in global functioning (e.g., daily living activities such as housekeeping; Inzitari et al., 2007), motor performance, and the onset of dementia (Prins et al., 2004). Although early studies suggested that WMH may not be relevant to understanding cognition in older adults, the past 10 years of research have revealed a relationship between white matter integrity and cognitive function that plays an important role in age-related changes in cognition.
Older individuals commonly complain of impaired memory performance. Neuroimaging and neuropsychological research has shown that interactions between prefrontal cortex and medial temporal lobe structures are important for normal memory function (Dickerson et al., 2007, Shimamura et al., 1990, Simons et al., 2002a, Simons et al., 2002b and Simons and Spiers, 2003) and that the frontal lobes and hippocampus are particularly vulnerable to effects of aging and age-related disease processes, respectively (Moscovitch and Winocur, 1995, Troyer et al., 1994, West, 1996 and Wu et al., 2008). Neuroimaging studies of memory in young adults and neuropsychological tests in older adults have demonstrated that both frontally mediated executive function and medial-temporal function are important predictors of memory and of age-related memory declines (e.g., Dickerson et al., 2007, Ferrer-Caja et al., 2002, Glisky et al., 1995 and Troyer et al., 1994).
The patterns found thus far between age, WMH, executive function and episodic memory parallel findings from recent investigations of frontal and medial temporal lobe functioning and age-related declines in memory and cognition. Specifically, age-related WMH are more prevalent in the frontal lobes than in posterior regions of the brain in cognitively normal older adults, and are more extensive throughout the brain in MCI and dementia patients (Fazekas et al., 1996, Wen and Sachdev, 2004 and Yoshita et al., 2006). Moreover, WMH, irrespective of location, are associated with reduced frontal lobe metabolism (DeCarli et al., 1995 and Tullberg et al., 2004) and recent work with cognitively normal individuals suggests that WMH are associated with disconnection of frontal lobe from functionally linked cortical areas (Nordahl et al., 2006). These findings converge with the frontal aging hypothesis (Buckner, 2004 and West, 1996) and point to the possibility that frontal lobe dysfunction caused by WMH may lead to executive function impairment that is sufficient to affect episodic memory performance.
The relationship between WMH and executive functioning, however, appears to be more robust than that between WMH and episodic memory. Although a relationship between WMH burden and executive functioning is typically observed, a relationship between WMH and memory has not always been found (e.g., Parks, DeCarli, Jacoby, & Yonelinas, 2010). It may be the case, therefore, that multiple brain regions and types of cognition need to be considered in order to understand relationships between WMH and episodic memory. For instance, Brickman et al. (2006) and Brickman, Habeck, Zarahn, Flynn, and Stern (2007) found that frontal lobe white matter volume mediated the relationship between age and executive functioning as well as the relationship between age and memory, and Charlton, Barrick, Markus, and Morris (2010) found that executive functioning partially mediated the effect of white matter integrity on memory performance in high-functioning healthy older controls.
To evaluate the hypothesis that WMH influence on episodic memory is mediated by impairments of executive function we examined the relationships between age, WMH volume, executive functioning and hippocampal volume. In addition, we specifically tested whether the effects of hippocampal volume and executive functioning on memory performance are interactive or additive.
