Circulating cortisol and cognitive and structural brain measures
The Framingham Heart Study
Abstract
Objective
To assess the association of early morning serum cortisol with cognitive performance and brain structural integrity in community-dwelling young and middle-aged adults without dementia.
Methods
We evaluated dementia-free Framingham Heart Study (generation 3) participants (mean age 48.5 years, 46.8% men) who underwent cognitive testing for memory, abstract reasoning, visual perception, attention, and executive function (n = 2,231) and brain MRI (n = 2018) to assess total white matter, lobar gray matter, and white matter hyperintensity volumes and fractional anisotropy (FA) measures. We used linear and logistic regression to assess the relations of cortisol (categorized in tertiles, with the middle tertile as referent) to measures of cognition, MRI volumes, presence of covert brain infarcts and cerebral microbleeds, and voxel-based microstructural white matter integrity and gray matter density, adjusting for age, sex, APOE, and vascular risk factors.
Results
Higher cortisol (highest tertile vs middle tertile) was associated with worse memory and visual perception, as well as lower total cerebral brain and occipital and frontal lobar gray matter volumes. Higher cortisol was associated with multiple areas of microstructural changes (decreased regional FA), especially in the splenium of corpus callosum and the posterior corona radiata. The association of cortisol with total cerebral brain volume varied by sex (p for interaction = 0.048); higher cortisol was inversely associated with cerebral brain volume in women (p = 0.001) but not in men (p = 0.717). There was no effect modification by the APOE4 genotype of the relations of cortisol and cognition or imaging traits.
Conclusion
Higher serum cortisol was associated with lower brain volumes and impaired memory in asymptomatic younger to middle-aged adults, with the association being evident particularly in women.
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Publication history
Received by Neurology March 6, 2018. Accepted in final form August 10, 2018.
References
1.
Walker BR. Glucocorticoids and cardiovascular disease. Eur J Endocrinol 2007;157:545–559.
2.
Mcewen BS, Gianaros PJ. Central role of the brain in stress and adaptation: links to socioeconomic status, health, and disease. Ann NY Acad Sci 2010;1186:190–222.
3.
Patil CG, Lad SP, Katznelson L, Laws ER. Brain atrophy and cognitive deficits in Cushing's disease. Neurosurg Focus 2007;23:E11.
4.
Bourdeau I, Bard C, Noël B, et al. Loss of brain volume in endogenous Cushing's syndrome and its reversibility after correction of hypercortisolism. J Clin Endocrinol Metab 2002;87:1949–1954.
5.
Forget H, Lacroix A, Cohen H. Persistent cognitive impairment following surgical treatment of Cushing's syndrome. Psychoneuroendocrinology 2002;27:367–383.
6.
Forget H, Lacroix A, Somma M, Cohen H. Cognitive decline in patients with Cushing's syndrome. J Int Neuropsychol Soc 2000;6:20–29.
7.
Herbert J, Goodyer IM, Grossman AB, et al. Do corticosteroids damage the brain? J Neuroendocrinol 2006;18:393–411.
8.
Lee BK, Glass Ta, McAtee MJ, et al. Associations of salivary cortisol with cognitive function in the Baltimore Memory Study. Arch Gen Psychiatry 2007;64:810–818.
9.
Pulopulos MM, Hidalgo V, Almela M, Puig-Perez S, Villada C, Salvador A. Hair cortisol and cognitive performance in healthy older people. Psychoneuroendocrinology 2014;44:100–111.
10.
MacLullich AMJ, Deary IJ, Starr JM, Ferguson KJ, Wardlaw JM, Seckl JR. Plasma cortisol levels, brain volumes and cognition in healthy elderly men. Psychoneuroendocrinology 2005;30:505–515.
11.
Geerlings MI, Sigurdsson S, Eiriksdottir G, et al. Salivary cortisol, brain volumes, and cognition in community-dwelling elderly without dementia. Neurology 2015;85:976–983.
12.
Cox SR, MacPherson SE, Ferguson KJ, et al. Does white matter structure or hippocampal volume mediate associations between cortisol and cognitive ageing? Psychoneuroendocrinology 2015;62:129–137.
13.
Cox SR, Bastin ME, Ferguson KJ, et al. Brain white matter integrity and cortisol in older men: the Lothian Birth Cohort 1936. Neurobiol Aging 2015;36:257–264.
14.
de Kloet ER, Joëls M, Holsboer F. Stress and the brain: from adaptation to disease. Nat Rev Neurosci 2005;6:463–475.
15.
Lyons DM, Lopez JM, Yang C, Schatzberg AF. Stress-level cortisol treatment impairs inhibitory control of behavior in monkeys. J Neurosci 2000;20:7816–7821.
16.
Cook SC, Wellman CL. Chronic stress alters dendritic morphology in rat medial prefrontal cortex. J Neurobiol 2004;60:236–248.
17.
Stomby A, Boraxbekk C-J, Lundquist A, et al. Higher diurnal salivary cortisol levels are related to smaller prefrontal cortex surface area in elderly men and women. Eur J Endocrinol 2016;175:117–126.
18.
Splansky GL, Corey D, Yang Q, et al. The Third Generation Cohort of the National Heart, Lung, and Blood Institute's Framingham Heart Study: design, recruitment, and initial examination. Am J Epidemiol 2007;165:1328–1335.
19.
Kannel WB, Feinleib M, McNamara PM, Garrison RJ, Castelli WP. An investigation of coronary heart disease in families: the Framingham offspring study. Am J Epidemiol 1979;110:281–290.
20.
Moms JC, Heyman A, Mohs RC, et al. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD), part I: clinical and neuropsychological assessment of Alzheimer's disease. Neurology 1989;39:1159.
21.
Pase MP, Beiser A, Enserro D, et al. Association of ideal cardiovascular health with vascular brain injury and incident dementia. Stroke 2016;47:1201–1206.
22.
DeCarli C, Massaro J, Harvey D, et al. Measures of brain morphology and infarction in the Framingham Heart Study: establishing what is normal. Neurobiol Aging 2005;26:491–510.
23.
DeCarli C, Fletcher E, Ramey V, Harvey D, Jagust WJ. Anatomical mapping of white matter hyperintensities (WMH): exploring the relationships between periventricular WMH, deep WMH, and total WMH burden. Stroke 2005;36:50–55.
24.
DeCarli C, Miller BL, Swan GE, et al. Predictors of brain morphology for the men of the NHLBI twin study. Stroke 1999;30:529–536.
25.
Aljabar P, Heckemann RA, Hammers A, Hajnal JV, Rueckert D. Multi-atlas based segmentation of brain images: atlas selection and its effect on accuracy. Neuroimage 2009;46:726–738.
26.
Carmichael O, Mungas D, Beckett L, et al. MRI predictors of cognitive change in a diverse and carefully characterized elderly population. Neurobiol Aging 2012;33:83–95.
27.
Lee DY, Fletcher E, Martinez O, et al. Regional pattern of white matter microstructural changes in normal aging, MCI, and AD. Neurology 2009;73:1722–1728.
28.
Kochunov P, Lancaster JL, Thompson P, et al. Regional spatial normalization: toward an optimal target. J Comput Assist Tomogr 2001;25:805–816.
29.
Maillard P, Fletcher E, Harvey D, et al. White matter hyperintensity penumbra. Stroke 2011;42:1917–1922.
30.
Smith SM, Jenkinson M, Woolrich MW, et al. Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage 2004;23(suppl 1):S208–S219.
31.
Jenkinson M, Beckmann CF, Behrens TEJ, Woolrich MW, Smith SM. FSL. Neuroimage 2012;62:782–790.
32.
Das RR, Seshadri S, Beiser AS, et al. Prevalence and correlates of silent cerebral infarcts in the Framingham Offspring Study. Stroke 2008;39:2929–2935.
33.
Radloff LS. The CES-D Scale: a self-report depression scale for research in the general population. Appl Psychol Meas 1977;1:385–401.
34.
Smith SM, Nichols TE. Threshold-free cluster enhancement: addressing problems of smoothing, threshold dependence and localisation in cluster inference. Neuroimage 2009;44:83–98.
35.
Zhang Y, Zhang J, Oishi K, et al. Atlas-guided tract reconstruction for automated and comprehensive examination of the white matter anatomy. Neuroimage 2010;52:1289–1301.
36.
Lupien SJ, de Leon M, de Santi S, et al. Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Nat Neurosci 1998;1:69–73.
37.
Wolf OT, Convit A, De Leon MJ, Caraos C, Qadri SF. Basal hypothalamo-pituitary-adrenal axis activity and corticotropin feedback in young and older men: relationships to magnetic resonance imaging-derived hippocampus and cingulate gyrus volumes. Neuroendocrinology 2002;75:241–249.
38.
Vythilingam M, Vermetten E, Anderson GM, et al. Hippocampal volume, memory, and cortisol status in major depressive disorder: effects of treatment. Biol Psychiatry 2004;56:101–112.
39.
O'Brien JT, Lloyd A, McKeith I, Gholkar A, Ferrier N. A longitudinal study of hippocampal volume, cortisol levels, and cognition in older depressed subjects. Am J Psychiatry 2004;161:2081–2090.
40.
Colla M, Kronenberg G, Deuschle M, et al. Hippocampal volume reduction and HPA-system activity in major depression. J Psychiatr Res 2007;41:553–560.
