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functionally connected with dorsal PFC in a task-related manner.

We used structural and functional MRI to examine the relationship between WMH and PFC activity in a group of cognitively normal, elderly individuals during an episodic retrieval and a verbal working memory task, two tasks in which age-related changes in PFC activity have been observed (Tisserand & Jolles, 2003; Grady, 2000). We used structural images to quantify WMH and examined the effects of both global WMH and regional dorsal PFC WMH on task-related activity in PFC and in areas that are functionally related to PFC during episodic and working memory task performance. To investigate the effect of WMH on activity, we first identified regions of interest (ROIs) based on task-related activity and then correlated WMH volumes with the magnitude of activity within these regions. Specifically, we hypothesized that (1) global white matter degeneration would result in reduced activation in the PFC during each of the mem- ory tasks and (2) regional white matter degeneration within dorsal PFC would result in reduced activation in PFC as well as in areas that interact with dorsal PFC in a task-specific manner. To control for the possibility that such correlations might be driven by nonspecific vascu- lar or neural changes, we additionally examined visual cortex activation during performance of a simple visual task (under the assumption that neural activity during this task should not be correlated with WMH volume).

METHODS Participants

Fifteen cognitively normal individuals (4 men/11 wom- en) over the age of 65 (range, 66–86) participated in this study. All participants were recruited through the Uni- versity of California-Davis Alzheimer’s Disease Center (ADC), which maintains a pool of control subjects recruited either from the community through advertis- ing or word of mouth, or through spouses or acquaint- ances of patients seen at the ADC. All participants received neurological examinations and neuropsycho- logical evaluations and were adjudicated as normal at a multidisciplinary case conference, based upon all avail- able clinical information. Neuropsychological testing included Mini Mental State Exam (MMSE), Wechsler Memory Scale-Revised (WMS-R) Logical Memory I and II, Memory Assessment Scales (MAS) List Learning, Boston Naming, Block Design, and Digit Span. All sub- jects scored in the normal range on all administered neuropsychological tests (within 1.5 SD of age and education normative data). Demographic information and neuropsychological testing scores are presented in Table 1.

Importantly, individuals in this study were not prese- lected for presence or absence of WMH; they were selected on the basis of normal cognitive ability. In this

Table 1. Demographic Information, Neuropsychological Testing Scores, and WMH Volumes

Age Education MMSE Digit Span Block Design Boston Naming Logical Memory I Logical Memory II MAS-Delayed Recall Total WMH volume

78.7 (6.06) 15.3 (2.29) 29.6 (.51) 14.5 (3.1) 25.1 (7.5) 55.2 (4.5) 25.8 (5.9) 23.3 (5.3) 10.8 (.84) 0.875% (.73)

Dorsal PFC WMH volume

0.390% (.53)

Where applicable, data are expressed as mean (SD). Total WMH is expressed as percent of total cranial volume. Regional WMH is ex- pressed as percent of total regional volume. MMSE =Mini Mental State Exam; MAS = Memory Assessment Scales; WMH = white matter hy- perintensity; PFC = prefrontal cortex.

respect, this sample is comparable to samples used in other functional neuroimaging studies of normal aging (e.g., Logan et al., 2002). Exclusion criteria included history of cortical stroke or other neurological disorder, clinical depression, major visual impairments, and any contraindications for MRI. Individuals with hypertension were not excluded from this study. Of the 15 subjects in this study, 7 individuals had hypertension and were taking antihypertensive medication. Systolic and diastol- ic blood pressure in individuals with (systolic: mean 139, SD 10.2; diastolic: mean 72, SD 5.0) and without hyper- tension (systolic: mean 140, SD 19.9; diastolic: mean 72, SD 11.1) did not differ ( ps > .05). In addition, there were no significant differences between hypertensive and nonhypertensive subjects for global and dorsal PFC WMH volumes or in the magnitude of activation in any of the task-related regions reported on below.

Behavioral Task Paradigms Episodic Memory Retrieval Task

The episodic memory test used in this study is a source memory task that has been shown to be sensitive to PFC and hippocampal function (Yonelinas, Hopfinger, Buonocore, Kroll, & Baynes, 2001). A schematic of this task is depicted in Figure 1A. During the study phase, participants viewed 36 pictures (18 red/18 green, self- paced) and were instructed to remember the color of the picture. Participants were instructed to verbalize an association between the object and the color in order to facilitate memory encoding. An immediate retrieval task was administered following the study phase. After a 1-hr delay, the delayed retrieval task was administered in the

Nordahl et al.


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