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Age (Dordr). 2009 September; 31(3): 231–255.
Published online 2009 July 2. doi:  10.1007/s11357-009-9101-8
PMCID: PMC2734244

Session summaries and abstracts from the 11th Biennial Graylyn Conference on women’s cognitive health, 24–26 October 2007

Session #1: Hormone Therapy and the Brain

Shannon Stark, BS1, Shannon L. S. Golden, MA2,3, Mary Lou Voytko, PhD2,4

1Department of Psychology, Wake Forest University, Winston-Salem, North Carolina;2Women’s Health Center of Excellence for Research, Leadership, Education, Wake Forest University School of Medicine, Winston-Salem, NC;3Division of Public Health Sciences, Department of Social Sciences and Health Policy, Wake Forest University School of Medicine, Winston-Salem, NC;4Department of Neurobiology and Anatomy, Wake Forest University School of Medicine, Winston-Salem, NC

e-mail: mlvoytko@wfubmc.edu

Key words: cell culture; rats; monkeys; cognition; mitochondria; critical period hypothesis

The first session of the 11th Biennial Graylyn Conference on Women’s Cognitive Health offered a view of the translational research response to the results of the Women’s Health Initiative Memory Study (WHIMS), an ancillary study to the Women’s Health Initiative (WHI), that investigated the effects of a continuous hormone therapy (HT) regimen of Premarin (conjugated equine estrogens) plus progestin on cognition and brain function in women over the age of 65 years (Shumaker et al. 2003). The women in the treatment group were found to have an increased incidence of dementia compared to the women receiving placebo. The speakers in this session, Roberta Diaz Brinton, PhD, Jill Daniel, PhD, and Mary Lou Voytko, PhD, described examples of their research response to the WHIMS findings in neural pathways, rodents, and monkeys, respectively.

Dr. Brinton presented findings from her research on the effects of estrogen in cell culture models, and implications for its effects on neuronal pathways in the brain. Her work has shown that the neuroprotective effects of estrogen on healthy cells are mediated through mitochondria and calcium homostatis. In neurons that have been previously exposed to neurodegenerative factors, likely comparable to those of the older women in the WHIMS trial, estrogen can intensify neural demise through altered calcium and mitochondrial function. Additional findings in her laboratory indicate that estrogen must be given prior to neural insult to have beneficial effects; giving estrogen at the time of insult or after the insult occurs results in poor survival. Her findings of a “healthy cell bias” suggest an important experimental shift is needed from using young animal models to conducting more research in middle-aged models to better mimic the neurobiology of older women at the time they receive hormone therapy.

Dr. Daniel’s lab used rat models to investigate the critical period hypothesis of estrogen replacement effects on cognition. Her results show that, in the middle-aged rat, chronic estrogen replacement improves hippocampal memory and increases levels of hippocampal cholinergic markers when the therapy is instituted immediately after ovariectomy, but not when instituted after long-term ovarian hormone deprivation. Her research suggests that estrogen replacement therapy may improve cognition only if it is begun soon after menopause, unlike the hormone regimen in the WHIMS trial, which was instituted in women almost 15 years post-menopause.

Dr. Voytko studied middle-age female nonhuman primates as a model of the middle-age women experiencing menopause. In her studies, she administered, beginning at the time of ovariectomy, an estrogen alone or estrogen plus progesterone regimen in fluctuating doses that mirrored the patterns of these hormones during the normal menstrual cycle of primates. This schedule and timing of HT differs from that used in WHIMS. She found unique effects of HT on visual, but not spatial, memory that are not immediately evident nor long-lasting. Her findings suggest that different cognitive domains may be more sensitive than others to HT in older primates.

The positive HT basic research findings presented in this session beg the question of why the results of the WHIMS trial showed an increased incidence of cognitive deficit in women who received HT when previous research had shown positive cognitive effects. The translational research performed in response to WHIMS offers two possible answers to this question. First, as Brinton’s and Daniel’s research suggests, estrogen could have had a negative effect on the neurons of the women in WHIMS because they were older (65+ years) by the time they received HT, and their neurons had likely already been exposed to considerable age-related and neurodegenerative factors. Potentially, if the hormone regimen had been administered earlier to women, i.e. closer in time to the menopause, it would have had a positive cognitive effect in WHIMS. Second, as Voytko suggests, hormone treatment did not have positive effects on cognition in the WHIMS trial because a constant administration of hormones was used which is unlike the normal menstrual hormone cycle. Potentially, fluctuating hormone treatment more closely mimicking natural hormone cycles in menstruation would have had a different effect on cognition.

The discussion following the session focused on attempts to better model the older human woman. Hormone dosage and the durability of the effects of estrogen in animal models were discussed. One important point concerned the accuracy of animal models of menopause, none of which are directly comparable to human menopause. The other main topic of discussion was ways to better understand the brain mechanisms occurring in response to estrogen post-menopause. Cholinergic markers and estrogen alternatives were discussed in this context. The panelists speculated that mitochondrial ATP or estrogen receptor changes may underlie brain changes in aging.

This session displayed an excellent sample of the research conducted across disciplines to address the findings of the WHIMS study. It was instrumental in generating new ways of thinking about HT and good translational practices in general.

References

Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, Hendrix SL, Jones BN 3 rd, Assaf AR, Jackson RD, Kotchen JM, Wassertheil-Smoller S, Wactawski-Wende J, WHIMS Investigators (2003) Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA 289:2651–2662. doi:10.1001/jama.289.20.2651

ABSTRACTS

The Healthy Cell Bias of Estrogen Action and Brain Selective Estrogen Alternatives: Bridging the Translational Divide

Roberta Diaz Brinton, PhD Pharmacology and Pharmaceutical Sciences, Neuroscience Program, University of Southern California

Sixty-eight percent of all victims of Alzheimer’s disease (AD) are women, which translates into 3.4 million of the 5 million current victims of Alzheimer’s disease and 9.52 of the projected 14 million future victims. The shock wave that followed the report that 65–85 year old women treated with hormone therapy (HT) in the Women’s Health Initiative Study (WHIMS) had a greater risk of developing AD was actually preceded by several warning tremors from both the basic and clinical sciences. Together, this small but important body of knowledge led to the next advance in the neurobiology of estrogen, i.e., the healthy cell bias of estrogen action. In healthy neurons and brains, 17β-estradiol (E2)-activated biochemical and genomic mechanisms converge upon key cell survival pathways that sustain calcium homeostasis, cholesterol trafficking / beta amyloid clearance and mitochondrial function. E2 promotes mitochondrial function to increase key enzymes required for the TCA cycle, efficiency of oxidative phosphorylation, and generation of ATP while simultaneously reducing oxidative stress. Collectively, optimal activation of these cellular pathways promotes neuronal survival and function, which can be manifested clinically by sustained cognitive function during aging and reduced risk of developing neurodegenerative diseases such as AD. In contrast, activation of E2 responses in neurons previously exposed to neurodegenerative insults can exacerbate neural demise. Candidate mechanisms to explain the diametrically different outcomes of estrogen exposure converge on regulation of calcium homeostasis and mitochondrial function. This fundamental understanding of estrogen neurobiology has implications for a ‘window of opportunity for HT’ benefit as well as development of alternative estrogenic therapies that promote neural responses to reduce the risk of sporadic AD while simultaneously reducing risks of adverse effects in reproductive organs.

This study was supported by grants from the National Institutes of Health (1RO1 MH67159-01 to R.D.B and J.N.), the Kenneth T. and Eileen L. Norris Foundation and the Jane and Gale Bensussen Gift for Therapeutic Development (R.D.B.)

Critical Period Hypothesis of Estrogen Effects on Cognition: Evidence from Rodent Models

Jill M. Daniel, PhD

Department of Psychology and Neuroscience Program, Tulane University

The study of the effects of aging and estrogens on cognitive function has been advanced by the experimental control afforded by the use of nonhuman animal models. Rodent models, which take advantage of the relatively short life spans of rats and mice, have been used extensively to characterize neuroendocrine aging. It is hypothesized that in women there is a critical period following the onset of menopause during which hormone replacement therapy must be initiated in order for it to benefit cognitive function. Results of basic research using rodent models provide support for this hypothesis. Using a rat model in our lab, we have demonstrated that the timing of initiation of estrogen replacement affects its subsequent efficacy. For example, chronic estradiol replacement enhanced performance on a hippocampal-dependent task in a radial-arm maze in middle-aged rats when initiated immediately after ovariectomy, but not after a long-term period of ovarian hormone deprivation. We had previously determined that the estradiol enhancement of performance on hippocampal dependent tasks is related to its ability to affect cholinergic neurotransmission in the hippocampus. Therefore, we recently assessed effects of the timing of the initiation of estradiol replacement on its ability to impact cholinergic markers in the hippocampus using Western blotting. Hippocampal levels of choline acetyltransferase (ChAT) in middle-aged rats that received 10 days of chronic estradiol replacement initiated at the time of ovariectomy were significantly higher than levels in ovariectomized controls. When estradiol replacement was initiated 5 months after ovariectomy, no significant changes in ChAT were evident. These results indicate that, whereas chronic estradiol replacement can positively affect the hippocampal memory system in middle-aged females when initiated immediately after ovariectomy, it is not effective when initiated after long-term ovarian hormone deprivation.

Supported by National Science Foundation Grant 0715725.

Effects of a Novel Regimen of Hormone Therapy on Memory in Middle-Aged Surgically Menopausal Monkeys

Mary Lou Voytko, PhD Department of Neurobiology and Anatomy, Wake Forest University School of Medicine

Postmenopausal women frequently note changes in their cognitive abilities, particularly memory function. Numerous clinical studies of postmenopausal women have shown that estrogen therapy may be beneficial to cognitive processes, although many other studies do not concur. In an effort to understand the extent to which loss of ovarian hormones and hormone therapy affect cognition in primates, our laboratory has been conducting studies in monkey models of menopause. Our initial studies were performed in young adult monkeys so that we could investigate the hormone effects without the confound of advanced age. Our more recent studies have been performed in middle-aged monkeys as a model that more closely mirrors that of a middle-aged woman experiencing menopause. In these studies, we employed a novel hormone therapy (HT) regimen that more closely mimics the natural fluctuations and patterns of hormones during the normal menstrual cycle. Middle-aged female rhesus monkeys were trained preoperatively on a visual and spatial working memory task. Their ovaries were removed and HT was initiated at the time of surgery. Groups of monkeys were treated with estradiol alone (ET), estradiol in combination with progesterone (E+P), or placebo (PL). The monkeys were reexamined on the tasks at three different time points following ovariectomy and HT initiation. Monkeys treated with estrogen alone or in combination with progesterone maintained their levels of accuracy on the visual working memory task, while PL monkeys demonstrated poorer accuracy at the second postoperative assessment. In contrast, there were no differences between the treatment groups on the spatial working memory task. These findings suggest that visual and spatial working memory may be differentially sensitive to ovarian HT in middle-aged surgically menopausal monkeys.

