Donepezil Effects on Cerebral Blood Flow in Older Adults With Mild Cognitive Deficits

Fifteen older adults with mild cognitive deficits were studied after written informed consent was obtained in accordance with the University of Iowa Institutional Review Board. The study involved a double-blind, placebo-controlled randomization to donepezil titrated to 10 mg daily over the first 6 weeks and then continued for a 6-month period with imaging sessions (described below) at baseline and at 6 months. Cognitive impairment was objectively assessed with several neuropsychological measures, including the Mini-Mental State Examination (MMSE) 12 and the Hopkins Verbal Learning Test–Revised (HVLT-R). 13 The MMSE is a widely used screening instrument that evaluates global cognitive functioning, and the HVLT-R is a list-learning test that assesses verbal learning and memory. Consistent with existing criteria for mild cognitive impairment (MCI), 14 all participants complained of memory problems and demonstrated objective memory deficits on at least one test of learning and memory (Mattis Dementia Rating Scale: Memory subscale, 15 Wechsler Memory Scale–III: Logical Memory, 16 Brief Visuospatial Memory Test–Revised), 13 which were defined as one or more standard deviations below age-adjusted expectations based on estimates of premorbid functioning. 17 Global cognition (MMSE, Mattis Dementia Rating Scale total score), however, was within normal limits for all participants. No subjects reported significant difficulties with activities of daily living.

Subjects were excluded if they had a history of major neurological, metabolic, or psychiatric disorders, cardiovascular disease, cerebrovascular events, substance abuse or other significant medical problems. Medical conditions were evaluated through a review of all available medical records, current medications, and patient examination. Any acute or unstable condition was exclusionary in the event that a medical condition was present (e.g., hypothyroidism with stable replacement therapy) or a consensus was achieved by the primary investigators that the condition and its treatment would not incur a variation in CBF. An independent clinical neuroradiologist also reviewed each subject’s structural MRI so that any evidence of a complicating disease state could be excluded (e.g., stroke). Not all subjects had taken donepezil prior to enrollment. At intake, all 15 subjects were imaged using both magnetic resonance (MR) and positron emission tomography (PET) imaging. Seven patients (two men, five women) were selected at random to receive donepezil (titrated to 10 mg/day), whereas eight patients (three men, five women) received placebo. Three subjects in the donepezil group and one subject in the placebo group chose not to continue participation through the second imaging session. Of these, two subjects withdrew because of noncompliance with study medication, one chose to participate in a competing medication study, and another withdrew because of a developing respiratory illness. These subjects were comparable to those who did continue the study in terms of age, education, and global cognition. However, on one memory measure, the Mattis DRS Memory Scale, the subjects who withdrew scored lower than continuing subjects. The remaining 11 subjects were reevaluated with PET and cognitive testing after 6 months of donepezil or placebo treatment. All procedures were conducted in a double-blind fashion such that the raters and PET imaging facility staff were not aware of the medication group status of each subject.

The structural MR images were obtained using a GE Signa 1.5T MR scanner. These images were used to localize regions of interest (ROI) on PET images and to exclude overt structural abnormalities (e.g., stroke). Two sequences were acquired for each subject. The T1 sequence was obtained as a 3 Da volume in the coronal plane using a spoiled GRASS sequence with the following parameters: TE = 6 msec, TR = 20 msec, flip angle = 30°, FOV = 160×160×192 mm, matrix = 256×256×124, NEX = 2. The T2 images were acquired using a 2 Da fast spin-echo sequence in the coronal plane with the following parameters: TE = 85 msec, TR = 4800 msec, slice thickness/gap = 1.8/0.0 mm, FOV = 160×160 mm, matrix = 256×256, NEX = 3, number of echoes = 8, number of slices = 124. The MRI data were transferred to the Department of Radiology Image Processing Laboratory for standard analysis by locally developed software (BRAINS2). The T1 weighted images were aligned spatially along the interhemispheric fissure and the AC-PC line was resampled to 1.0 mm ³ voxels. The T2 weighted scans were coregistered with the resampled T1 weighted images using the automated image registration (AIR) program. 18 The Talairach bounding box and the AC and PC points were defined to allow warping of the Talairach grid onto each subject in the study. The T1 and T2 weighted scans were used to perform a multispectral tissue classification, generating a continuous (fuzzy) classification of the brain tissue. 19 The resulting image contained the percentage of gray matter, white matter, and cerebro-spinal fluid (CSF) at every voxel. These continuous tissue classification images were entered into the neural network to define the brain regions. 20 – 22 The Talairach atlas system defined brain lobes including frontal, temporal, parietal, and occipital lobes. 23 The lobar and brain regions were limited to tissue only (e.g., CSF voxels were excluded).

Quantitative [ ¹⁵ O]water PET images were acquired on a GE 4096 whole-body PET scanner (GE Medical Systems, Milwaukee) at intake and 6 months after the start of a placebo-controlled donepezil trial. The imaging technical methodology employed was identical to methods previously reported for our institution, 24 – 27 including the insertion of radial artery catheters and the sampling and analysis of arterial blood via an online sampler. 27 Global CBF and rCBF were assessed during a verbal production task (counting) and a memory task (word list recall). The counting task served as a control for the aspects of verbal production associated with articulating words so that the memory functions of interest in the verbal recall memory task could be isolated. Subjects counted aloud from 1 to 3 repetitively during the image acquisition period. For the verbal recall memory task, the subjects were given a word list to learn prior to the imaging session. During the imaging session they were asked to name as many of the words as they were able to remember. During the two tasks, the subjects performed at a rate of approximately one word/second and continued for the 100 seconds of image acquisition. The 40 seconds immediately postbolus transit were used to create a static image. This static image and the arterial input function calculated the corresponding parametric (i.e., flow) image (scaled in mL/min/100g). The cerebral blood flow images were coregistered with their corresponding MR scan using AIR. 18 All analyses were performed on the flow, not on the activity images.

The group receiving donepezil consisted of four subjects (one man, three women) with a mean age of 74.8 (SD = 7.4) years and mean baseline MMSE score of 29.8 (SD = 0.50). The placebo group was composed of seven subjects (three men, four women); the mean age was 68.4 (SD = 4.0) years and the mean baseline MMSE score was 29.6 (SD = 0.8). The two groups were not significantly different in age (p = 0.1), education (p = 0.4), or gender (p = 0.7). At the intake visit, global cognition, as assessed by the MMSE, Mattis Dementia Rating Scale Total score, and Barona IQ estimate, was comparable between the two groups (p = 0.9, p = 0.6, p = 0.6, respectively). Despite random assignment, the two groups were not equivalent for performance on a list-learning test (HVLT Total Learning) at baseline, with the placebo group performing significantly better than the donepezil group (23.4 words versus 18.0 words; t (9) = 2.37, p = 0.042). Performance on the same measure at the 6-month follow-up visit, however, was similar for the two groups (25.3 words versus 23.2 words, p = 0.42), suggesting that the placebo group remained stable across time, whereas the participants taking donepezil improved in list-learning performance across time.

This study utilized [ ¹⁵ O]water PET imaging as a functional neuroimaging technique to assess the effects of donepezil in a group of older adults with mild cognitive deficits by monitoring changes in CBF as a measure of neuronal function. The region of interest (ROI) results revealed decreases in CBF during the verbal memory task in the left frontal and temporal lobes of the placebo group across a 6-month period. In contrast, no changes were observed across the same time frame for the donepezil group. These results resemble the findings from the SPECT study by Nobili et al. 9 (2002) which used ^99m Tc-HMPAO SPECT to evaluate the effect of donepezil in a group of patients with mild to moderate Alzheimer’s disease. Nobili et al. also found significant reductions in the CBF in the left temporal lobe and occipital-temporal cortex in the untreated group after 12 months, but no changes in the donepezil group across time. 9 Furthermore, one fluorodeoxyglucose positron emisson tomography (FDG-PET) study showed a similar pattern in brain glucose metabolism in 28 patients with Alzheimer’s disease participating in a placebo-controlled treatment study of donepezil 10 mg/day for 6 months. 28 Striatal glucose metabolism was maintained in donepezil-treated patients but demonstrated a mean decline of 10.4% in placebo-treated patients over the study period.

The cognitive changes reported here over the 6-month period demonstrated a similar pattern to the findings observed in cerebral blood flow. During the baseline evaluation, the placebo group performed better than the donepezil group on a list-learning test. At follow-up, however, the groups were comparable on the same measure. One interpretation of these findings is that the donepezil group improved across time, whereas the placebo group remained stable. With repeated assessments, some improvements in performance are expected (i.e., practice effects); an absence of the expected practice effects could indicate cognitive decline. 29 Therefore, an alternative interpretation of these findings is that the placebo group declined cognitively, as evident in their inability to benefit from practice, whereas the donepezil group remained stable. This latter interpretation of the cognitive data also is consistent with the rCBF data reported here. Despite reasons for caution in interpreting these results in this small sample, all four of the rCBF findings in the placebo group reflected lower flow at 6 months compared to intake. Although the donepezil group showed the same pattern, none of the ROIs showed a significant change in rCBF. This is consistent with the FOI analysis which also showed several regions of decreased rCBF at 6 months in the placebo group and no differences in the donepezil group.

The finding that the donepezil and placebo groups showed different patterns over time in CBF measures obtained during a verbal memory task is consistent with the neuroimaging literature regarding the utility of a cognitive stimulation, in contrast to resting [ ¹⁸ F]fluorodeoxyglucose (FDG) PET imaging for the prediction of the severity of dementia. 30, 31 Just as with other physiological processes, decrements in performance ability may become evident only under the exertion of an activation task. The use of activation tasks may be particularly important in the context of treatment studies as well as in milder syndromes such as mild cognitive impairment where the severity of neurobiologic deficits may be more subtle and variable among individuals.

In conclusion, these data suggest that the CBF in certain regions appeared stable during a 6-month treatment period in subjects receiving donepezil. However, given that cerebral blood flow measures may be affected by age, gender and the methods used in their calculation, 32 one must be cautious in inferring abnormalities in CBF without accounting for the composition of each sample and the methods employed. The conclusions that may be derived from these findings are clearly limited by several factors, including the small number of cases and heterogeneity in cognition reflecting possible variations in cholinergic deficit, as well as variations in effort in performing the verbal recall task. While these limitations may reduce the applicability of these findings, this type of exploratory work may aid in the development of methods to detect treatment effects of cognitive agents. These findings convey the possibility that there may be an effect of cholinesterase inhibitors in early cognitive decline which may be further explored in larger studies.

This study was supported by the National Institute of Mental Health award R21 MH-61801-01A1.