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National Institute on Aging (S.M.R., P.M.M.), Baltimore, Maryland 21224-6825; Wake Forest University Health Sciences (S.R.R., M.A.E., L.H.C., P.H., S.A.S.), Winston-Salem, North Carolina 27157; University of Nevada School of Medicine (R.B.), Reno, Nevada 89557; State University of New York (I.A.G.), Stony Brook, New York 11794; and University of Massachusetts Medical School (J.K.O.), Worcester, Massachusetts 01655
Address all correspondence and requests for reprints to: Susan M. Resnick, Laboratory of Personality and Cognition, National Institute on Aging, National Institutes of Health, Box 03, 5600 Nathan Shock Drive, Baltimore, Maryland 21224-6825. E-mail: Susan.Resnick{at}nih.gov.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Objective: The objective of this study was to determine whether hormone therapy influences changes in specific cognitive functions and affect in older women.
Design: This study was a randomized, double-blind, placebo-controlled clinical trial.
Setting: Participants were women from 14 of 40 clinical centers of the Women’s Health Initiative (WHI).
Participants: Postmenopausal women (1416) aged 65 yr and older, free of probable dementia, and enrolled in WHI and the WHI Memory Study (WHIMS) trial of combination estrogen and progestin for a mean of 3 yr and followed for a mean of 1.35 yr, were studied.
Intervention: Intervention was conjugated equine estrogen (CEE; 0.625 mg) with 2.5 mg medroxyprogesterone acetate (MPA) in one daily tablet (CEE + MPA) or placebo.
Main Outcome Measures: Annual rates of change in specific cognitive functions and affect, adjusted for time since randomization, were measured.
Results: CEE + MPA had a negative impact on verbal memory (P 
0.01) and a trend to a positive impact on figural memory (P = 0.012) over time compared with placebo, but other cognitive domains were not affected. Both effects on memory were evident only after long-term therapy. CEE + MPA did not significantly influence positive affect, negative affect, or depressive symptoms.
Conclusions: The effect of CEE + MPA on cognitive function varies across cognitive domains in older women, reflecting both possible beneficial and detrimental actions of ovarian steroids on the aging brain. Our results extend prior findings about dementia and global cognitive function to age-related changes in specific cognitive functions and suggest directions for future research.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Although studies using animal models provide support for beneficial effects of estrogens on the central nervous system (6), investigations of the effects of HT on cognitive function have yielded inconsistent findings. Conclusions from observational studies are limited by the healthy user bias, the tendency of women who choose to use HT to be more educated and healthier overall (7). On the other hand, data from randomized clinical trials are limited by small samples comprised of younger women after surgical menopause (8) or older women with preexisting coronary disease (9) and cognitive tests of unclear sensitivity. Previous reports of cognitive function in WHIMS were based on annual assessments of global cognition on the Modified Mini Mental State Exam (3MS), a brief mental status test. More comprehensive cognitive assessments were restricted to women scoring below specified 3MS cutoff points (10). Results from WHIMS indicated significant increases in risk for probable dementia in the combination HT subtrial alone and in the combined analysis of combination HT and conjugated equine estrogen (CEE)-alone subtrials (1, 3) and poorer performance on the 3MS (2, 4) after initiation of HT in postmenopausal women aged 65 and older. However, the WHIMS findings did not address the effects of HT on specific cognitive domains.
Here, we report findings from the largest longitudinal study of HT on standardized tests of memory and other cognitive functions. Data are drawn from the WHI Study of Cognitive Aging (WHISCA), an ancillary study to the WHI (11) and WHIMS. WHISCA was designed to determine whether HT affects the rates of age-related changes in specific cognitive functions, particularly memory, and affect in postmenopausal women without dementia (12) and was initiated 3 yr after WHI randomization. This report focuses on 1416 WHISCA participants in the HT subtrial receiving combination CEE and medroxyprogesterone acetate (MPA). Based on our earlier findings in the Baltimore Longitudinal Study of Aging (13, 14, 15), we predicted that CEE + MPA would protect against age-related declines in particular domains of cognition, with greatest effects on verbal and figural memory, but would not have global effects on all aspects of cognitive function in women without dementia.