Session #2: WHIMS: Where Are We Now and Where Are We Heading?

Barbara B. Sherwin, PhD

Department of Psychology, McGill University, 1205 Dr. Penfield Ave, Montreal, Quebec, Canada, H3A 1B1

e-mail: barbara.sherwin@mcgill.ca

Key words: Women’s Health Initiative (WHI); Cognition in the Study of Tamoxifen and Raloxifene (Co-STAR); hormone therapy; dementia; cognitive function; brain imaging

The speakers in Session 2 of the 11th Biennial Graylyn Conference on Women’s Cognitive Health, Stephen Rapp, PhD, Susan Resnick, PhD, Claudine Legault, PhD, Laura Coker, PhD, and Christos Davatzikos, PhD, provided updates on findings from the Women’s Health Initiative Memory Study (WHIMS), an ancillary study to the Women’s Health Initiative (WHI) that investigated effects of hormone therapy (HT) on cognition and brain function in women over the age of 65 years (Shumaker et al. 2003). Initial reports found an increased risk of all-cause dementia in women who had received either conjugated equine estrogen alone (CEE-alone) and those who received CEE plus medroxyprogesterone acetate (CEE + MPA) compared to women who had randomly received placebo (Shumaker et al. 2003, 2004) as well as a small adverse effect of HT on global cognitive functioning (Rapp et al. 2003; Espeland et al. 2004). After the WHIMS trial was terminated, 86% of the study’s subjects agreed to participate in the WHIMS Extension Study in order to determine the impact of the discontinuation of HT on global cognitive functioning and on the incidence of dementia. Rapp reported that the adverse effect of HT on global cognitive functioning seen in the WHIMS trial remained unchanged by the end of the 3.4-year (CEE + MPA) and the 2-year (CEE) extension phase when women were no longer taking HT. Plans are underway to continue the Extension Study.

Resnick reported on the Women’s Health Initiative Study of Cognitive Aging (WHISCA), which was initiated an average of 3 years after women in the WHI had been randomized to hormonal treatments or placebo. Its goal was to investigate whether HT had beneficial effects on memory or on other aspects of cognitive functioning in these women, whose average age was 74 years, as measured by their performance on a battery of domain-specific cognitive tests. Following the early discontinuation of the trial, it was found that CEE + MPA had a negative effect on performance on tasks of verbal memory but a trend towards a positive effect on performance of tests of visual memory across time (Resnick et al. 2006). In the as yet unpublished findings of the CEE-alone arm of the study, no beneficial effects of CEE-alone occurred on any of the cognitive tests administered and a deficit in performance on spatial abilities was evident at the first WHISCA visit. Therefore, no benefits on cognitive functioning have been found for either CEE+MPA or for CEE-alone thus far in the analysis of the WHISCA data.

The WHIMS Magnetic Resonance Imaging Study (WHIMS-MRI) was designed to determine whether clinically silent cerebrovascular disease seen on magnetic resonance imaging (MRI) would be more frequent in women randomized to HT compared to those randomized to placebo in the WHI. At the time of scanning, the women had a mean age of 78.5 years. Coker reported no differences in ischemic brain lesion volumes between groups of women who had been randomized to CEE+MPA, to CEE-alone, or to placebo. Moreover, there were no treatment differences in ischemic lesion volumes in the basal ganglia or in the white and gray matter outside the basal ganglia. The findings were consistent within each trial and in pooled analysis across trials.

Davatzikos described further imaging findings from the 1,403 women who participated in the WHIMS-MRI. At the time of scanning, subjects had a mean age of 76.8 years of age. They had been randomized to HT or placebo 8 years earlier when the WHI started, but treatment had been discontinued for 1.4 to 3 years prior to their brain scan. Advanced methods of computational neuroanatomy were used to obtain measurements of brain volumes as well as volumes of individual brain structures, including the hippocampus. Significant reductions in certain brain regions were found in the women who had been randomized to CEE and to CEE + MPA. More specific information will be available shortly.

Finally, Legault presented the results of the Cognition in the Study of Tamoxifen and Raloxifene (Co-STAR), an ancillary study to the Study of Tamoxifen and Raloxifene (STAR). STAR is a 5-year, multi-center randomized clinical trial initiated and funded by the National Cancer Institute (NCI), involving 19,747 women who are at risk for breast cancer. It was designed to compare the effects of tamoxifen and raloxifene on the risk of breast cancer. The intent of Co-STAR was to compare the effects of tamoxifen and raloxifene on age-associated cognitive decline in 1,498 women over the age of 65 years who were participants in STAR. Cognitive performance was tested using a comprehensive battery of neuropsychological tests. Following treatment, no significant differences in cognitive performance occurred in either drug group except for the slightly higher (but nonsignificant) scores in the raloxifene group on a measure of verbal memory.

It would seem from these reports that the failure of HT to benefit aspects of cognitive functioning that appeared in the original WHIMS publications has been further confirmed. Indeed, the increase in all-cause dementia in the hormone-treated groups is still evident 2–3 years following discontinuation of HT in these older women. Although no differences occurred in ischemic brain lesion volumes between hormone and placebo-treated women, the finding that reductions in the volumes of certain brain regions were apparent in hormone-treated women suggests that the administration of HT to women over the age of 65 years may cause harm. While treatment with CEE+MPA had a beneficial effect on visual memory but a negative effect on verbal memory, CEE-alone failed to positively influence functioning in any cognitive domain in the most recent WHISCA findings. Finally, while there were no differences in cognitive functioning between women randomly assigned to tamoxifen or raloxifene in Co-STAR, it is not possible to know whether either drug had a positive, negative, or neutral influence on cognitive functions since pretreatment baseline scores are not available.

References

Espeland MA, Rapp SR, Shumaker SA, Brunner R, Manson JE, Sherwin BB, Hsia J, Margolis KL, Hogan PE, Wallace R, Dailey M, Freeman R, Hays J, Women’s Health Initiative Memory Study (2004) Conjugated equine estrogens and global cognitive function in postmenopausal women: Women’s Health Initiative Memory Study. JAMA 291:2959–2968. doi:10.1001/jama.291.24.2959

Rapp SR, Espeland MA, Shumaker SA, Henderson VW, Brunner RL, Manson JE, Gass ML, Stefanick ML, Lane DS, Hays J, Johnson KC, Coker LH, Dailey M, Bowen D, WHIMS Investigators (2003) Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA 289:2663–2672. doi:10.1001/jama.289.20.2663

Resnick SM, Maki PM, Rapp SR, Espeland MA, Brunner R, Coker LH, Granek IA, Hogan P, Ockene JK, Shumaker SA, Women’s Health Initiative Study of Cognitive Aging Investigators (2006) Effects of combination estrogen plus progestin hormone treatment on cognition and affect. J Clin Endocrinol Metab 91:1802–1810. doi:10.1210/jc.2005–2097

Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, Hendrix SL, Jones BN 3rd, Assaf AR, Jackson RD, Kotchen JM, Wassertheil-Smoller S, Wactawski-Wende J, WHIMS Investigators (2003) Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA 289:2651–2662. doi:10.1001/jama.289.20.2651

Shumaker SA, Legault C, Kuller L, Rapp SR, Thal L, Lane DS, Fillit H, Stefanick ML, Hendrix SL, Lewis CE, Masaki K, Coker LH, Women’s Health Iniative Memory Study (2004) Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory Study. JAMA 291:2947–2958. doi:10.1001/jama.291.24.2947

ABSTRACTS

An Update on the Women’s Health Initiative Memory Study (WHIMS) Extension Study

Stephen R. Rapp, PhD Department of Psychiatry and Behavioral Medicine, Wake Forest University School of Medicine

The Women’s Health Initiative Memory Study (WHIMS) consisted of two parallel randomized, placebo-controlled clinical trials comparing the effects of conjugated equine estrogen (CEE, N = 2,947) and CEE plus medroxyprogesterone acetate (CEE+MPA, N = 4,532) with placebo on the incidence of all-cause probable dementia (PD), mild cognitive impairment and global cognitive function in postmenopausal women 65 years of age and older. Previously published results from WHIMS showed an increased incidence of dementia for women receiving both forms of hormone therapy (HT) compared with placebo(Shumaker et al. 2004, 2003). Data from the combined trials yielded a hazard ratio of 1.76 (CI, 1.19-2.60; P = 0.005). HT also produced a small adverse effect on global cognitive functioning (Rapp et al. 2003; Espeland et al. 2004). The similar results in both HT trials suggest that the adverse effects on cognition and incident dementia cannot be attributed primarily to MPA.

Eighty-six percent of WHIMS participants active at the termination of both trials (N = 2,262 in CEE+MPA, N = 1,346 in CEE-alone) agreed to continue in the WHIMS Extension study, an observational cohort study examining the impact of HT cessation on global cognitive function and the incidence of dementia. The same WHIMS protocol for determining the cognitive outcomes was continued in WHIMS Extension. Post-trial data were collected over an average of 3.4 years (CEE+MPA) and 2.0 years (CEE-alone). The greater risk of PD among women who received HT during the trial continued during the post-trial extension phase (HR = 1.52, CI 1.15, 2.02; P = 0.008). Similarly the adverse effect of HT on global cognitive function remained unchanged through the extension phase (P = 0.0008).

In summary, the detriment to cognition caused by CEE (with and without MPA) during the trial remained after stopping treatment for both incident dementia and global cognitive function. A continuation of the WHIMS Extension is currently planned. The WHIMS Epidemiology of Cognitive Health study (WHIMS ECHO) will model the rates and correlates of transitions over time among cognitively normal women and those with PD and MCI; examine the ability of cognitive tests administered to a subset of WHIMS participants in the WHI Study of Cognitive Aging (WHISCA) to predict PD and MCI; examine the progression of specific subtypes of cognitive deficits (e.g., MCI); model the relationships among risk factors associated with MCI and PD; and examine correlations between MRI outcomes (from the WHIMS MRI study) and subsequent incidence of cognitive impairment. As an innovation, WHIMS ECHO will use a telephone-based neurocognitive battery and questionnaires and follow women over a 2-year period.

