Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Cortisol levels during human aging predict hippocampal atrophy and memory deficits

A Correction to this article was published on 01 August 1998

Abstract

Elevated glucocorticoid levels produce hippocampal dysfunction and correlate with individual deficits in spatial learning in aged rats. Previously we related persistent cortisol increases to memory impairments in elderly humans studied over five years. Here we demonstrate that aged humans with significant prolonged cortisol elevations showed reduced hippocampal volume and deficits in hippocampus-dependent memory tasks compared to normal-cortisol controls. Moreover, the degree of hippocampal atrophy correlated strongly with both the degree of cortisol elevation over time and current basal cortisol levels. Therefore, basal cortisol elevation may cause hippocampal damage and impair hippocampus-dependent learning and memory in humans.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Mean (± SEM) correct recall of the increasing/high and decreasing/moderate cortisol groups on the immediate and delayed memory task.
Figure 2: Mean (±SEM) time [log(sec)] for the increasing/high and decreasing/moderate cortisol groups to find their way through a human maze for a simple and a complex path.
Figure 3
Figure 4
Figure 5

References

  1. McEwen, B.S. Protective and damaging effects of stress mediators. New Engl. J. Med. 238, 171–179 (1998)

    Article  Google Scholar 

  2. Jacobson, L. & Sapolsky, R.M. The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenal axis. Endo. Rev. 12, 118–134 (1991)

    CAS  Article  Google Scholar 

  3. Brindley, D.N. & Rolland, Y. Possible connections between stress, diabetes, obesity, hypertension and altered lipoprotein metabolism that may result in atherosclerosis. Clin. Sci. 77, 453–461 (1989)

    CAS  Article  Google Scholar 

  4. Sapolsky, R. Stress, the aging brain, and the mechanisms of neuron death. (MIT Press, Cambridge, 1992)

    Google Scholar 

  5. Landfield, P., Baskin, R. K. & Pitler, T. A. Brain-aging correlates: Retardation by hormonal-pharmacological treatments. Science 214, 581– 583 (1981)

    CAS  Article  Google Scholar 

  6. Landfield, P., Waymire, J. & Lynch, G. Hippocampal aging and adrenocorticoids: Quantitative correlations. Science 202, 1098–1102 (1978)

    CAS  Article  Google Scholar 

  7. Issa, A., Gauthier, S. & Meaney, M. J. Hypothalamic-pituitary-adrenal activity in aged cognitively impaired and cognitively unimpaired aged rats. J. Neurosci. 10, 3247 –3254 (1990)

    CAS  Article  Google Scholar 

  8. Squire, L. R. Memory and the hippocampus : A synthesis from findings with rats, monkeys, and humans . Psychol. Rev. 99, 195– 231 (1992)

    CAS  Article  Google Scholar 

  9. Starkman, M. N., Gebarski, S. S., Berent, S. & Schteingart, D. E. Hippocampal formation volume, memory dysfunction, and cortisol levels in patients with Cushing's syndrome. Biol. Psychiatry 32, 756–765 (1992)

    CAS  Article  Google Scholar 

  10. Davis, K. L. et al. Cortisol and Alzheimer's disease, I : Basal studies. Am. J. Psychiatry 143, 300–305 (1986)

    CAS  Article  Google Scholar 

  11. Lupien, S. J. et al. Longitudinal study of basal cortisol levels in healthy elderly subjects : Evidence for sub-groups. Neurobiol. Aging 17, 95– 105 (1995)

    Article  Google Scholar 

  12. Lupien, S. J. . & McEwen, B. S. The acute effects of corticosteroids on cognition: Integration of animal and human model studies. Brain Res. Rev. 24, 1–27 (1997)

    CAS  Article  Google Scholar 

  13. Wolkowitz, O. M., Reus, V. I., Canick, J., Levin, B. & Lupien, S.J. Glucocorticoid medication, memory and steroid psychosis in medical illness. Ann. NY Acad. Sci. 823, 81–96 (1997)

