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Figure 4. Global WMH volume is negatively correlated with activity in the dorsal prefrontal cortex during the high-load working memory task. Parameter estimates, indexing magnitude of activity during episodic retrieval relative to baseline, were averaged over each ROI for each subject. Global WMH volume is expressed as the log transform of total WMH load.

PFC may be involved in successful working memory performance (Kondo et al., 2004) and difficult episodic retrieval conditions (Bunge et al., 2004). Our results sug- gest that disruption of this circuit may underlie the age- related deficits in working memory and episodic retrieval.

These results are consistent with our hypothesis that disruption of white matter tracts within dorsal PFC results in decreased recruitment of both PFC and func- tionally linked targets in other brain regions. However, we cannot rule out the possibility that decreased re- cruitment in the other brain regions results from a more generalized effect of global damage to white matter tracts affecting a larger network of regions that underlie memory function rather than specific disruption of white matter tracts within dorsal PFC. Additional studies specifically addressing connectivity, perhaps using diffu- sion tensor imaging in conjunction with functional MRI will allow for investigation into these functional and anatomical circuits with more specificity.

WMH, Aging, and Cognition

emphasize two factors when considering these results. First, the present study was not designed to elicit large intersubject variability in performance. Our objective was to assess activation while holding behavioral perform- ance at a high accuracy level to reduce the possibility for performance to confound any activation results. Sec- ond, with 15 subjects, assuming an alpha = 0.05 and a two-sided test, we have 80% power to detect a correla- tion of R = .62. Although this level of statistical power is commensurate with most published fMRI studies, we emphasize that a failure to find a significant correlation must be interpreted cautiously. It is possible, and even likely, that either increasing the sample size or using more demanding versions of these tasks would elicit greater behavioral deficits, and that these deficits would be associated with WMH volume. Indeed, in a recent study of elderly individuals with mild cognitive impair- ment, a subgroup with extensive WMH showed sig- nificant behavioral deficits on the memory tasks used in this study (Nordahl, Ranganath, Yonelinas, DeCarli, & Jagust, 2005).

Psychological data suggest that elderly individuals are selectively impaired on tasks that tap prefrontal cortex function, including working memory tasks (MacPherson et al., 2002) as well as standard neuropsychological tests such as the Wisconsin Card Sorting Test (WCST) (MacPherson et al., 2002; Craik, Morris, Morris, & Loewen, 1990). In a parallel line of research, several studies have shown that WMH are also correlated with deficits on the WCST and other neuropsychological tests that are sensitive to prefrontal function (Gunning-Dixon & Raz, 2000; DeCarli et al., 1995).

In this study, there were modest associations be- tween WMH volumes and performance on episodic re- trieval and working memory tasks. It is important to

WMH, Cerebrovascular Disease, and Aging Studies

WMH are associated with various cerebrovascular risk factors such as hypertension, atherosclerosis, smoking, and diabetes (Bronge, 2002), and epidemiological sur- veys suggest that the prevalence of WMH in elderly individuals is close to 100% (Wen & Sachdev, 2004; Soderlund et al., 2003; de Leeuw et al., 2001). Given that WMH and the associated risk factors, especially hypertension, are so prevalent and may play a role in producing cognitive impairment (Raz, Rodrigue, & Acker, 2003), understanding the role that they play in the aging brain is crucial. Importantly, the presence of WMH can often go undetected because obvious clinical

Nordahl et al.

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