References

Espeland MA, Rapp SR, Shumaker SA, Brunner R, Manson JE, Sherwin BB, Hsia J, Margolis KL, Hogan PE, Wallace R, Dailey M, Freeman R, Hays J, Women’s Health Initiative Memory Study (2004) Conjugated equine estrogens and global cognitive function in postmenopausal women: Women’s Health Initiative Memory Study. JAMA 291:2959–2968. doi:10.1001/jama.291.24.2959

Rapp SR, Espeland MA, Shumaker SA, Henderson VW, Brunner RL, Manson JE, Gass ML, Stefanick ML, Lane DS, Hays J, Johnson KC, Coker LH, Dailey M, Bowen D, WHIMS Investigators (2003) Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA 289:2663–2672. doi:10.1001/jama.289.20.2663

Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, Hendrix SL, Jones BN 3rd, Assaf AR, Jackson RD, Kotchen JM, Wassertheil-Smoller S, Wactawski-Wende J, WHIMS Investigators (2003) Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA 289:2651–2662. doi:10.1001/jama.289.20.2651

Shumaker SA, Legault C, Kuller L, Rapp SR, Thal L, Lane DS, Fillit H, Stefanick ML, Hendrix SL, Lewis CE, Masaki K, Coker LH, Women’s Health Iniative Memory Study (2004) Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory Study. JAMA 291:2947–2958. doi:10.1001/jama.291.24.2947

The Women’s Health Initiative Study of Cognitive Aging (WHISCA): An Update

Susan M. Resnick, PhD Intramural Research Program, National Institute on Aging

WHISCA, an ancillary study to the Women’s Health Initiative (WHI) and WHI Memory Study (WHIMS), was developed to test the hypothesis that hormone therapy (HT) has beneficial effects on memory and other specific cognitive functions in older postmenopausal women. WHISCA was conducted within the context of the WHI randomized, placebo-controlled clinical trials of conjugated equine estrogen alone (CEE-Alone) or in combination with medroxyprogesterone acetate (CEE+MPA). WHISCA enrolled 2,302 women distributed across the two parallel trials, who were followed annually with a battery of domain-specific cognitive tests. WHISCA was initiated on average 3 years after WHI randomization and study medications were discontinued early due to the termination of study medications in the main WHI trials. WHISCA results for the CEE+MPA trial have been published [Resnick et al. JCEM 2006;91(5):1802–1810]. CEE+MPA had a negative effect on verbal memory performance over time and a trend to a positive effect on visual memory performance over time. Analysis of data from the CEE-Alone subtrial showed no beneficial effects of CEE-Alone and a deficit in spatial rotational ability at initial WHISCA assessment (after an average of 3 years of treatment). Results from the CEE-Alone trial will be compared with those from the CEE+MPA trial and plans for analysis of the post-trial data collected through the WHISCA extension study will be described.

Supported in part by the Intramural Research Program, NIA, NIH and Research and Development Contract N01-AG-9-2115.

Cognition in the Study of Tamoxifen and Raloxifene (Co-STAR)

Claudine Legault, PhD Division of Public Health Sciences, Wake Forest University School of Medicine

The National Cancer Institute (NCI) initiated the Study of Tamoxifen and Raloxifene (STAR), a multi-center, 5-year, randomized clinical trial among 22,000 women at risk for breast cancer, to compare the effect of tamoxifen and raloxifene on the risk of breast cancer. Cognition in the study of Tamoxifen and Raloxifene (Co-STAR) is an ancillary study to STAR to compare the effects of tamoxifen and raloxifene on age-associated cognitive decline in 1,532 women 65 years and older who are at increased risk for breast cancer, through a series of neuropsychological tests. A standardized neuropsychological test battery, designed to be sensitive to the effects of age and hormone therapy, was administered according to a standardized set of instructions. The battery included tests that screened for global cognition, verbal knowledge and reasoning ability, language, memory, visuo-spatial ability, motor function and mood. The entire test battery took approximately 90 min to administer.

Overall, there were no significant differences between treatment arms except for the California Verbal Learning Test where mean scores were slightly higher in the Raloxifene group than in the Tamoxifen group. In the subset of women who entered Co-STAR at the same time they were randomized into STAR, this difference was not present. Further results will also be presented comparing results from the Co-STAR trial to those in the Women’s Health Initiative Memory Study.

WHIMS-MRI: Effects of Postmenopausal Hormone Therapy on Volumetric Sub-clinical Cerebrovascular Disease

Laura H. Coker, PhD Division of Public Health Sciences, Wake Forest University School of Medicine

The primary outcome of the Women’s Health Initiative Memory Study–Magnetic Resonance Imaging (WHIMS-MRI) study is to determine whether clinically silent cerebrovascular disease on MRI is associated hormone therapy (HT) compared to placebo assigned at enrollment to the Women’s Health Initiative (WHI) HT trials. A subgroup of 1,426 women from 14 WHIMS clinics who were assigned to conjugated equine estrogen (CEE) with and without medroxyprogesterone acetate (MPA) or CEE-Alone versus placebo in the WHI and later joined WHIMS and its ancillary WHIMS-MRI study, received volumetric brain MRI an average of 8 years following randomization to WH treatment assignment. This talk addresses the association of CEE-based HT on total ischemic lesion volumes on cerebral MRI.

WHIMS-MRI: Regional Brain Volumetric Measurements and Their Relation to Hormone Therapy and Cognition

Christos Davatzikos, PhD Biomedical Image Analysis Section, University of Pennsylvania

This talk will discuss results from structural brain imaging of 1,403 women (mean age 76.8, range: 72–89) participating in the Women’s Health Initiative Magnetic Resonance Imaging (WHIMS-MRI) study. These women had, an average of 8.0 years ago, been enrolled in one of two placebo-controlled clinical trials that assessed the effect of conjugated equine estrogens therapy with and without medroxyprogesterone acetate on dementia and global cognition, which had ended an average of 3.0 and 1.4 years prior to the MRI scanning, respectively. Advanced methods of computational neuroanatomy were used to obtain measurements of brain volumes, as well as of volumes of individual brain structures, including the hippocampus. Hormone therapy was associated with regional brain volumes, and this effect was greatest in women already experiencing cognitive deficits.

Session #3: Vascular Disease, Hormones and Cognition

Sylvia Wassertheil-Smoller, PhD Department of Epidemiology & Population Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Belfer Building, Room 1312, Bronx, NY 10461, USA e-mail: smoller@aecom.yu.edu

Key words: cerebrovascular disease; hormone therapy; stroke; women; rats; Alzheimer’s disease

The focus of Session 3 of the 11th Biennial Graylyn Conference on Women’s Cognitive Health was the relationship between vascular risk factors and events, and dementia. Typically these studies used magnetic resonance imaging (MRI) technology. Four speakers contributed: Cheryl Bushnell, MD, MHS; Farida Sohrabji, PhD; Richard O’Brien, MD, PhD; and David Bennett, MD.

Bushnell discussed hormone therapy (HT) use and the severity of stroke. Her study compared users of HT with non-users, at time of stroke, on the severity of the stroke. Stroke severity was assessed with the National Institutes of Health Stroke Scale. Results indicated that HT use was not associated with stroke severity at baseline or for outcomes at 90 days; however, the study was small and lacked sufficient power to make definitive conclusions. Only 40 of the 133 subjects were HT users. It should be noted that the Women’s Health Initiative (WHI) found clear and consistent evidence that estrogen unaccompanied or accompanied by progesterone, was a cause of stroke and was associated with a significant increase in dementia risk.

Sohrabji presented results of animal studies indicating that acyclic females had larger infarcts than cycling females, attributing this to greater blood brain barrier permeability in older animals. Estrogen replacement also increases the permeability in acyclic females. Since permeability is increased with both age and hormone status, it is difficult to “unconfound” these two factors. In any case, we do know the acyclic females were worse off than the cycling females, that stroke is worse in older than in younger females and that estrogen increases permeability.

O’Brien discussed the effect of cerebrovascular lesions on cognition and dementia seen in the Baltimore Aging Study. He showed the importance of preventing microscopic infarcts to prevent a large proportion of dementia cases, and made a convincing case for the role of microscopic infarcts in dementia as being equivalent in risk to macroscopic infarcts. Of interest would be detailed studies of the role of substances such as anti hypertensive medications, lipid lowering agents and the like in preventing such microscopic lesions.

Bennett discussed the concept of dementia as a National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) diagnosis. He discussed the multifactorial nature of dementia as well as the concept of progression from a completely asymptomatic phase to mild cognitive impairment (MCI) to dementia. He also noted that Alzheimer’s disease can cause non-cognitive symptoms like motor problems for example. He proposes that people in the field look at dementia and Alzheimer’s disease in a more global way.

In summary, this session’s translational nature brought together animal studies, human studies, MRI studies of disease endpoints and severity of disease, with implications for prevention. Perhaps the most salient message was that preventing microscopic lesions may have a large impact on preventing many forms of dementia.

ABSTRACTS

Does Hormone Therapy Impact Stroke Outcomes? Data from the Stroke Hormones and Outcomes in Women (SHOW) Study

Cheryl Bushnell, MD, MHS Department of Neurology, Wake Forest University School of Medicine

Background: Stroke prevention studies with hormone therapy have shown that women are not protected from stroke with chronic use. However, animal studies have shown a robust neuroprotection in intact females compared with males. For example, treatment with estradiol preceding and early following induction of experimental stroke leads to smaller stroke volumes. In an attempt to more closely parallel the animal studies, we collected a retrospective study of women with ischemic stroke, and found a trend toward lesser stroke severity in women who were using hormone therapy at the time of stroke compared with non-users. To further explore these results, we conducted a prospective study to determine stroke severity and outcome in women who were users of hormone therapy at the time of stroke vs non-users.

Methods: We assessed initial ischemic stroke severity with the National Institutes of Health Stroke Scale (NIHSS) in women who were HT users vs non-users at the time of stroke. In addition to current use of HTs, HT type, duration of HT use, and reason for HT use, we collected information on prior HT use and when it was stopped in relation to the stroke. Subjects were contacted 90 days or more after enrollment in person or by telephone. Outcomes assessed at this follow-up visit included modified Rankin score (primary outcome), NIHSS, Barthel Index (BI), and Stroke Impact Scale (SIS).

Results: From September 2001 to January 2005, 133 subjects were enrolled; 40 (30%) were using HT at the time of stroke and 90 (70%) were non-users. HT users were more likely to be Caucasian, have a lower body mass index (BMI), and were less likely to have hypertension. There was no difference in stroke severity between HT users (median NIHSS = 3.5, range 1–21) vs non-users (median 4.0, range 4.0, range 1–22; P = 0.4). Of HT users, there was a negative correlation between duration of use and NIHSS, suggesting that longer use was associated with lesser stroke severity. There was no association between HT use and outcomes at 90 days including mRS, NIHSS, BI, and SIS. However, the presence of coronary heart disease was associated with initial stroke severity, and CHD and diabetes were independently associated with mRS at 90 days.

Conclusions: Although the cohort of HT users was smaller than originally planned, there was no significant impact of HT use at the time of stroke with initial stroke severity or with long-term outcome. More importantly, baseline co-morbid conditions play an important role in stroke outcomes in women.

Bushnell CD, Lee J, Duncan PW, Newby LK, Goldstein LB (2008) Impact of comorbidities on ischemic stroke outcomes in women. Stroke (in press).

Estrogen and the Aging Blood–Brain Barrier: Implications for Stroke

Farida Sohrabji, PhD Neuroscience and Experimental Therapeutics, Texas A&M HSC College of Medicine

The blood–brain barrier is important for maintaining the homeostatic environment of the brain, and specifically excludes pathogens, toxins, circulating immune cells and their products. Conditions and compounds that increase the permeability of the blood–brain barrier also result in more serious tissue damage in a stroke or neurovascular injury. Our recent studies in a rodent model comparing young normally cycling female rats with older acyclic females show that the blood–brain barrier is constitutively more permeable in the older acyclic females. Furthermore, estrogen replacement increases the permeability of the barrier in this acyclic group. IgG expression, which is indicative of barrier permeability in aging and neurological disease, is significantly higher in the hippocampal region of the older female. To determine whether increased barrier permeability increases the severity of neural injury, young and senescent animals were subject to a stroke-like injury using the endothelin-1-induced MCA occlusion. This occlusion model results in more clinically relevant time course of occlusion and reperfusion than the intraluminal occlusion method, with virtually no extraneural damage. Using this stroke injury model, acyclic females sustained a larger cortical and striatal infarct as compared to their younger (still cycling) counterparts. A forelimb placing task indicated that both younger and acyclic females performed more poorly after the stroke injury, but a cross midline forelimb placing task indicated a more severe deficit in older females.

Vascular Dementia in the Baltimore Longitudinal Study of Aging

Richard O’Brien, MD, PhD Department of Neurology, Johns Hopkins University School of Medicine

Objective: To define the magnitude and mechanism of the effect of cerebrovascular lesions on cognition and dementia in a prospective study.

Methods: We examined the effects of cerebrovascular lesions and Alzheimer’s disease (AD) pathology on the risk of dementia in 179 subjects from the Baltimore Longitudinal Study of Aging (BLSA) Autopsy Program. All subjects had longitudinal clinical and cognitive evaluations and underwent postmortem examination of the brain. A subset of subjects (n = 23) had pre- or postmortem MRI of the brain.

Results: Cerebral infarcts were common in our cohort and both symptomatic and asymptomatic infarcts conferred a significant increase in the risk for dementia. Risk factors for stroke in the absence of a cerebral infarct did not increase dementia risk. The risk of dementia was quantitatively related to the number but not the size of cortical infarcts; non-cortical infarcts conferred no increased risk of dementia. The contribution of microscopic infarcts to the risk for dementia was significant and equivalent to that of macroscopic infarcts. In subjects with intermediate AD pathology scores, a single macroscopic cortical infarct was sufficient to cause dementia. A logistic regression model of the effect of cerebral infarcts and AD pathology on dementia risk indicated that AD pathology accounts for 50% of the dementia seen in this cohort and cortical infarcts for 35%. White matter disease on MRI did not confer any additional risk for dementia.

Interpretation: Cerebrovascular disease is a significant and potentially preventable cause of dementia in the Baltimore Longitudinal Study of Aging. The effect of cerebral infarcts on cognition is mediated in a quantitative and site-specific manner.

Cerebrovascular Disease and the Relation of Alzheimer's Disease Pathology to Cognition

David A. Bennett, MD Rush Alzheimer’s Disease Center; Rush University Medical Center, Chicago, IL

The goal of this analysis was to examine the relation of AD pathology and cerebrovascular disease to clinically diagnosed dementia and level of global cognition and five different cognitive abilities proximate to death. Data come from two large, longitudinal clinical-pathologic studies of aging and AD. The Religious Orders Study, which has enrolled more than 1,100 persons without known dementia who agreed to annual clinical evaluation and brain donation with more than 400 brain autopsies to date; and the Rush Memory and Aging Project, which has enrolled more than 1,200 persons without known dementia who agreed to annual clinical evaluation and donation of brain and spinal cord with more than 200 brain autopsies to date. AD pathology was quantified by counts of neuritic plaques, diffuse plaques, and neurofibrillary tangles based on silver stain, amyloid load (10D5) by image analysis, and tangle density (PHF1) by stereology. The age, number, volume, and location of all cerebral infarctions were quantified. In both studies, measures of AD pathology and cerebral infarctions, had additive effects on the odds of dementia. In fact, the combination of AD pathology and cerebrovascular disease was the most common cause of dementia. Further, in both studies, cortical and subcortical infarctions were related to episodic memory so that mixed pathology was also the most common cause of clinically probable AD. These findings have implications for the identification of risk factors for AD, since factors associated with risk of cerebral infarctions will appear to increase risk of clinical AD. For example, diabetes was shown to be related to risk of incident AD; however, diabetes was related to cerebral infarctions but not to measures of AD pathology.

These studies were supported by NIH grants P30AG10161, R01AG15819, R01AG17917.

Session #4: Additional Approaches to Improving Cognitive Function

Victor W. Henderson Departments of Health Research and Policy (Epidemiology) and of Neurology and Neurological Sciences, Stanford University, 259 Campus Drive, mc 5405 Stanford, CA 94305-5405, USA e-mail: vhenderson@stanford.edu

Key words: Alzheimer’s disease; cognition; depression; estrogen; antioxidants; testosterone

Cognitive aging is perhaps the single most important health concern of an aging baby boomer population. Cognitive aging encompasses not only Alzheimer’s disease and other age-related dementias, but also premonitory stages classified as mild cognitive impairment and other forms of cognitive decline that accompany usual aging in the absence of dementia. Speakers in other sessions of the 11th Biennial Graylyn Conference on Women’s Cognitive Health focused largely on how hormone therapy, vascular disease, and physical activity affect the brain and brain function. However, this session provided the opportunity for five investigators to consider additional strategies for improving cognitive and mental health in midlife and beyond. The overarching theme was the translation of animal and human research to the prevention and amelioration of cognitive aging and illnesses prevalent during old age.

Recent work from the laboratory of Cheryl Frye, AB, MS, PhD, at the University at Albany–State University of New York has focused primarily on estrogen receptor beta (ERβ) as a putative mediator of some estrogen and androgen effects on cognition and affective behavior. To elucidate the importance of actions at ERβ in mediating these effects, she and her colleagues have conducted a series of experiments. Their studies with wild type and ERβ knockout (βERKO) mice, ER antagonists, ERβ-specific selective estrogen receptor modulators (SERMS), and ERβ antisense oligonucleotides convincingly demonstrate a role for ERβ in enhancing cognitive performance and ameliorating behavioral measures of depression and anxiety.

Depression, a major contributor to the global burden of disease, is more prevalent among women than men. Nicotinic receptors, which exist in a variety of isoforms, are distributed widely within the cerebral cortex. Geoffrey Dunbar, MD, from Targacept, reviewed the potential relevance of nicotinic receptors in depression. He reported encouraging findings from a Phase II augmentation study of a broad spectrum nicotinic antagonist (mecamylamine) in men and women with major depressive disorder. In this study, participants had responded poorly or had failed to respond to the selective serotonin receptor inhibitor antidepressant they were already receiving.

Elizabeth Head, PhD, from the University of California at Irvine, described innovative interventions that targeted cognitive aging in canines. In a four-arm randomized trial, aged beagles were assigned to behavioral enrichment, an antioxidant-rich diet, or both interventions. Behavioral enrichment consisted of social and cognitive enrichment plus physical exercise. A fourth control group consisted of aged animals housed alone and fed a standard diet. After nearly 3 years, benefits were seen in each of the three active treatment groups. Interestingly, behavioral and anatomical effects of the interventions differed. The dietary intervention led to improved spatial attention and complex learning ability in old animals. Learning ability was maintained during the period of observation in both groups but declined in the control group. Spatial memory was improved only in the combined intervention group. In postmortem studies, mitochondrial production of reactive oxygen species was reduced by the antioxidant diet, as was deposition of the beta-amyloid protein, and key biochemical abnormality seen in the human brain during the course of Alzheimer’s disease. In contrast, the behavioral intervention was associated with reduced neuronal loss in the entorhinal cortex and hippocampus.

William Sonntag, PhD, from the Oklahoma University Health Science Center, examined the potential role of aging-associated declines in plasma growth hormone and insulin-like growth factor-1 (IGF-1) in brain function and structure. Short term studies in a laboratory animal model indicate that administration of these compounds has a surprising variety of seemingly beneficial effects, one important component of which is to increase capillary density, arteriolar density, and cerebral blood flow. There are also effects on synaptic function and neurogenesis. In the behavioral sphere, performance is improved on tasks of learning and memory.

The final presentation of this session was by Jeri Janowsky, PhD, from the Oregon Health and Science University, who summarized human studies examining effects of the sex steroid testosterone on cognition. Although testosterone affects brain function in men and women, research to date has focused largely on men. Most research implies that testosterone exerts a modulatory effect on certain cognitive processes, particularly those involved in spatial cognition. In addition, there appears to be a neuroprotective effect against neurodegenerative changes that presage disorders such as Alzheimer’s disease.

General discussion in this session addressed the issue of target specificity in interventions intended to improve cognitive function. Presentations in this session supported the rationale for both highly selective interventions as well as those whose targets were more broadly distributed.

ABSTRACTS

Estrogen Receptor Beta as a Target of Steroid Hormones’ Actions for Affective and Cognitive Behavior

Cheryl A. Frye1-4, Alicia A. Walf1

Departments of Psychology1, Biological Sciences2, and the Centers for Neuroscience3 and Life Science4 Research, University at Albany-SUNY

Estrogens, such as 17β-estradiol (E2), and androgens, such as 3α-androstanediol (3α-diol), have anti-anxiety, anti-depressant-like, and cognitive-enhancing effects in female and male rodents. Our laboratory has been investigating estrogen receptors (ERs), particularly the β isoform of ER, as a putative target for these effects. We have utilized three approaches: (1) mice with targeted deletions of ERβ (βERKOs), (2) systemic or intra-brain administration of ER antagonists or ER isoform-specific (α or β) antisense oligonucleotides, (3) administration of selective ER modulators (SERMs). Using these approaches has revealed the role of steroids’ actions at ERβ in the hippocampus for affective and cognitive behavior.

Whether E2’s effects among female rodents involve activity at ERβ was investigated. First, the effects of natural fluctuations in E2, and the effects of subcutaneous (SC) E2 (equal affinity for ERα and ERβ) or an ERβ-selective SERM (DPN) administration to WT and βERKO mice for anxiety, depression, and cognitive performance were investigated. Unlike WT mice, βERKO mice do not have decreased anxiety and depression behavior and improved cognitive performance across a variety of tasks in higher endogenous or exogenous E2 states. Second, the effects of blocking ER actions for anxiety and depression behavior were determined. ER antagonists, SC or to the hippocampus, similarly attenuate the anti-anxiety and anti-depressant-like effects of SC E2 or ERβ-SERMs to ovariectomized (ovx) rats. Intrabrain infusions of ERβ, but not ERα, antisense oligonucleotides attenuate the anti-anxiety and anti-depressive effects of SC E2 to ovx rats, and reduces ERβ expression in the hippocampus. Third, ovx rats were administered SC E2, ERα SERMs (PPT; 17α-E2), ERβ SERMs (coumestrol; DPN) or vehicle before testing in anxiety (open field, elevated plus maze) and depression (forced swim test) tasks, or following training in cognitive (object recognition) tasks. ERβ SERMs, compared to vehicle, decreased anxiety in the open field and elevated plus maze, decreased depression-like behavior in the forced swim task, and improved performance in the object recognition task. Similar anti-anxiety and anti-depressive effects were observed in ovx rats administered ERβ-selective SERMs to the hippocampus. Thus, E2 may require ERβ for its effects on anxiety, depression, and cognitive behavior.

Whether androgens’ effects among male rodents involve activity at ERβ was investigated. First, the effects of SERMs administration to gonadectomized (gdx) WT or βERKO mice were investigated. SC SERMs with higher affinity for ERβ (3α-diol and 3β-diol) to WT mice decreased anxiety behavior and enhanced cognitive performance compared to that seen with vehicle or a SERM with low affinity for ERβ (androsterone). This pattern was not observed in βERKO mice. Second, the effects of knocking down ERβ for cognitive performance were assessed. Compared to vehicle, scrambled, or ERα antisense oligonucleotides, infusions of ERβ antisense oligonucleotides to the hippocampus of 3α-diol-administered rats attenuated performance in the inhibitory avoidance task. Third, gdx rats were administered SC SERMs that have different affinity for ERβ and anxiety and cognitive behavior was assessed. SC 3α-diol enhanced performance in the object recognition, conditioned contextual fear, and inhibitory avoidance tasks when administered SC or to the hippocampus of gdx rats. SC 3α-diol and 3β-diol decreased anxiety in the open field and elevated plus maze, compared to vehicle or androsterone. Thus, androgens may require ERβ in the hippocampus for their antianxiety and cognitive-enhancing effects.

Supported by: NSF (IBN03-16083) and USAMRMC Dept. of Defense BCRP (BC051001)

Mecamylamine as Augmentation Treatment for Depressed Patients Who Were Poor Responders to Citalopram First Line Therapy

Geoffrey C Dunbar, MD VP Clinical Development, Targacept

Introduction: The STAR*D study re-emphasized the poor remission rates seen following first line treatment for depression. Mecamylamine is a broad spectrum nicotinic antagonist that has been used as a hypotensive agent (doses 25–90 mg daily) and with the mood/behavioral problems seen in Tourette’s disorder (2.5–7.5 mg daily). In a small pilot study, mecamylamine was added single-blind to patients who had an inadequate response on SSRI antidepressant medication and was found to be more effective than placebo. The present study assessed in a larger population the effectiveness of mecamylamine, as an augmentation treatment for depressed patients who were poor responders to first line treatment with citalopram.

Methods: Male or female subjects aged 18–70 suffering from Major Depressive Disorder according to DSM-IV criteria with a Hamilton Depression Rating Scale (HAMD-17) score of > 21 and a Clinical Global Impression–severity of illness score (CGI-S) ≥ 4 were started on open label citalopram therapy. The dose of citalopram was increased from 20 to 40 mg over a 6-week period. At the end of treatment, subjects with a HAMD-17 score ≥ 14 and a CGI-S ≥ 4 were considered non-responders and were randomized into the double blind (DB) phase of the trial. This lasted 8 weeks and subjects received either placebo or mecamylamine added to their citalopram therapy. The dose of mecamylamine could be increased from 5 to 7.5 to 10 mg at the investigator’s discretion.

Results: Of the 472 subjects enrolled, 450 entered the open label phase of the trial and 192 were randomized to DB medication. There were 184 subjects included in the analysis. Considering the primary measures, a statistically significant result was found in favor of mecamylamine on the HAMD-17 scale. Results favoring mecamylamine were also seen on the CGI-S, the Sheehan Disability Scale and the Sheehan Irritability Scale.

Conclusions: Mecamylamine as an augmentation treatment had positive effects for subjects who were poor responders to first line citalopram. Improvement in both depressed mood and symptoms of irritability suggest the compound may have a unique place in treating this group of patients with high unmet medical need.

A Combination of Antioxidants and Behavioral Enrichment as an Approach to Improving Cognition

Elizabeth Head, PhD Institute for Brain Aging and Dementia, Department of Neurology, University of California

Oxidative damage may contribute to cognitive dysfunction and β-amyloid (Aβ) neuropathology associated with aging. In addition, behavioral enrichment may be protective against the development of pathological aging. To test these hypotheses, aged canines received a long-term treatment (>2.5 years) with a diet rich in antioxidants (AOX), either alone or in combination with behavioral enrichment (BEH). Twenty-four aged beagles (Mean age = 10.69) were placed into one of four treatment groups: (1) control/control (C/C), (2) BEH/control diet (E/C), (3) control enrichment/AOX diet (C/A), and (4) BEH/AOX diet (E/A). The AOX diet contained α-tocopherol (800 IU), vitamin C (10 mg/kg), fruit and vegetable extracts (1%), dl-lipoic acid (2.7 mg/kg), and l-carnitine (6 mg/kg). The BEH enrichment consisted of social and cognitive enrichment, and physical exercise. The AOX diet led to improved spatial attention (landmark discrimination) and complex learning ability (oddity discrimination). Learning ability was maintained over time with both treatments while untreated animals showed a progressive decline. Spatial memory was improved but only after long-term treatment with a combination of the two interventions. Further, the combination treatment group was superior to either treatment group alone. To determine the neurobiological mechanisms underlying improved cognition in response to AOX and BEH treatments, we measured the extent of beta-amyloid (Aβ) plaque accumulation. Aβ deposition in the AOX treated animals was reduced by 27–84% in the parietal, entorhinal, and occipital cortices, but not in the prefrontal cortex. Aβ-lowering effects were not observed in animals receiving the BEH intervention alone. In contrast, animals provided with BEH treatment showed less neuronal loss in the hippocampus compared to untreated dogs and those treated with the AOX diet alone. The AOX dose levels used in the current study are consistent with human clinical trials and indicate that dietary supplementation with a broad spectrum of antioxidants may shift beta-amyloid precursor protein processing in favor of nonamyloidogenic pathways leading to reduced Aβ accumulation in plaques. The BEH treatment improved neuronal function independently of Aβ but may serve to maintain neuronal number or plasticity. Thus, the combination of an AOX diet with behavioral enrichment may improve neuronal function through separate yet complimentary molecular pathways.

Funding provided by NIH/NIA AG12694, AG17066 and U. S. Department of the Army, Contract No. DAMD17-98-1-8622.

Growth Hormone, Insulin-like growth factor (IGF)-1 and the Aging Brain

William E. Sonntag, PhD Department of Geriatrics, Oklahoma University Health Science Center

The progressive decline in plasma growth hormone and IGF-1 throughout the lifespan not only has an important effect on aging of peripheral tissues but also influences key neuronal elements that contribute to functional and structural changes within the brain, resulting in a decline in cognitive function. We have demonstrated that short-term administration of growth hormone and/or IGF-1 increases vascular density, glucose metabolism, neurogenesis, neuronal survival and synaptic complexity, regulates NMDA receptor subtypes, decreases oxidative stress and enhances working memory in aged animals. The results of our studies have provided important information related to the interactions between the decline in the growth hormone/IGF-1 axis and the genesis of brain aging. Concomitantly, our results suggest that specific brain regions maintain a remarkable structural integrity during healthy aging, demonstrating few changes in overall synaptic density or neuronal number.

In addition to age-related comparisons and direct investigation of the effects of growth hormone and/or IGF-1 administration in older animals, we have developed an animal model of adult-onset growth hormone/IGF-1 deficiency. This is the only model currently available of a primary, specific deficiency of growth hormone and IGF-1 in adults. We have identified that a reduction in growth hormone and IGF-1 in adulthood results in an early decline in cognitive function and that these changes are associated with decreased cerebral glucose metabolism, ATP levels as well as deficits in the maturation and survival of hippocampal dentate granule neurons. These results and reports recently published in the literature have led us to hypothesize that deficiency in circulating growth hormone and IGF-1 with age leads to vascular dysfunction as well as deficits in synaptic function and cell replacement in the CNS. These changes are significant for cognitive function and leave the aging brain vulnerable to damage from challenge.

Supported by NIH grants P01 AG11370 and R01 AG26607.

Testosterone and Cognition in Men

Jeri S. Janowsky Oregon Health and Science University

Observational studies suggest that testosterone influences specific aspects of cognition. However, neither the neural basis nor whether testosterones has special effects in aging is clear. Thus, in two studies, we examined the effects of significant modifications of testosterone (T) on cognition in healthy normal younger (25–35, n = 26) vs older men (60–80, n = 62) in a placebo-controlled manner, and in a second study examined the effects of long-term T deprivation on memory-induced brain activity using fMRI (mean age 70). In the first study, treatment resulted in a 30.25% increase in free T for the T-treated men, a 47.85% decrease in E2 for aromatase-inhibited men, or a 97.3% decrease in free T. Higher free T was related to better spatial cognition and increased negative emotional ratings. E2 was related to poorer working memory. Relationships were not found for verbal memory, before hormone manipulation, or in younger men. In contrast, men with complete T deprivation as a treatment for prostate cancer (~51 months) had worse verbal memory. Brain activity (fMRI) during word encoding showed a significant increase in prefrontal activity in men without testosterone. We suggest that two different processes impact cognition in aging men: testosterone can have a modulatory effect when cognition is fragile, but that long-term testosterone deprivation impairs neuroprotective mechanisms and accelerates neurodegenerative changes such as are seen in the preclinical phase of Alzheimer’s disease.

Supported by NIH RO1AG18843 & DOD.

Session #5: Physical Activity & Cognition

W. Jack Rejeski, PhD Department of Health and Exercise Science, Wake Forest University Winston-Salem, NC 27109, USA e-mail: rejeski@wfu.edu

Key words: physical activity; rats; humans; cognitive function; intervention

The overriding theme of Session 5 of the 11th Biennial Graylyn Conference on Women’s Cognitive Health was that physical activity has both broad and specific effects on cognitive and brain function in aging. There was enthusiasm across presenters for combining aerobic forms of physical activity with other interventions such as mental training and environmental enrichment. Art Kramer, PhD, pointed out that fitness training has positive effects on cognitive function for both normal adults and those in the early stages of dementia. He underscored the fact that although cognitive training paradigms typically produce very specific effects, fitness training has both specific and broad effects on cognitive function. Kramer suggested that areas in need of research include the following: (1) understanding the parameters of fitness training that maximize effects on cognition and brain function, (2) studying the effects of physical activity on cognitive function in conjunction with other health behaviors, (3) examining the effects of multimodal interventions (i.e. combining social interaction, intellectual engagement, physical activity and nutritional interventions) on cognition, and (4) exploring the role of genetics in moderating study outcomes.

Using a rat model, Tom Foster, PhD, provided evidence that lifestyle physical activity behavior can reduce DNA damage across the lifespan. However, these effects have not been observed when studying increased physical activity in older rats that had been previously sedentary. On the positive side, he did note that physical activity in older rats that were previously sedentary did afford some protection against oxidative damage to lipids. Building on Kramer’s comments, Foster emphasized the fact that the effects of physical activity in rats are enhanced when combined with environmental enrichment. This suggests that physical activity training may be an ideal medium in which to train older adults for more effective self-regulation.

Mark Espeland, PhD, described how research on physical activity is consistent with the objectives of the healthy brain initiative. He overviewed a currently funded pilot project on older adults, Seniors Health and Activity Research Program-Pilot (SHARP-P), that is targeting the independent and combined effects of physical activity and mental training on executive function. The goals of the pilot study are to understand whether such a trial is feasible, to pin down the primary outcome, and to gather data that can be used to determine the sample size needed for a full trial. The design of this proposed trial is clearly responsive to the points raised by both Kramer and Foster. Espeland also discussed the potential use of new statistical methods in latent variable analysis that might help to elucidate what outcomes are most sensitive to treatment at different points in the course of cognitive decline.

Jeffrey Katula, PhD, built on the themes of both specificity and multimodal interventions that had been discussed by earlier presenters. Based on existing research, he suggested that there are attentional costs of walking and that this cost may be a partial mediator in the beneficial effects that physical activity has on cognition. Katula reviewed the results of a multimodal pilot study conducted in which older adults were assigned to either a traditional walking program or walking + balance/agility training intervention. He reported that scores on tests of executive function were correlated with performance on a walking/decision task and that participants with low baseline function derived substantially more benefit in physical function from the walk+ intervention than the traditional walking intervention. This pilot study did not have the power required to test for group differences on tests of executive function.

During a period of general discussion, additional issues were addressed, including the effectiveness of forced versus volitional exercise in animals (human studies involve only volitional exercise). On the other hand, no systematic studies of cognition in animals have been conducted to examine the effects of gap in training that might be caused by acute illness and other barriers during aging. In humans, how to successfully motivate older adults to be active comes into play and has a large body of literature addressing it, but was beyond the scope of this session. It is an area of research that should have a high priority in older adults, particularly those 70 years and older.

ABSTRACTS

Fitness Training Effects on Brain & Cognition

Arthur F. Kramer, PhD Department of Psychology, University of Illinois

Given the increased aging population throughout the world there is a growing interest in lifestyle factors and interventions that enhance the cognitive vitality of older adults and reduce the risk for age-related neurological disorders, such as Alzheimer’s disease. In this talk, I will review research from our laboratory and from other researchers that suggests that aerobic exercise interventions can serve to protect and enhance cognitive and brain function in community-dwelling older adults, and that these effects may also extend to pathological populations. I will also briefly discuss relevant non-human animal research that provides important clues concerning the molecular and cellular mechanisms that underlie the beneficial effects of exercise training interventions on brain and mind.

Influence of an Active Lifestyle on Cognition and Markers of Brain Aging in Rodents

Thomas Foster, PhD Department of Neuroscience, University of Florida

The aging process is associated with a cascade of biochemical events that accumulate, ultimately resulting in senescent physiology and a decline in cognitive and motor function. A sedentary life style has been proposed to be a risk factor that aggravates the aging process, while an active life style is linked to slowing of cognition and motor decline during aging. Similarly, environmental enrichment can promote memory in aging animals and ameliorates markers of brain aging. I will present the results from recent studies examining the influence of environmental enrichment or exercise as a therapeutic intervention for age-related decline in cognitive and motor function. The effectiveness of behavioral treatments was age-dependent. Both treatments enhanced sensory/motor function and limited certain age-related changes in brain physiology or oxidative damage. The improvement in sensory/motor function contributed to a decrease in the number of animals that met exclusion criteria and influenced performance on some cognitive tasks. It is concluded that the functional outcome for a task depends on the type of behavioral treatment and the task demands.

Design of the SENIORS HEALTH and ACTIVITY RESEARCH PROGRAM (SHARP) Pilot Study

Mark A. Espeland, PhD, for the SHARP Study Group* Division of Public Health Sciences, Wake Forest University School of Medicine

The incidence of age-associated cognitive impairment is increasing rapidly and looms as a major clinical and public health issue. Pharmacological interventions hold promise for prevention and treatment of cognitive impairment but, to date, their effectiveness has been limited. Evidence from small or uncontrolled studies indicates that physical exercise and cognitive training have considerable promise as prevention strategies; however, their efficacy has not been established by adequately powered randomized clinical trials (RCTs). The goal of the SHARP study group is to address this void in the literature by examining whether a multi-factorial intervention involving physical activity and cognitive training reduces the risk of significant cognitive decline in older individuals. We have recently received NIA funding to prepare ourselves for this by conducting a pilot study, which will provide the experience and data to assess whether physical activity and cognitive training separately improve cognitive function over 6 months, to determine whether a combination intervention holds promise beyond individual interventions without compromising adherence, and to design a well-organized and efficient full scale, multi-center RCT. A composite outcome derived from measures of executive function and episodic memory was chosen as the primary outcome because of the importance of these domains in cognitive aging and because they may be most responsive to the proposed interventions. Participants (N = 100) will be aged 70–85 years, at risk for mild cognitive impairment, and appropriate candidates for the full scale RCT. They will be randomly assigned to one of four conditions: an educational control condition, moderate-intensity physical activity training, repetition lag cognitive training, or both physical activity and repetitive lag training. Secondary outcomes include measures of other cognitive domains, perceived cognitive functioning problems, quality of life, adherence, satisfaction, and fitness. This work represents the collaboration of a team of investigators across three institutions with extensive expertise in the underlying sciences and technology. To reduce costs, the pilot will be conducted at only one site. The results of a planned full-scale RCT will answer whether non-pharmacological approaches are effective in preventing significant cognitive decline, fill an important gap in knowledge for practicing evidence-based geriatric medicine, and provide critical context for evaluating future trials of pharmacologic agents.

*Hal H. Atkinson, MD; Deborah E. Barnes, PhD; Dale Dagenbach, PhD; Mark A. Espeland, PhD; Debbie Felton; Victor W. Henderson, MD, MS; Amelia Hodges; Sarah A. Jaramillo, MS; Janine M. Jennings, PhD; Jeffrey A. Katula, PhD; Abby C. King, PhD; Mark D. King; Claudine Legault, PhD; Stephen R. Rapp, PhD; W. Jack Rejeski, PhD; Sally A. Shumaker, PhD; and Marcia L. Stefanick, PhD

Preventing Disability: The Integration of Physical and Cognitive Function

Jeffrey A. Katula, PhD, MA Department of Health & Exercise Science, Wake Forest University

The capacity to live independently and to function well, represents a critical priority to public health and the geriatric community. Mobility and the activities of daily living are tasks that are necessary for the maintenance of basic independent functioning. Fortunately, several randomized clinical trials have demonstrated that regular physical activity can improve physical and cognitive functioning. However, traditional physical activity environments tend to lack the complexity inherent in everyday life. Thus, the physical and cognitive effects of physical activity programs may be underestimated and, perhaps do not translate to day-to-day functioning. We examined the influence of a more complex physical activity environment that challenged multiple physical, perceptual, and attentional systems in older adult participants with impaired lower extremity functioning on physical and cognitive functioning. Participants (n = 37) were randomly assigned to 12 weeks of either a traditional walking program (Walk) or a complex walking program (Walk+) that involved several stations designed to challenge different components of lower extremity functioning, balance, and executive functioning. The Short Physical Performance Battery (SPPB), One Leg Balance, Timed Up and Go, and Lateral Mobility were used to assess physical functioning. Several measures of executive functioning were used to assess cognitive functioning (e.g., selective attention, alternating attention). The pattern of results indicates that physical function improved in the Walk+ group (e.g., SPPB mean change = 1.31; ES = .84) more than the Walk group (SPPB mean change = .65; ES = .36). Contrary to hypotheses, however, whereas both groups experienced improvements in measures of working memory [F(1, 26) = 9.04, P = .006] and alternating attention [F(1, 25) = 2.88, P = .10], the Walk group improved more in selective attention [time x condition interaction F(1, 25) = 3.26, P = .083]. The results of this pilot study indicate that a novel, complex physical activity program that challenges multiple physical, perceptual, and cognitive processes offers benefits beyond traditional walking. Additional studies with larger sample sizes are needed to extend these findings and to determine whether the benefits gained from this type of program are more translatable than traditional physical activity.

Session #6: Technological Advances in Translational Research

Ronald C. Petersen, PhD, MD Department of Neurology, Mayo Clinic College of Medicine and Mayo Alzheimer’s Disease Research Center, Gonda 8 South, 200 First Street, SW Rochester, MN 55905, USA e-mail: peter8@mayo.edu

Key words: Magnetic Resonance Imaging (MRI); Positron Emission Tomography (PET); brain imaging; brain function; neuroanatomy; cognition

Session 6 of the 11th Biennial Graylyn Conference on Women’s Cognitive Health involved several different approaches to the translation of basic science research into applications in the clinical setting. Jeffrey D. Schmitt, PhD, presented a paper on, “Rational Design Approaches in Developing Treatments for Nervous System Disorders,” in which he discussed evidence for gender differences in certain aspects of neurotransmission with respect to neuronal nicotinic receptors in the brain. He presented work done at his company, Targacept, that has implications for drug design and personalized medicine. This approach to individualized medicine, particularly with respect to gender differences, is becoming increasingly important in neuroscience research. Schmitt discussed findings from his research in the context of the development of more effective treatments for cognitive impairment which may very well be gender specific.

Paul Laurienti, MD, PhD, discussed several imaging techniques in his presentation, “Evaluating Age-Related Cognitive Decline and Cognitive Interventions with Physiological Brain Imaging.” He discussed how certain non-invasive brain imaging techniques have revolutionized cognitive neurosciences. He emphasized the utility of magnetic resonance imaging (MRI) in evaluating serial brain function over time. Since MRI scanning incurs minimal risk, the same subjects can be imaged at multiple points in time, yielding valuable information on the aging brain. He highlighted data from the Cardiovascular Health Study which has used MRI to perform repeated anatomical studies looking at structural changes and yielding important information on the evolution of the brain over time. In addition to the structural studies, MRI has been used to evaluate physiologic changes in the brain such as that arising from functional MRI, diffusion tensor imaging and perfusion imaging, as well. These types of investigations may yield more insight into the aging brain than can be provided solely by structural studies. Both structural and functional imaging techniques are becoming more commonplace in longitudinal aging studies, and the combination of them will likely yield sensitive markers of age-related changes in the brain over time. It is likely that studies combining both structural and functional aspects of the brain will be most promising with respect to characterizing and predicting cognitive changes with aging.

R. Nick Bryan, MD, PhD, concluded this session with his discussion of, “Imaging of the Mind: State-of-the-Art.” Bryan reviewed the evolution of imaging of the brain over several decades and commented that much of the early work on neuroimaging involved the characterization of various anatomical structures. As such, important information has emanated from these studies, revealing regional anatomy and behavior. This work led to the field of “experimental” neuroanatomy, and he also documented the importance of lesion studies in inferring brain function. He acknowledged that, while these studies were very informative, they did not give definitive information regarding physiological or molecular mechanisms. The historical perspective of how the study of anatomy and behavior has evolved over time was reviewed and its importance emphasized. He also discussed the more recent studies of functional imaging of the brain and indicated how this discipline has added to the prior anatomical work concerning structure and behavior. Activation studies using Positron Emission Tomography (PET) technology provided additional information on normal and abnormal function of the brain, and functional MRI has also expanded these horizons. While the noninvasive imaging studies have provided a great deal of information regarding function of the brain, certain questions remained unanswered. Bryan asked the ultimate question, “Are we imaging the Mind?” Ultimately, he concluded that we are unable to do so at present, and while we have extensive information on structure and function of the brain, certain aspects such as mechanisms of thought remain a mystery. Chemical imaging of neurotransmitter systems provide certain regional information, but once again, this is not equivalent to the assessment of human thought. As such, while a great deal of progress has been made in the area of neuroimaging, we still have a fundamental challenge regarding some of the most human aspects of our function. Bryan speculated on how these investigations may evolve in the future and left us with provocative considerations.

ABSTRACTS

Rational Design Approaches in Developing Treatments for Nervous System Disorders

Jeffrey D. Schmitt, PhD Bent Creek Institute

Striking evidence suggests that significant gender differences exist in almost every system of neurotransmission— neuronal nicotinic receptors (NNRs) are no exception. Exploration of this receptor system at Targacept has uncovered significant gender-related differences in NNRs, with significant implications for drug design and personalized medicine. Today’s presentation will highlight some of our findings cast in the context of the broad imperative of finding path-breaking translational means of developing more effective treatments for women’s cognitive health.

Evaluating Age-related Cognitive Decline and Cognitive Interventions with Physiological Brain Imaging

Paul Laurienti, MD, PhD Department of Radiologic Sciences, Wake Forest University School of Medicine

Non-invasive brain imaging has revolutionized the study of the human aging brain. A major advantage of magnetic resonance imaging (MRI) is that participants can be scanned multiple times with no known adverse effects, thereby allowing for the performance of longitudinal studies to “watch” the brain age. Such brain imaging techniques have played a pivotal role in clinical studies since the Cardiovascular Health Study (CHS). The CHS utilized repeated anatomical studies to evaluate changes in brain size and structure, and this model has been repeated many times, which has allowed this study of anatomical changes over time. Recent technological advances in MRI have allowed researchers to study physiological changes in the brain. Many of these advanced techniques such as functional MRI, diffusion tensor imaging, and perfusion imaging are not standardized across research sites and are not easily adapted to large clinical studies. However, most translational research projects that are evaluating new hypotheses concerning the aging brain are typically modest in size and limited in the number of participating research sites. Such studies are able to utilize these advanced techniques in small cohorts to measure physiological changes associated with age as well as following interventions. These studies are, therefore, poised to identify the most powerful physiological imaging techniques sensitive to age-related changes that can be used in future large clinical studies. Examples will demonstrate the use of advanced imaging methods in cross-sectional studies of aging and in a longitudinal evaluation of cognitive intervention.

Imaging of the Mind: State-of-the-Art*

R. Nick Bryan, MD, PhD Department of Radiology, University of Pennsylvania Health System

Imaging of the Brain has become trivial; imaging of Mind has not. Given the current depth of knowledge about the brain, it is difficult to appreciate that barely 200 years ago this organ was almost a complete mystery, particularly as to its function. While the brain has been recognized as an ‘organ’ since antiquity, no functional role had been ascribed to it until Descartes placed the soul in the pineal gland (1). Descartes’ non-scientific attribution of the soul to the pineal gland was, fortunately, quickly followed by the much more rigorous description of the structure of the brain and nerves by Thomas Willis. While Willis’ application of scientific observations to the brain was seminal, the primitive scientific tools available at the time limited his direct observations to anatomy, which in and of itself does not convey function. However, despite little direct evidence, Willis began to argue that certain functions, including cognition, reside in the brain, as do certain diseases such as epilepsy and dementia (2). Subsequently, the brain was found to indeed have strong correlations between structure (anatomy) and function (behavior). This intimate relationship provided the basis for the still robust field of “experimental” neuroanatomy—the destruction of a portion of the brain followed by observations of altered behavior. Such ‘dysfunctional’ imaging documented the brain’s direct influence on the body. While lesion/deficit correlation has been a very informative means of studying the brain, it is limited by its morphological basis, which does not provide any direct information about the brain’s physiological or molecular mechanisms.

While the anatomists and physiologists clearly and tightly linked the brain to the body, the Mind with its cognition and abstractions remained relatively recalcitrant to union with the brain. Herbert Spencer with the publication of his Principles of Psychology in 1855 made major contributions to the Mind/Brain problem (3). He built on the concept of the simple reflex, which was viewed as a behavioral response of an organism to its environment; the physical substrate of that response was the nervous system. Arguing from an evolutionary perspective, Spencer proposed that any behavior, whether in a primitive organism or man, whether involving the simplest reflex or most complex thought, was an adaptation of an organism to its environment. While some aspects of these ideas have been challenged, Spencer’s linkage of the brain to the highest levels of cognition is now generally accepted.

Many of the early methods of studying the brain involved some form of imaging. Given the spatially heterogeneous nature of the brain (both structurally and functionally), imaging of the brain is an absolute necessity in order to document the location of an anatomic structure, experimental or natural lesion, or functioning region of the brain. However, early neuroimaging techniques were very limited, often being invasive and applicable only to animals or human autopsy material. In 1974 clinical neuroscience experienced a profound change with the invention of the X-ray computed tomographic (CT) scanner, an instrument that for the first time could non-invasively produce images of the whole, living human brain (4). With this technology, more and better ‘dysfunctional’ imaging can be performed, as illustrated by the extensive structure/function correlative work by the Dimasios (5). Non-invasive brain imaging could now be performed contemporaneously with detailed neurological, neuropsychological and cognitive testing. X-ray CT imaging was quickly and unexpectedly followed by the development of magnetic resonance imaging (MRI), which yields exquisite images of normal neuroanatomy and pathology. However, there is little useful physiological or functional information in conventional CT and MRI images.

While we now understand many relationships between the gross structure and function of the brain, there remains the overpowering need to be able to directly ‘see’ physiological and molecular functioning of the brain. After all, it is more important to know what the brain is doing than what it looks like! PET measurement of cerebral blood flow using H2O15 was the initial functional neuroimaging technique and is well suited to activation studies (6). Focal increases in cerebral blood flow have been demonstrated with H2O15 PET in response to a variety of visual, auditory and tactile stimuli, as well as visual and verbal memory tasks. Furthermore, PET activation paradigms have been applied in pathologic states, such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Recently, fMRI techniques have been developed that depend primarily on the detection of signal changes dependent on local cerebral blood flow and hemoglobin oxygen saturation (7). The popular acronym for this general class of methods is BOLD, blood oxygenation level dependent imaging. Advances in fMR technology resulting in greater spatial coverage and temporal resolution, as well as its lack of ionizing radiation, has lead to its dominant place in today’s functional neuroimaging.

We are certainly now imaging the brain—anatomically, physiologically, and biochemically. But we have to ask the question, “Are we imaging the Mind?” Building on Spencer’s union of brain and mind through behavior (by definition intimately related to Mind) and our ability to image aspects of the brain clearly associated with behavior, we are led to the conclusion that we are imaging something related to Mind. But what are we actually imaging? Blood flow—yes; glucose metabolism—yes; neurotransmitters—sometimes; thoughts—NO. Do current functional neuroimaging techniques even address the neural mechanisms of thought? Certainly not directly and possibly not at all with current human in vivo techniques. Neurophysiologically, the brain’s Mind activities are dependent on local electrical or molecular events: action/synaptic potentials and neurotransmitter systems. Contemporary neuroimaging techniques image blood flow and bioenergetic metabolism that are closely linked to local brain activity but they do not directly reflect these intrinsic neurophysiological signaling mechanisms, much less ‘thought.’ Human in vivo techniques basically image ‘where’ the brain is active, but not how it is acting. And certainly not what it is thinking. To falsely exaggerate the point, contemporary functional imaging is like watching the brain eat sugar or listening to blood whistle through its veins.

What do we actually know about an area of the brain that is active, as reflected by cerebral blood flow or glucose metabolism? If an area is active, is it always doing the same thing? Consider the primary visual cortex, which is activated by nearly all visual stimuli. The same gross anatomic area, V1, is active when processing color, shape and/or motion, quite different tasks that are thought to be processed by different sets of neurons and neurophysiological mechanisms. Another cause for reflection is the observation that there is relatively little difference in the activation pattern of the sensorimotor cortex when one is actively finger tapping versus imagining the same task. How are imagination, volition and action reflected, respectively, in these images? What about consciousness? A recent article by Owen et al., using fMRI, purportedly demonstrated “preserved conscious awareness” in a patient fulfilling the criteria for a diagnosis of vegetative state (8). Certainly this is an intriguing observation, but was consciousness imaged? The ability to image spirituality, the behavioral approach to God, has been suggested by the work of Andy Newberg who has performed functional SPECT scans during various psychic states such as meditation and reported distinctive blood flow patterns that may reflect a physiological aspect of this most subtle aspect of the human mind (9). But did he image the soul? Clearly we have come a long way in understanding the human brain and its functions, but we are probably just now on the verge of imaging the Mind—that is our future.

* Modified from: Bryan RN. Imaging of the Mind: Yesterday’s Triumphs and Tomorrow’s Challenges. Neuroimaging Clin N Am. (in press).