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Subjects and Methods |
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Participants
Procedures for enrollment and baseline sample characteristics for WHI (11) and WHIMS (10) and the subsamples in the CEE + MPA trial (1, 16) have been reported. The WHISCA study began in October 1999. This paper includes follow-up data through July 7, 2002, the day before WHI termination of study pills for the CEE + MPA subtrial due to an adverse risk-benefit profile (16). WHISCA participants were recruited from 14 of 39 WHIMS sites. In addition to the major exclusions for WHI and WHIMS, participants were eligible for WHISCA if they were English-speaking and did not have probable dementia, as determined by the WHIMS protocol (1). All participants provided written informed consent. The WHISCA protocol was approved by Institutional Review Boards at each clinic site, the Clinical Coordinating Center (CCC), and the National Institute on Aging.
Hormone treatment
Randomized assignment to treatment was performed through the WHI HT protocol. Women with uteri were randomly assigned to take one daily tablet containing either 0.625 mg CEE and 2.5 mg medroxyprogesterone acetate (MPA) (Prempro, Wyeth Pharmaceuticals, Collegeville, PA) or a matching placebo (also provided by Wyeth Pharmaceuticals). Because WHISCA was initiated after WHI randomization, women had received treatment for 1.1–5.6 yr (mean 3.0) before WHISCA initial assessment.
Objective
The primary objective of this study was to determine whether CEE + MPA modifies the rates of change and slows age-related decline in specific cognitive functions, particularly verbal and figural memory, in women without dementia.
Tests of cognition and affect
The WHISCA test battery (Table 1
) was designed to test a broad range of specific cognitive functions and affect, emphasizing tests that are sensitive to longitudinal age changes or effects of hormones (12). Measures of verbal and figural memory were expected to show the greatest sensitivity to treatment.
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Assessments of cognitive function and affect were conducted for all WHISCA participants annually. The same test battery was administered at each visit, with the exception of the California Verbal Learning Test (CVLT). Due to substantial effects of repeated testing on this key outcome (17), we employed two forms of the CVLT according to the following schedule: assessments 1 and 2, form A; and assessment 3, form B (18). Test administrators are trained centrally through the WHISCA CCC (12), using test procedures consistent with those in the Baltimore Longitudinal Study of Aging (19). Quality control is maintained by the CCC through recertification of test administrators every 6 months for the first year and annually thereafter (12).
Statistical analysis
All analyses were conducted using SAS version 8.2 (SAS Institute, Inc., Cary, NC). Differences between WHISCA women randomized to CEE + MPA vs. placebo with respect to demographic characteristics at the time of WHI enrollment were determined using 
2 tests and Student’s t tests. Analyses were repeated for participants who completed three WHISCA assessments before July 8, 2002.
The principal outcome measures for WHISCA are the mean rates of change across follow-up for tests of specific cognitive functions and affect. Generalized linear models with random effects (for intercepts and slopes) were used to estimate the difference in the mean rate of change (slope) for women grouped by treatment assignment. Covariates included visit number and time from WHI randomization to WHISCA enrollment. We adopted a linear model for visit unless a class model (to absorb learning effects that were common across treatment groups) improved the fit significantly. We also examined mean differences between treatment groups at the time of enrollment into WHISCA, using analyses of covariance to adjust for time since randomization. To control type I error across the multiple outcome measures, a two-sided 0.01 critical level for statistical significance was specified a priori by the WHISCA protocol; a strict Bonferroni adjustment would be overly conservative due to correlations among outcomes.
We conducted several supporting secondary analyses. Although participants with existing diagnoses of dementia were not enrolled in WHISCA, all enrolled participants, including those who developed dementia during follow-up, were included in the primary intention-to-treat analyses. To examine the impact of treatment assignment on women free of clinically detectable disease throughout the trial, analyses were repeated for participants who remained free of probable dementia, mild cognitive impairment, and stroke. The same analyses were performed for the subgroup completing three follow-up visits before termination of study medications. To examine the impact of treatment adherence, we repeated the intention-to-treat analyses after excluding test scores from visits after which participants became nonadherent by WHI criteria: 1) stopped study pills (drop-outs), 2) took fewer than 80% of study pills between dispensation and collection, or 3) began prescription hormones outside the main WHI trials (drop-ins). Analyses also were repeated adjusting for 3MS score at WHIMS baseline to control for variability in global cognition at the time of WHIMS enrollment. Finally, subgroup analyses were conducted on WHI baseline factors thought to either influence test scores or the impact of CEE + MPA treatment.
