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White Matter Changes Compromise Prefrontal Cortex Function in Healthy Elderly Individuals

C h r i s t i n e W u N o r d a h l 1 , C h a r a n R a n g a n a t h 1 , A n d r e w P . Y o n e l i n a s 1 , C h a r l e s D e C a r l i 1 , E v a n F l e t c h e r 1 , a n d W i l l i a m J . J a g u s t 2


& Changes in memory function in elderly individuals are often attributed to dysfunction of the prefrontal cortex (PFC). One mechanism for this dysfunction may be disruption of white matter tracts that connect the PFC with its anatomical targets. Here, we tested the hypothesis that white matter degeneration is associated with reduced prefrontal activation. We used white matter hyperintensities (WMH), a magnetic resonance imaging (MRI) finding associated with cerebrovascular disease in elderly individuals, as a marker for white matter degeneration. Specifically, we used structural MRI to quantify the extent of WMH in a group of cognitively normal elderly individuals and tested whether these measures were predictive of the magni- tude of prefrontal activity (fMRI) observed during performance of an episodic retrieval task and a verbal working memory task.

We also examined the effects of WMH located in the dorsolat- eral frontal regions with the hypothesis that dorsal PFC WMH would be strongly associated with not only PFC function, but also with areas that are anatomically and functionally linked to the PFC in a task-dependent manner. Results showed that increases in both global and regional dorsal PFC WMH volume were associated with decreases in PFC activity. In addition, dorsal PFC WMH volume was associated with decreased activ- ity in medial temporal and anterior cingulate regions during episodic retrieval and decreased activity in the posterior pari- etal and anterior cingulate cortex during working memory performance. These results suggest that disruption of white matter tracts, especially within the PFC, may be a mechanism for age-related changes in memory functioning. &


Evidence from behavioral and imaging studies suggests that aging is associated with prefrontal cortex (PFC) dys- function (Cabeza, 2002; Logan, Sanders, Snyder, Morris, & Buckner, 2002; Rosen et al., 2002; Grady & Craik, 2000; Rypma & D’Esposito, 2000; Salat, Kaye, & Janowsky, 1999; Raz et al., 1997; West, 1996), but little is known about the underlying mechanisms. In this study, we test the hypothesis that deterioration of white matter tracts re- lated to the presence of white matter hyperintensities (WMH) may be a mechanism for PFC dysfunction in elderly individuals. WMH are areas of high signal inten- sity on T2-weighted magnetic resonance imaging (MRI) scans, and the underlying pathology includes myelin loss, gliosis, and neuropil atrophy (Bronge, 2002). WMH are associated with small-vessel cerebrovascular disease and hypertension (DeCarli et al., 1995; Breteler, van Swieten, et al., 1994) and are commonly seen in cog- nitively normal elderly individuals (Wen & Sachdev, 2004; Soderlund, Nyberg, Adolfsson, Nilsson, & Launer, 2003).

1University of California at Davis, 2University of California at Berkeley

Moreover, there is evidence that WMH are especial- ly detrimental to the frontal lobes relative to the rest of the brain, with reports of selective decreases in N-acetylaspartate levels (a measure of neuronal viability) (Schuff et al., 2003) and resting glucose metabolism in the frontal lobes (Tullberg et al., 2004). There is also evidence that WMH are correlated with executive con- trol deficits thought to arise from PFC dysfunction (Gunning-Dixon and Raz, 2000; DeCarli et al., 1995). Thus, we predicted that global WMH would be associ- ated with a reduction in prefrontal function in elderly individuals during memory performance.

In addition, we were especially interested in the effects of regional WMH localized to dorsal PFC given the evidence suggesting that dorsal PFC may be dispro- portionately affected in aging (MacPherson, Phillips, & Della Sala, 2002; Rypma & D’Esposito, 2000). Dorsal PFC implements cognitive control processes that modulate activity in other areas during working memory and episodic memory tasks (Bunge, Burrows, & Wagner, 2004; Kondo et al., 2004; Ranganath, Johnson, & D’Esposito, 2003; Ranganath & Knight, 2003). We pre- dicted that regional damage to white matter tracts within the dorsal PFC may disconnect the dorsal PFC from its targets and result in reduced recruitment in both the PFC and other brain regions that are

D 2006 Massachusetts Institute of Technology

Journal of Cognitive Neuroscience 18:3, pp. 418–429

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