References

1. Descartes R Rules for the direction of the mind. Discourse on the method. Meditations on first philosophy. Objections against the meditations and replies. The Geometry. In: Hutchins JA, ed.-in-chief. Great Books of the Western World. Vol. 31. Chicago: Encyclopedia Britannica, Inc., 1952.

2. Willis T Cerebri Anatome. (1664) ENG: The Anatomy of the Brain and Nerves. In: Feindel W, ed. The Classics of Medicine Library. Birmingham, AL; McGill-Queens University Press; 1965.

3. Spencer H The Principles of Psychology. 2nd edn. London: Williams and Norgate; 1870.

4. Hounsfield GN (1973) Computerized transverse axial scanning (tomography): Part 1. Description of system. BJR 46:1016–1022.

5. Damasio H, Damasio AR Lesion analysis in neuropsychology. New York: Oxford University Press; 1989.

6. Fox PT, Raichle ME, Mintun MA, Dence C (1988) Nonoxidative glucose consumption during focal physiologic neural activity. Science 241:462–464. doi:10.1126/science.3260686

7. Ogawa S, Lee TM, Kay AR, Tank DW (1990) Brain magnetic imaging with contrast dependent on blood oxygenation. Proc Natl Acad Sci USA 87:9868–9872. doi:10.1073/pnas.87.24.9868

8. Owen AM, Coleman MR, Boly M, Davis MH, Laureys S, Pickard JD (2006) Detecting awareness in the vegetative state. Science 313:1402. doi:10.1126/science.1130197

Newberg. A. Why we believe what we believe. New York: Free Press; 2006.

Session #7: Critical Issues in Women’s Cognitive Aging

David Mount, PsyD, MA Department of Internal Medicine and Maya Angelou Research Center on Minority Health, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA e-mail: dmount@wfubmc.edu

Key words: health disparities; ethics; research bias; recruitment; consent; cognition

Low participation rates of women and minorities in clinical trials seriously limit the diversity of data and restrict generalization of study findings. The National Institutes of Health (NIH) Revitalization of Act of 1993 established a policy urgency regarding the inclusion of heterogeneous populations, particularly women and minorities, in clinical trials. Differential alteration in physical health, disease burden, access to healthcare, and disease outcomes are defined as health disparities. While the evidence-base has matured in the direction of describing and documenting physical health disparities, less is known about determinants of cognitive health disparities. It is becoming increasingly important to examine differences in cognitive health and the need for culturally appropriate neurobehavioral assessment strategies.

During the seventh and final session of the 11th Biennial Graylyn Conference on Women’s Cognitive Health, Kashemi Rorie, PhD, lectured on the topic of Neurobehavioral Assessment in Minority and Underserved Populations, and Nancy M. P. King, JD, lectured on Balancing on the Cutting Edge: Ethical Issues in Cognition Research. Rorie presented data underscoring that minority healthcare disparities are nested in patient–physician interactions, provider unconscious and conscious bias behavior toward ethnicity minority. Such factors likely increase the challenges frequently voiced around the recruiting and enrolling of ethnic minority groups in clinical trials research.

As it relates to the assessment of cognitive functioning, Rorie presented information suggesting that culturally fair neurobehavioral assessment is slowly emerging, which is a potential problem when researchers are extrapolating from such data to inform interventions and practice delivery strategies for ethnic minority women. Rorie’s presentation warrants a call to action as ethnic minority women may have a greater risk for premature deterioration in their cognitive health secondary to leading chronic disease factors including uncontrolled high blood pressure, diabetes, and cardiovascular disease. While a pressing need exist for research in ethnic minority women and their cognitive health, a lack of culturally valid instruments to detect downward shifts in cognitive agility remains a barrier. While researchers have assembled a laundry list of factors impeding minority women from participating in clinical trials, including distrust of the medical/scientific community, power-difference barriers, poor access to primary medical care, Rorie’s concluding statements echoed the message that valid cognitive assessment influences data interpretation precision and discussion about participant outcomes. She noted that minorities may be more responsive to recruitment attempts that employ culturally meaningful language and provide culturally sensitive information. Rorie provided examples of factors clinical trialists would want to consider as they reach out to the minority community. In her presentation, King pointed out that because ethical issues arise throughout the design and conduct of research, during data analysis, and in the reporting of results, research ethics is fundamentally translational. The researcher’s responsibility to balance the desire for results with the need to ask genuinely open questions, the capacity to anticipate questions and the readiness to address them, all have ethical dimensions that are deeply intertwined with the science”. Building on Emanuel et al. (2000), and using examples presented throughout the conference, her presentation examined key ethical criteria for cognition research. Two big challenges in research are balancing basic analytic science with targeted, goal-directed research, and addressing and managing irreducible uncertainty and ambiguity in the data.

King echoed Rorie by noting that research must have validity, and that participant selection must reflect ethical principles by focusing on those who can provide the best data at least risk to themselves, by ensuring that the fruits of the research can benefit the populations from which the research participants have been drawn, and by concomitantly including participants from underserved populations. This reality heightens the importance of informed consent—both the content of research consent forms and the process of information exchange. In long-term cognition research, it is essential to undertake advance planning to address the possibility of participants’ future cognitive decline.

King provided insight into ethnical dimensions of research validity, translational intent, and human consenting to participate in biomedical research. King concluded her presentation by observing that cognition researchers’ ethical responsibilities extend well beyond the research itself. It is part of their task to help elucidate the meaning and implications of their research findings in their social context—that is, in the lives of everyday people as they age—so that the findings can be interpreted and applied appropriately. This ongoing responsibility connects research with practice, and applies across populations, making cognition research both genuinely translational and morally meaningful.

Post-presentation discussion included further conversation about informed consent process and frequency in studies of cognition, as well as inherent biases in recruitment and subject selection. Filtering subjects into clinical trials may have differential impact by race and culture, and may artificially influence subpopulation analyses and interpretation of results. Low minority participation in clinical trials limits the generaliziblity of findings and may do little to foster our understanding of minority communities. Researchers must ask questions to discern how effective and relevant the science is to the community they purport to inform and strengthen.

The legitimate and successful recruitment and enrollment of minority women into clinical trials continues to necessitate critical analysis, and requires addressing, from a historical and ethical perspective. In cognitive functioning based research, the stakes are especially high for ethnic minority women. Bioethical guidance and ethical decision-making has the potential to assist researchers in maximizing clinical trial transparency. It is critical and highly valuable for researchers to remain cognizant of the cultural competencies needed to infuse minority women in the functions of cognition related clinical trials. As federal regulations and legislation have established mandates for protection of human participants in research, there is reason to believe ethnic minority women will see how their cognitive health interest is intertwined in their clinical trials participation. Yet, researchers are challenged in identifying and developing culturally valid methods to assess cognitive functioning across racial and ethnic groups.

References

Emanuel EJ, Wendler D, Grady C (2000) What makes clinical research ethical? JAMA 283:2701–2711. doi:10.1001/jama.283.20.2701

ABSTRACTS

Neurobehavioral Assessment in Minority and Underserved Populations

Kashemi Rorie, PhD Clinical Liaison, CME/CMP Medica

There has been increased concern regarding both racial and ethnic disparities in the healthcare of minority Americans. Data to understand which factors (e.g., race, socioeconomic status, gender, etc.) contribute to poorer health outcomes of ethnic minorities are still relatively limited, and may be attributed to diminished levels of minority participation in clinical trials research. This lecture will examine recruitment strategies that may elicit increased participation in clinical trials research. The significance of personal, sociocultural, and socioeconomic factors will be addressed, as well as the role of the patient–physician interaction. This lecture will also address neurobehavioral assessment issues in minority populations. There is a considerable body of data addressing cultural bias in cognitive assessment tools. Subsequently, several measures have adopted modified norms to account for this bias. However, culture, in and of itself, is a difficult concept to define, and the emergence of this approach may impose constraints on the definitions of neuropsychological competencies in minorities.

Finally, this lecture will propose didactic techniques to retain patients in clinical trials. Considerations for both patients and clinical research personnel will be addressed.

Balancing on the Cutting Edge: Ethical Issues in Cognition Research

Nancy M. P. King, JD Department of Social Sciences and Health Policy, Program in Bioethics, Health, and Society, Wake Forest University School of Medicine

Like everyone in society, scientists are moral actors. Ethical issues arise throughout the design and conduct of research, during data analysis, and in the reporting of results. Researchers must balance the desire for results with the need to ask genuinely open questions, and must anticipate ethical questions and be ready to address them.

Building on Emanuel, Wendler, and Grady (2000) and using conference examples, this presentation examined key ethical criteria for cognition research. For research to have value, the question asked must have a useful answer, and results must be translatable into the next stage of research or into practice. Cognition research should be able to: move from associations to causal relationships; apply findings to general and vulnerable populations; and translate findings into reasonably achievable goals, while addressing and managing irreducible uncertainty and data ambiguity.

Research must also have validity: the study must be able to answer the questions asked. Invalid research is unethical; thus, trial design, sample size, and recruitment raise ethical issues. Participant selection must focus on those who can provide the best data at least risk to themselves, ensure that the fruits of research can benefit the populations from which participants are drawn, and include underserved populations. Balancing potential harms and benefits of research requires continual reassessment in light of new information—as is seen in the history of WHI research. Scientific skepticism is an essential component of researchers’ ethics; yet belief in the beneficial nature of HRT has been widespread and persistent until recently.

This reality heightens the importance of informed consent. Both the content of research consent forms and the process of information exchange must address the nature of research, the role of uncertainty, and the opportunity to reassess participation when new information is available. In cognition research, advance planning is needed to address the possibility of participants’ cognitive decline. Participants can be asked to choose “study partners” whom they trust to join them in the consent process, help researchers assess loss of decision-making capacity, and even serve as substitute decision makers.

Other ways of promoting respectful relationships between researchers and participants include protecting privacy and confidentiality; using community advisory boards to help identify and address concerns; and cultural sensitivity. Finally, justice in research (especially genetic research) requires attention to group interests and group harms: avoiding stigmatization of groups in data gathering, analysis, and dissemination; choosing research questions that can address disparities in health and access; and fair access to research results. Group categories like race, ethnicity, and gender require critical assessment to ensure that they are free of biases in data collection and analysis.

Cognition researchers’ ethical responsibilities include helping elucidate the meaning and implications of research findings in social context, i.e., in the lives of everyday people as they age. This connects research with practice, and applies across populations, making cognition research both genuinely translational and morally meaningful.

References

Emanuel EJ, Wendler D, Grady C (2000) What makes clinical research ethical? JAMA 283:2701–2711.

Footnotes

Keywords are included on the first page of each session summary. There are 7 session summaries.


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