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Results |
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Of CEE + MPA trial participants, 2089 were eligible for WHISCA, and 1416 (68%) agreed to participate. Compared with 673 eligible women in the CEE + MPA trial at the 14 sites who did not enroll in WHISCA, WHISCA participants were slightly younger, more highly educated, and had higher scores at WHI baseline on the 3MS (P < 0.001), had a higher proportion of Caucasians (P < 0.001), a lower prevalence of hypertension (P < 0.01), and were less likely to report moderate/severe vasomotor symptoms at WHI baseline (P < 0.05). Sample characteristics of WHISCA participants in both treatment groups at WHI and WHISCA initial assessments are shown in Table 2, and the WHISCA sample profile is summarized in Fig. 1. The numbers of participants completing first, second, and third annual assessments before WHI termination of study medications were, respectively, 690, 636 (92.2%), and 291 (42.2%) for the CEE + MPA group and 726, 673 (92.7%), and 320 (44.1%) for the placebo group. The mean (SD) follow-up intervals from the initial WHISCA assessment were 1.35 (0.61) yr for the entire sample, 1.33 (0.61) yr for the CEE + MPA group, and 1.36 (0.62) yr for the placebo group. The reduction in number of participants at the third assessment primarily reflects the exclusion of data collected after July 8, 2002.
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WHISCA CEE + MPA and placebo groups were not significantly different at WHI baseline for demographic and health-related characteristics or for global cognitive function (Table 2
; all P > 0.05). Treatment groups also did not differ significantly in 3MS score at WHISCA initial assessment [mean (SD), CEE + MPA, 96.93 (3.15); placebo, 96.91 (3.29); P = 0.93] or in rates of change in 3MS over the WHISCA follow-up interval (mean ± SE, CEE + MPA, 0.156 ± 0.074; placebo, 0.162 ± 0.074; P = 0.87). Treatment groups were also comparable with respect to body mass index (BMI), alcohol intake, and antihypertensive use at WHISCA enrollment and numbers of incident cases of diabetes and myocardial infarction since randomization (P > 0.05). Comparisons of the subgroups completing three WHISCA assessments before July 8, 2002 showed that treatment groups remained comparable and did not differ significantly on demographic and health-related measures. However, women in the CEE + MPA compared with placebo group were significantly less likely to meet the WHI criteria for adherence [initial WHISCA assessment, CEE + MPA, 399 of 690 (57.8%); placebo, 492 of 726 (67.8%), P < 0.001; 1-yr follow-up, CEE + MPA, 336 of 636 (52.8%); placebo, 430 of 673 (63.9%), P < 0.001; and 2-yr follow-up, CEE + MPA, 138 of 291 (47.4%); placebo, 196 of 320 (61.2%), P < 0.001].
Effects of CEE + MPA
After enrollment in WHISCA, 11 participants were diagnosed with probable dementia (five CEE + MPA, six placebo), 19 with mild cognitive impairment (six CEE + MPA, 13 placebo), and 14 with incident strokes (nine CEE + MPA, five placebo).
Mean unadjusted scores and SD values for the outcome measures are presented by treatment group and visit in Table 3. With the exception of category fluency and digits backward, scores on the cognitive tests indicated overall improvements in performance over time across treatment groups (P < 0.05). Positive affect scores increased slightly over time (P < 0.01) across treatment groups, and negative affect scores were unchanged, despite small increases in depressive symptom scores (P < 0.001). Results of the primary analyses are summarized in Table 4 for the intention-to-treat sample. Mean differences between treatment groups at the initial WHISCA assessment, adjusted for time since randomization, are shown in the left column of Table 4, with positive values indicating higher scores for the CEE + MPA compared with placebo group. No differences across the 16 outcomes reached the 0.01 level of significance. The largest differences were for the attention/working memory scales; on average, women randomized to CEE + MPA scored slightly lower at initial WHISCA assessment than those randomized to placebo on the digits forward (P = 0.05) and digits backward (P = 0.08) tests. Results were similar in analyses excluding individuals with probable dementia, mild cognitive impairment, and stroke.