    CAS  Article  Google Scholar 

  14. Lupien, S. et al. Basal cortisol levels and cognitive deficits in human aging, J. Neurosci . 14, 2893–2903 (1994)

    CAS  Article  Google Scholar 

  15. Scolville, W. B. & Milner, B. Hippocampal damage and memory dysfunction . J. Neurol. Psychiatry 20, 11– 21 (1957)

    Article  Google Scholar 

  16. O'Keefe, J. & Nadel, L. The Hippocampus as a Cognitive Map (Oxford, Clarendon, 1978)

    Google Scholar 

  17. de Leon, M. J. et al. Frequency of hippocampal formation atrophy in normal aging and Alzheimer's disease. Neurobiol. Aging 18, 1–11 (1997)

    CAS  Article  Google Scholar 

  18. de Leon, M. et al. Abnormal cortisol response in Alzheimer's disease linked to hippocampal atrophy. Lancet 2, 391–392 (1988)

    CAS  Article  Google Scholar 

  19. Fischette, C. T., Komisurak, B. R., Ediner, H. M., Feder, H. H. & Siegal, A. Differential fornix ablations and the circadian rhythmicity of adrenal corticosterone secretion. Brain Res. 195, 373–380 (1980)

    CAS  Article  Google Scholar 

  20. DeKloet, E. R. Brain corticosteroid receptor balance and homeostatic control. Front. Neuroendocrinol. 12, 95–123 (1991)

    Google Scholar 

  21. Sapolsky, R. M., Krey, L. C. & McEwen, B. S. The neuroendocrinology of stress and aging: The glucocorticoid cascade hypothesis. Endo. Rev. 7, 284– 301 (1986)

    CAS  Article  Google Scholar 

  22. Joels, M. Steroid hormones and excitability in the mammalian brain. Front. Neuroendocrinol. 18, 495–4498 (1997)

    Article  Google Scholar 

  23. Sloviter, R. et al. Selective loss of hippocampal granule cells in the mature rat brain after adrenalectomy . Science 243, 535–538 (1989)

    CAS  Article  Google Scholar 

  24. Reul, J. M. H. M. & De Kloet, E. R. Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation. Endocrinology 117, 2505–2512 (1985)

    CAS  Article  Google Scholar 

  25. Kerr, D. S., Campbell, L. W., Hao, S. -Y. & Landfield, P. W. Corticosteroid modulation of hippocampal potentials: Increased effect with aging. Science 245, 1505–1509 (1989)

    CAS  Article  Google Scholar 

  26. Diamond, D. M., Bennett, M. C., Fleshner, M. & Rose, G. M. Inverted-U relationship between the level of peripheral corticosterone and the magnitude of hippocampal primed burst potentiation. Hippocampus 2, 421–430 (1992)

    CAS  Article  Google Scholar 

  27. Joels, M. & De Kloet, E. R. Effect of glucocorticoids and norepinephrine on excitability in the hippocampus. Science 245, 1502–1504 (1989)

    CAS  Article  Google Scholar 

  28. Magarinos, A. M., McEwen, B. S., Flugge, G. & Fuchs, E. Chronic psychosocial stress causes apical dendritic atrophy of hippocampal CA3 pyramidal neurons in subordinate tree shrews. J. Neurosci. 16 , 3534–3540 (1996)

    CAS  Article  Google Scholar 

  29. Gould, E., Tanapat, P., McEwen, B. S., Flugge, G. & Fuchs, E. Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proc. Natl. Acad. Sci. USA 95, 3168–3171 (1998)

    CAS  Article  Google Scholar 

  30. Landfield, P. W. & Elridge, J. C. Evolving aspects of the glucocorticoid hypothesis of brain aging: Hormonal modulation of neuronal calcium homeostasis . Neurobiol. Aging 15, 579– 588 (1994)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

This research was supported by grants from the American Alzheimer's Association and the National Institute of Aging (AG09488) to MJM, by a fellowship from the Fonds de la recherche en santé du Québec (FRSQ) to SJL, and was supported in part by NIH grants to MdeL (AG12101, AG13616), and as a part of the NIA Alzheimer's disease core center grant (P30 AG08051). It was also supported by a grant from the John D. and Catherine T. MacArthur Foundation. RLH was a recipient of the VA Clinical Investigator career development award and partially supported by the UCSD NIMH CRC (PHS MH30914-14). The Aging Research Program of the Douglas Hospital is generously supported by ALCAN Canada Ltd.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sonia J. Lupien.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lupien, S., de Leon, M., de Santi, S. et al. Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Nat Neurosci 1, 69–73 (1998). https://doi.org/10.1038/271

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/271

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing