Neurobiology of Aging 35 (2014) 1654e1655
Contents lists available at ScienceDirect
Neurobiology of Aging journal homepage: www.elsevier.com/locate/neuaging
Negative results
Dehydroepiandrosterone sulfate and cognition in midlife, post-menopausal women Charlene K.Z. Chua a, Victor W. Henderson b, c, Lorraine Dennerstein d, David Ames e, Cassandra Szoeke a, * a
Department of Medicine, University of Melbourne, Parkville, Victoria, Australia Department of Health Research and Policy (Epidemiology), Stanford University, Stanford, CA, USA Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA d Department of Psychiatry, University of Melbourne, Parkville, Victoria, Australia e National Ageing Research Institute, Parkville, Victoria, Australia b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 22 August 2013 Received in revised form 21 January 2014 Accepted 27 January 2014 Available online 31 January 2014
The association between serum dehydroepiandrosterone sulfate (DHEAS) and cognition was assessed in 218 healthy, midlife, post-menopausal women, aged 55e65 years. In cross-sectional analyses, DHEAS level was not significantly associated with a standardized score of global cognition or with individual test scores from a comprehensive neuropsychological battery (all p-values >0.05). In longitudinal analyses of 176 women, DHEAS level was unassociated with cognition 2 years later or with 2-year change in cognition. These findings fail to support the view that DHEAS is substantially related to cognitive function in midlife, post-menopausal women. Ó 2014 Elsevier Inc. All rights reserved.
Keywords: Cognition Dehydroepiandrosterone sulfate Menopause Midlife Women
1. Introduction The discovery of de novo synthesis of dehydroepiandrosterone sulfate (DHEAS) in human brain (Baulieu, 1981), and the observation that serum levels of DHEAS fall with age (Valenti et al., 2009), have fueled speculation that age-related decrements in DHEAS may mediate cognitive decline. However, the extent to which DHEAS may influence cognition in humans is not well understood (Maninger et al., 2009). Epidemiologic studies on the association between DHEAS level and cognition have yielded inconsistent findings. Most research has focused on elderly individuals. Less is known of the effect of DHEAS on cognition in midlife women, a time of important shifts in the internal steroid hormonal milieu. In a population-based midlife cohort of post-menopausal women, we examined cross-sectional and longitudinal associations between the serum DHEAS and cognitive function, assessed
* Corresponding author at: Women’s Healthy Ageing Project (WHAP), PO Box 2026, Royal Melbourne Hospital, Parkville, Victoria, 3050, Australia. Tel.: þ61 3 8344 1835. E-mail address: [email protected] (C. Szoeke). 0197-4580/$ e see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.neurobiolaging.2014.01.140
twice, 2 years apart, with a comprehensive neuropsychological battery. 2. Methods Participants were 218 Australian-born, post-menopausal women below the age of 65 years enrolled in the Women’s Healthy Ageing Project, established in 1991 as the Melbourne Women’s Midlife Health Project (Dennerstein et al., 1993). Serum from fasting blood samples were assayed for DHEAS levels on Immulite 2000 DHEA-SO4 (Siemens Healthcare Diagnostics Products Ltd, Los Angeles, CA, USA). A comprehensive battery of 13-item neuropsychological tests (17 measures) was administered to the participants in 2002 and 2004. Global cognition was assessed with a composite derived from standardized scores of 17 individual test scores. One hundred seventy-six women who completed follow-up assessments 2 years later were included in longitudinal analyses. Multivariate linear analyses were used to test for association between DHEAS and cognitive scores, adjusting for age, total years of education, body mass index, possible depression, time since menopause, current use of hormone therapy, past use of hormone therapy, alcohol consumption, smoking status, participation in physical activity,
C.K.Z. Chua et al. / Neurobiology of Aging 35 (2014) 1654e1655
employment status, and for cognitive changedbaseline neuropsychological test scores (see Supplementary data). 3. Results The mean participant age was 59.7 years (range 55.9e64.9 years), and about half had at least 12 years of education (Supplementary Table 1A). The DHEAS level declined significantly with age (b ¼ 0.19, p ¼ 0.004). In cross-sectional analyses, DHEAS level was not significantly associated with the global cognitive composite or individual neuropsychological test scores (all p-values >0.05). In longitudinal analyses, baseline DHEAS level was not predictive of cognitive findings 2 years later. Similarly, the baseline DHEAS level was unassociated with 2-year cognitive change, after covariate adjustment (Supplementary Table 2). 4. Discussion Our cross-sectional and longitudinal analyses demonstrated no significant relation between DHEAS level and cognitive function in midlife, post-menopausal women. Results, based on a broad sampling of cognitive domains and a robust measure of global cognition, help to clarify contradictory findings on the relation of DHEAS to cognitive function, based in part on analyses in different age groups involving limited measures of cognitive outcomes (Maninger et al., 2009). These findings in healthy, relatively well-educated midlife women do not generalize to men, older post-menopausal women, or women of reproductive age. Some of the neuropsychological tests may be insufficiently sensitive to cognitive change during midlife, and we did not have power to detect small effects. A single DHEAS level provides a less precise estimate of exposure than repeated measures over time. In summary, our results support the view that the serum DHEAS level is not substantially associated with cognitive function or 2-year cognitive change in healthy midlife, post-menopausal women. Longer follow-up may help clarify the relation between serum DHEAS level and cognitive function as women transition from midlife to old age. Disclosure statement Authors have no potential or actual conflicts of interest except as follows: Lorraine Dennerstein has received consulting fees from
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Pfizer and honorarium and travel expenses from Bayer Schering. David Ames has received consulting fees from Prana, Lilly, and Pfizer, and he has received research support from Lilly, Prana, and Quintiles. Cassandra Szoeke has provided clinical consultancy and been on scientific advisory committees for the Australian Commonwealth Scientific and Industrial Research Organisation (CSIRO), Merck, GE Healthcare, Mayne Pharma, and Sanofi. She has been the Senior Chief Investigator on research funds in partnership with Pfizer, Merck, Bayer Pharmaceuticals, and GE Healthcare. She may accrue revenues from patent in pharmacogenomics prediction of seizure recurrence. Acknowledgements This study has been partly supported by the Brain Foundation, Alzheimer’s Association of Australia, Alzheimer’s Association (IIRG01e2684), Australian Menopausal Society, Shepherd Foundation, Scobie and Claire McKinnon Foundation, Collier Trust Fund, Ramaciotti Foundation, Bayer Pharmaceuticals, J.O. & J.R. Wicking Trust, and the National Health and Medical Research Council. The authors are indebted to the women in the project, who generously donated their time to participate in this research study. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.neurobiolaging. 2014.01.140. References Baulieu, E.E., 1981. Steroid hormones in the brain: several mechanisms? In: Fuxe, K., Gustafsson, J.A., Wetterberg, L. (Eds.), Steroid Hormone Regulation of the Brain. Pergamon Press, Oxford, pp. 3e14. Dennerstein, L., Smith, A.M.A., Morse, C., Burger, H., Green, A., Hopper, J., Ryan, M., 1993. Menopausal symptoms in Australian women. Med. J. Aust. 159, 232e236. Maninger, N., Wolkowitz, O.M., Reus, V.I., Epel, E.S., Mellon, S.H., 2009. Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). Front. Neuroendocrinol. 30, 65e91. Valenti, G., Ferrucci, L., Lauretani, F., Ceresini, G., Bandinelli, S., Luci, M., Ceda, G., Maggio, M., Schwartz, R.S., 2009. Dehydroepiandrosterone sulfate and cognitive function in the elderly: the InCHIANTI Study. J. Endocrinol. Invest. 32, 766e772.
Contents lists available at ScienceDirect
Neurobiology of Aging journal homepage: www.elsevier.com/locate/neuaging
Negative results
Dehydroepiandrosterone sulfate and cognition in midlife, post-menopausal women Charlene K.Z. Chua a, Victor W. Henderson b, c, Lorraine Dennerstein d, David Ames e, Cassandra Szoeke a, * a
Department of Medicine, University of Melbourne, Parkville, Victoria, Australia Department of Health Research and Policy (Epidemiology), Stanford University, Stanford, CA, USA Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA d Department of Psychiatry, University of Melbourne, Parkville, Victoria, Australia e National Ageing Research Institute, Parkville, Victoria, Australia b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 22 August 2013 Received in revised form 21 January 2014 Accepted 27 January 2014 Available online 31 January 2014
The association between serum dehydroepiandrosterone sulfate (DHEAS) and cognition was assessed in 218 healthy, midlife, post-menopausal women, aged 55e65 years. In cross-sectional analyses, DHEAS level was not significantly associated with a standardized score of global cognition or with individual test scores from a comprehensive neuropsychological battery (all p-values >0.05). In longitudinal analyses of 176 women, DHEAS level was unassociated with cognition 2 years later or with 2-year change in cognition. These findings fail to support the view that DHEAS is substantially related to cognitive function in midlife, post-menopausal women. Ó 2014 Elsevier Inc. All rights reserved.
Keywords: Cognition Dehydroepiandrosterone sulfate Menopause Midlife Women
1. Introduction The discovery of de novo synthesis of dehydroepiandrosterone sulfate (DHEAS) in human brain (Baulieu, 1981), and the observation that serum levels of DHEAS fall with age (Valenti et al., 2009), have fueled speculation that age-related decrements in DHEAS may mediate cognitive decline. However, the extent to which DHEAS may influence cognition in humans is not well understood (Maninger et al., 2009). Epidemiologic studies on the association between DHEAS level and cognition have yielded inconsistent findings. Most research has focused on elderly individuals. Less is known of the effect of DHEAS on cognition in midlife women, a time of important shifts in the internal steroid hormonal milieu. In a population-based midlife cohort of post-menopausal women, we examined cross-sectional and longitudinal associations between the serum DHEAS and cognitive function, assessed
* Corresponding author at: Women’s Healthy Ageing Project (WHAP), PO Box 2026, Royal Melbourne Hospital, Parkville, Victoria, 3050, Australia. Tel.: þ61 3 8344 1835. E-mail address: [email protected] (C. Szoeke). 0197-4580/$ e see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.neurobiolaging.2014.01.140
twice, 2 years apart, with a comprehensive neuropsychological battery. 2. Methods Participants were 218 Australian-born, post-menopausal women below the age of 65 years enrolled in the Women’s Healthy Ageing Project, established in 1991 as the Melbourne Women’s Midlife Health Project (Dennerstein et al., 1993). Serum from fasting blood samples were assayed for DHEAS levels on Immulite 2000 DHEA-SO4 (Siemens Healthcare Diagnostics Products Ltd, Los Angeles, CA, USA). A comprehensive battery of 13-item neuropsychological tests (17 measures) was administered to the participants in 2002 and 2004. Global cognition was assessed with a composite derived from standardized scores of 17 individual test scores. One hundred seventy-six women who completed follow-up assessments 2 years later were included in longitudinal analyses. Multivariate linear analyses were used to test for association between DHEAS and cognitive scores, adjusting for age, total years of education, body mass index, possible depression, time since menopause, current use of hormone therapy, past use of hormone therapy, alcohol consumption, smoking status, participation in physical activity,
C.K.Z. Chua et al. / Neurobiology of Aging 35 (2014) 1654e1655
employment status, and for cognitive changedbaseline neuropsychological test scores (see Supplementary data). 3. Results The mean participant age was 59.7 years (range 55.9e64.9 years), and about half had at least 12 years of education (Supplementary Table 1A). The DHEAS level declined significantly with age (b ¼ 0.19, p ¼ 0.004). In cross-sectional analyses, DHEAS level was not significantly associated with the global cognitive composite or individual neuropsychological test scores (all p-values >0.05). In longitudinal analyses, baseline DHEAS level was not predictive of cognitive findings 2 years later. Similarly, the baseline DHEAS level was unassociated with 2-year cognitive change, after covariate adjustment (Supplementary Table 2). 4. Discussion Our cross-sectional and longitudinal analyses demonstrated no significant relation between DHEAS level and cognitive function in midlife, post-menopausal women. Results, based on a broad sampling of cognitive domains and a robust measure of global cognition, help to clarify contradictory findings on the relation of DHEAS to cognitive function, based in part on analyses in different age groups involving limited measures of cognitive outcomes (Maninger et al., 2009). These findings in healthy, relatively well-educated midlife women do not generalize to men, older post-menopausal women, or women of reproductive age. Some of the neuropsychological tests may be insufficiently sensitive to cognitive change during midlife, and we did not have power to detect small effects. A single DHEAS level provides a less precise estimate of exposure than repeated measures over time. In summary, our results support the view that the serum DHEAS level is not substantially associated with cognitive function or 2-year cognitive change in healthy midlife, post-menopausal women. Longer follow-up may help clarify the relation between serum DHEAS level and cognitive function as women transition from midlife to old age. Disclosure statement Authors have no potential or actual conflicts of interest except as follows: Lorraine Dennerstein has received consulting fees from
1655
Pfizer and honorarium and travel expenses from Bayer Schering. David Ames has received consulting fees from Prana, Lilly, and Pfizer, and he has received research support from Lilly, Prana, and Quintiles. Cassandra Szoeke has provided clinical consultancy and been on scientific advisory committees for the Australian Commonwealth Scientific and Industrial Research Organisation (CSIRO), Merck, GE Healthcare, Mayne Pharma, and Sanofi. She has been the Senior Chief Investigator on research funds in partnership with Pfizer, Merck, Bayer Pharmaceuticals, and GE Healthcare. She may accrue revenues from patent in pharmacogenomics prediction of seizure recurrence. Acknowledgements This study has been partly supported by the Brain Foundation, Alzheimer’s Association of Australia, Alzheimer’s Association (IIRG01e2684), Australian Menopausal Society, Shepherd Foundation, Scobie and Claire McKinnon Foundation, Collier Trust Fund, Ramaciotti Foundation, Bayer Pharmaceuticals, J.O. & J.R. Wicking Trust, and the National Health and Medical Research Council. The authors are indebted to the women in the project, who generously donated their time to participate in this research study. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.neurobiolaging. 2014.01.140. References Baulieu, E.E., 1981. Steroid hormones in the brain: several mechanisms? In: Fuxe, K., Gustafsson, J.A., Wetterberg, L. (Eds.), Steroid Hormone Regulation of the Brain. Pergamon Press, Oxford, pp. 3e14. Dennerstein, L., Smith, A.M.A., Morse, C., Burger, H., Green, A., Hopper, J., Ryan, M., 1993. Menopausal symptoms in Australian women. Med. J. Aust. 159, 232e236. Maninger, N., Wolkowitz, O.M., Reus, V.I., Epel, E.S., Mellon, S.H., 2009. Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). Front. Neuroendocrinol. 30, 65e91. Valenti, G., Ferrucci, L., Lauretani, F., Ceresini, G., Bandinelli, S., Luci, M., Ceda, G., Maggio, M., Schwartz, R.S., 2009. Dehydroepiandrosterone sulfate and cognitive function in the elderly: the InCHIANTI Study. J. Endocrinol. Invest. 32, 766e772.