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for all participants and in the right columns for women completing three visits. Positive values indicate greater longitudinal increases or smaller decreases in scores for the CEE + MPA compared with placebo group and negative values indicate greater longitudinal increases or smaller decreases for the placebo group. [Note that the Benton Visual Retention Test (BVRT) scores reflect errors rather than correct responses.] Rates of change over time showed significant differences between treatment groups that varied across specific cognitive functions. CVLT scores among CEE + MPA women showed significant declines relative to placebo for learning (P = 0.009), and trends for short (P = 0.016) and long (P = 0.015) delay free recall but not learning after interference. In contrast to the results for verbal memory, women assigned to CEE + MPA compared with placebo showed a trend for greater improvement (fewer errors) over time on the BVRT test of figural memory and visuoconstructional skills, with a mean difference in rates of 0.27 errors/yr (P = 0.012). Rates of change for the remaining tests did not differ significantly between treatment groups.
Results remained similar in secondary analyses for the subsample completing three visits, after excluding participants with probable dementia, mild cognitive impairment and stroke, and after adjustment for WHI baseline 3MS scores. Although trends were also consistent in analyses restricted to women meeting the WHI criterion for adherence, only the greater decline for the CEE + MPA group on CVLT short delay free recall score reached the 0.01 significance level. Correlations between longitudinal changes on the BVRT and CVLT were nonsignificant and near zero. There were no significant effects of CEE + MPA treatment on scores at initial WHISCA assessment or on longitudinal changes for positive affect, negative affect, or self-reported symptoms of depression. None of the subgrouping variables showed robust interactions with treatment effects, although power was limited by small samples.
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Discussion |
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On CVLT measures of verbal learning and memory, a deleterious effect of CEE + MPA treatment was observed after long-term treatment (average of 4–5 yr). Measures of new learning and short and long-delay free recall showed greater declines in the CEE + MPA group. The lack of benefit of CEE + MPA on verbal memory and evidence of a modest decrement are contrary to predictions from randomized trials of estradiol alone after surgical menopause (8), after pharmacological ovarian hormone suppression (20), and from some observational studies of women who typically initiated treatment around menopause (14, 21). However, the lack of a benefit of HT on verbal memory in our older sample is consistent with trials in older women (9, 22), although prior studies examined pre- vs. posttreatment effects rather than effects on longitudinal age changes.
In contrast to the effect of HT on verbal memory, the CEE + MPA compared with placebo group showed a trend toward greater improvement over time on the BVRT, a measure of short-term figural memory and visuoconstructional abilities. Performance was comparable across groups at initial WHISCA evaluation (after 3 yr of treatment), with improvement in the CEE + MPA group and little change over time for the placebo group. The finding that longer but not shorter durations of CEE + MPA treatment were associated with a trend toward better figural memory performance may clarify discrepancies among some studies of HT and cognition that vary in duration of use. For example, short-term estradiol treatment did not influence figural memory performance in some studies (23, 24), but long-term HT use since menopause was associated with enhanced performance (13, 25).
In WHISCA, longitudinal changes in CVLT performance were unrelated to BVRT changes, suggesting different underlying mechanisms. The longitudinal stability and lack of significant treatment effects on measures of positive affect, negative affect, and depressive symptoms also indicate that HT effects on memory are not mediated through changes in affect. Treatment effects on rates of change for other cognitive domains did not approach significance and offered no support for either decreased (9) or increased (26) category fluency in association with HT.
A number of limitations of this study should be considered in interpreting these results. Although a double-blind randomized clinical trial, WHISCA was initiated 3 yr after WHI randomization. The two treatment groups were well-balanced at WHI and WHISCA initial assessments on demographic and health-related characteristics and global cognitive functioning, but pretreatment levels of specific cognitive abilities were unavailable. At the initial WHISCA assessment, only digits forward and digits backward tests showed trends toward differences between treatment groups. The slight decrement on these measures is at odds with some prior reports of better attentional functioning after short-term estradiol (8) and longer term HT (27, 28), and the effect did not endure over follow-up.
Another issue in longitudinal studies of cognition, particularly memory, is the complex relationship between practice effects and age-related changes. Learning is observed even with 1 yr between assessments, highlighting the importance of a placebo-treated control group tested with the same schedule. With increasing follow-up intervals and age, learning effects become less apparent, and longitudinal age changes predominate (17). With the 1-yr retest and short follow-up interval in this study, expected improvements in performance predominated over age-related declines.
Early termination of the intervention also limited the follow-up assessments included in analyses. Demographic and health-related characteristics remained comparable for women completing three assessments before the termination of study medications, and analyses restricted to these participants yielded similar findings. Furthermore, treatment-related differences in rates of change were unchanged after controlling for variability in 3MS at WHI baseline. Early termination of the WHI CEE + MPA trial also limited power to detect treatment effects. The original sample size and 4-yr follow-up for WHISCA was chosen to provide 90% statistical power to detect a 50% effect of active treatment (CEE-only and CEE + MPA) on rates of change in the BVRT. WHISCA CEE + MPA trial women averaged 1.35 yr (maximum 2.51 yr), with approximately 35% power to detect the effect size originally targeted for the BVRT (a difference in rates of change of 0.23 errors/yr). Our power to detect significant changes may be reduced further by the substantial rate of nonadherence. Despite these limitations, the observed difference in BVRT rate of change of 0.27 errors/yr is consistent with our original projection, and we detected significant deleterious treatment effects on verbal memory. Although treatment effects on rates of change were expected to be small over the study duration, they could produce clinically relevant, albeit modest, cumulative effects over time if they endure.
How can the current findings be reconciled with the WHIMS results indicating a 2-fold increase in the risk of all-cause dementia in the CEE + MPA compared with placebo group? The deleterious effect of CEE + MPA on verbal memory is consistent with the WHIMS findings (1, 2) and may be mediated by risks for ischemic and thromboembolic events associated with CEE + MPA (16, 29). Recent investigations (30, 31, 32, 33) demonstrate increases in dementia risk in individuals with infarcts. It also has been suggested that the progestin, MPA, may antagonize some beneficial effects of estrogens on the central nervous system (34, 35, 36). Estrogen and MPA, but not estrogen alone, were associated with increased cognitive decline in one longitudinal study (37), and additional research on the central nervous system effects of different progestins is indicated.
In contrast to the detrimental effects of CEE + MPA on risk for dementia and verbal memory, the modest benefits of CEE + MPA on longitudinal changes in figural memory in WHISCA may reflect a different process. Substantial neurobiological evidence indicates that estrogens have neurotrophic and neuroprotective effects on the central nervous system, including enhancement of synaptic plasticity, reduction in ß-amyloid formation, and modulation of neurotransmission and cerebral glucose metabolism (6, 38, 39). Thus, risks for thromboembolic and ischemic events, on the one hand, and possible benefits on the pathological processes that lead to memory decline and Alzheimer’s disease (AD), on the other, may represent competing effects. In the WHISCA sample of women who were without dementia after 3 yr of CEE + MPA treatment, modest beneficial effects of CEE + MPA on BVRT performance may predominate over adverse effects. In this regard, it is notable that in another study, BVRT scores predicted risk for AD as long as 15 yr before diagnosis (40). Thus, beneficial effects of CEE + MPA on the BVRT may be apparent where possibly reduced risk of AD exists for genetic or other reasons. The relative health of older women enrolled in WHISCA compared with WHIMS is supported by the lack of an effect of CEE + MPA on global cognition in WHISCA participants after 3 yr of treatment and on rates of change during WHIMS and WHISCA follow-up periods.
WHISCA findings of different effects of CEE + MPA on specific cognitive functions do not change current recommendations that older postmenopausal women should not initiate combination CEE + MPA because the risks outweigh benefits (16). However, they suggest that HT may have different effects on specific cognitive domains, perhaps in women with different risks for vascular events or AD-type pathology. These findings also may help explain differences in dementia risk between observational studies of HT and the WHIMS randomized clinical trial. The observational studies focus on ever use of HT, and most use of HT has been relatively short-term during the menopausal transition. The WHIMS and WHISCA studies in older women do not address short-term effects in younger women. In addition, full results from the CEE-only arm of WHISCA are pending, and these data will be important in understanding the effects of estrogen alone on specific aspects of cognitive function. The WHISCA data highlight the importance of future studies to determine short- and long-term effects of particular hormone regimens on specific cognitive functions, particularly memory, in women with different liabilities to dementia. The challenge to researchers is to further investigate potential neuroprotective benefits of HT without putting women at increased risk for other negative outcomes.
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Acknowledgments |
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WHISCA Central Coordinating Center: Sally Shumaker, Principal Investigator; Stephen Rapp; Mark Espeland; Laura Coker; Deborah Farmer; Anita Hege; Patricia Hogan; Darrin Harris; Cynthia McQuellon; Anne Safrit; Lee Ann Andrews; Candace Warren; Carolyn Bell; Linda Allred.
WHISCA Clinical Sites: WHI, Durham, North Carolina, Carol Murphy; Rush Presbyterian-St. Luke’s Medical Center, Chicago, Illinois, Linda Powell; Ohio State University Medical Center, Columbus, Ohio, Rebecca Jackson; University of California at Davis, Sacramento, California, John Robbins; University of Iowa College of Medicine, Des Moines, Iowa, Robert Wallace; University of Florida, Gainesville/Jacksonville, Florida, Marian Limacher; University of California at Los Angeles, Los Angeles, California, Howard Judd; Medical College of Wisconsin, Milwaukee, Wisconsin, Jane Kotchen; The Berman Center for Outcomes and Clinical Research, Minneapolis, Minnesota, Karen Margolis; University of Nevada School of Medicine, Reno, Nevada, Robert Brunner; Albert Einstein College of Medicine, Bronx, New York, Sylvia Smoller; The Leland Stanford Junior University, San Jose, California, Marcia Stefanick; The State University of New York, Stony Brook, New York, Dorothy Lane; University of Massachusetts/Fallon Clinic, Worcester, Massachusetts, Judith Ockene. The following investigators were the original investigators for these sites: Mary Haan, Davis, California; Richard Grimm, Minneapolis, Minnesota; and Sandra Daugherty (deceased), Reno, Nevada.
WHI Central Coordinating Center: Fred Hutchinson Cancer Research Center, Seattle, Washington, Deborah Bowen, Gretchen VanLom, Carolyn Burns.
WHIMS Central Coordinating Center: Wake Forest University Health Sciences, Winston-Salem, North Carolina, Sally Shumaker, Mark Espeland, Stephen Rapp, John Absher, Beverly Jones, Beth Reboussin, Beth Dugan, Claudine Legault.
Short list of WHI investigators
Program Office: National Heart, Lung, and Blood Institute, Bethesda, Maryland, Barbara Alving, Jacques Rossouw, Linda Pottern.
CCC: Fred Hutchinson Cancer Research Center, Seattle, Washington, Ross Prentice, Garnet Anderson, Andrea LaCroix, Ruth E. Patterson, Anne McTiernan; Wake Forest University School of Medicine, Winston-Salem, North Carolina, Sally Shumaker, Pentti Rautaharju; Medical Research Labs, Highland Heights, Kentucky, Evan Stein; University of California at San Francisco, San Francisco, California, Steven Cummings; University of Minnesota, Minneapolis, Minnesota, John Himes; University of Washington, Seattle, Washington, Bruce Psaty.
Clinical Centers: Albert Einstein College of Medicine, Bronx, New York, Sylvia Wassertheil-Smoller; Baylor College of Medicine, Houston, Texas, Jennifer Hays; Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, JoAnn Manson; Brown University, Providence, Rhode Island, Annlouise R. Assaf; Emory University, Atlanta, Georgia, Lawrence Phillips; Fred Hutchinson Cancer Research Center, Seattle, Washington, Shirley Beresford; George Washington University Medical Center, Washington, D.C., Judith Hsia; Harbor-University of California Los Angeles Research and Education Institute, Torrance, California, Rowan Chlebowski; Kaiser Permanente Center for Health Research, Portland, Oregon, Cheryl Ritenbaugh; Kaiser Permanente Division of Research, Oakland, California, Bette Caan; Medical College of Wisconsin, Milwaukee, Wisconsin, Jane Morley Kotchen; MedStar Research Institute/Howard University, Washington, D.C., Barbara V. Howard; Northwestern University, Chicago/Evanston, Illinois, Linda Van Horn; Rush-Presbyterian St. Luke’s Medical Center, Chicago, Illinois, Henry Black; Stanford Center for Research in Disease Prevention, Stanford University, Stanford, California, Marcia L. Stefanick; State University of New York at Stony Brook, Stony Brook, New York, Dorothy Lane; The Ohio State University, Columbus, Ohio, Rebecca Jackson; University of Alabama at Birmingham, Birmingham, Alabama, Cora Beth Lewis; University of Arizona, Tucson/Phoenix, Arizona, Tamsen Bassford; University at Buffalo, Buffalo, New York, Maurizio Trevisan; University of California at Davis, Sacramento, California, John Robbins; University of California at Irvine, Orange, California, Allan Hubbell; University of California at Los Angeles, Los Angeles, California, Howard Judd; University of California at San Diego, La Jolla/Chula Vista, California, Robert D. Langer; University of Cincinnati, Cincinnati, Ohio, Margery Gass; University of Florida, Gainesville/Jacksonville, Florida, Marian Limacher; University of Hawaii, Honolulu, Hawaii, David Curb; University of Iowa, Iowa City/Davenport, Iowa, Robert Wallace; University of Massachusetts/Fallon Clinic, Worcester, Massachusetts, Judith Ockene; University of Medicine and Dentistry of New Jersey, Newark, New Jersey, Norman Lasser; University of Miami, Miami, Florida, Mary Jo O’Sullivan; University of Minnesota, Minneapolis, Minnesota, Karen Margolis; University of Nevada, Reno, Nevada, Robert Brunner; University of North Carolina, Chapel Hill, North Carolina, Gerardo Heiss; University of Pittsburgh, Pittsburgh, Pennsylvania, Lewis Kuller; University of Tennessee, Memphis, Tennessee, Karen C. Johnson; University of Texas Health Science Center, San Antonio, Texas, Robert Brzyski; University of Wisconsin, Madison, Wisconsin, Catherine Allen; Wake Forest University School of Medicine, Winston-Salem, North Carolina, Gregory Burke; Wayne State University School of Medicine/Hutzel Hospital, Detroit, Michigan, Susan Hendrix.
The WHISCA writing group gratefully acknowledges the dedicated efforts of the WHISCA participants, the WHISCA investigators and staff at the clinical centers, and Melissa Kitner-Triolo and Wendy Elkins at the National Institute on Aging.
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Footnotes |
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Present address for P.M.M.: Neuropsychiatric Institute, University of Illinois at Chicago, Chicago, Illinois 60612.
The WHIMS parent study was funded by Wyeth Pharmaceuticals, and M.A.E., S.R.R., R.B., L.H.C., I.A.G., P.H., J.K.O., and S.A.S. received grant support through the WHIMS study. S.M.R. and P.M.M. received previous grant support (nonsalary) from Wyeth Pharmaceuticals for other studies related to HT. M.A.E. and S.A.S. have received consulting fees from Wyeth Pharmaceuticals; P.M.M. has received consulting fees and speaker honoraria from Wyeth Pharmaceuticals and from the Council on Hormone Education and QED Communications, which are both supported through unrestricted education grants from Wyeth Pharmaceuticals.
First Published Online March 7, 2006
Abbreviations: AD, Alzheimer’s disease; BMI, body mass index; BVRT, Benton Visual Retention Test; CCC, Clinical Coordinating Center; CEE, conjugated equine estrogen; CVLT, California Verbal Learning Test; HT, hormone therapy; MPA, medroxyprogesterone acetate; 3MS, Modified Mini Mental State Exam; WHI, Women’s Health Initiative; WHIMS, WHI Memory Study; WHISCA, WHI Study of Cognitive Aging.
Received September 20, 2005.
Accepted February 24, 2006.
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