41.
Knoops AJG, Gerritsen L, van der Graaf Y, Mali WPTM, Geerlings MI. Basal hypothalamic pituitary adrenal axis activity and hippocampal volumes: the SMART-Medea study. Biol Psychiatry 2010;67:1191–1198.
42.
Pires P, Santos A, Vives-Gilabert Y, et al. White matter alterations in the brains of patients with active, remitted, and cured Cushing syndrome: a DTI study. Am J Neuroradiol 2015;36:1043–1048.
43.
Pires P, Santos A, Vives-Gilabert Y, et al. White matter involvement on DTI-MRI in Cushing's syndrome relates to mood disturbances and processing speed: a case-control study. Pituitary 2017;20:340–348.
44.
Liu X, Watanabe K, Kakeda S, et al. Relationship between white matter integrity and serum cortisol levels in drug-naive patients with major depressive disorder: diffusion tensor imaging study using tract-based spatial statistics. Br J Psychiatry 2016;208:585–590.
45.
Penke L, Maniega SM, Bastin ME, et al. Brain white matter tract integrity as a neural foundation for general intelligence. Mol Psychiatry 2012;17:1026–1030.
46.
Patel PD, Lopez JF, Lyons DM, Burke S, Wallace M, Schatzberg AF. Glucocorticoid and mineralocorticoid receptor mRNA expression in squirrel monkey brain. J Psychiatr Res 2001;34:383–392.
47.
Sanchez MM, Young LJ, Plotsky PM, Insel TR. Distribution of corticosteroid receptors in the Rhesus brain: relative absence of glucocorticoid receptors in the hippocampal formation. J Neurosci 2000;20:4657–4668.
48.
De Kloet ER, Vreugdenhil E, Oitzl MS, Joëls M. Brain corticosteroid receptor balance in health and disease. Endocr Rev 1998;19:269–301.
49.
Sapolsky RM, Plotsky PM. Hypercortisolism and its possible neural bases. Biol Psychiatry 1990;27:937–952.
50.
Kalimi M. Glucocorticoid receptors: from development to aging: a review. Mech Ageing Dev 1984;24:129–138.
51.
Fotenos AF, Snyder AZ, Girton LE, Morris JC, Buckner RL. Normative estimates of cross-sectional and longitudinal brain volume decline in aging and AD. Neurology 2005;64:1032–1039.
52.
Seeman TE, McEwen BS, Rowe JW, Singer BH. Allostatic load as a marker of cumulative biological risk: MacArthur studies of successful aging. Proc Natl Acad Sci USA 2001;98:4770–4775.
53.
Karlamangla AS, Singer BH, McEwen BS, Rowe JW, Seeman TE. Allostatic load as a predictor of functional decline: MacArthur Studies of Successful Aging. J Clin Epidemiol 2002;55:696–710.
54.
Stetler C, Miller GE. Depression and hypothalamic-pituitary-adrenal activation: a quantitative summary of four decades of research. Psychosom Med 2011;73:114–126.
55.
Rosmalen JGM, Kema IP, Wüst S, et al. 24 H urinary free cortisol in large-scale epidemiological studies: short-term and long-term stability and sources of variability. Psychoneuroendocrinology 2014;47:10–16.
Information & Authors
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Copyright
© 2018 American Academy of Neurology.
Publication History
Received: March 6, 2018
Accepted: August 10, 2018
Published online: October 24, 2018
Published in print: November 20, 2018
Disclosure
The authors report no disclosures relevant to the manuscript. Go to Neurology.org/N for full disclosures.
Study Funding
This work was supported by the Framingham Heart Study’s National Heart, Lung, and Blood Institute Study (contract N01-HC-25195) and HHSN268201500001I (R.S.V.) and by grants from the NIH, National Institute of Neurologic Disorders and Stroke (R01-NS017950 and UH2 NS100605 [S.S.]) and the National Institute on Aging (R01 AG054076, AG008122, AG033193, AG033040, U01 AG049505, and AG052409 [all S.S.]), as well as the following grants: T32 HL125232 (J.B.E-T.), R01HL093328 (R.S.V.), R01HL107385 (R.S.V.), and R01HL126136 (R.S.V.).
Authors
Author Contributions
Drs. Echouffo-Tcheugui and Seshadri had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Echouffo-Tcheugui and Seshadri. Acquisition of data: Vasan, Beiser, DeCarli, and Seshadri. Analysis and interpretation of data: Conner, Maillard, Himali, Echouffo-Tcheugui, Beiser, and Seshadri; Drafting of the manuscript: Echouffo-Tcheugui. Critical revision of the manuscript for important intellectual content: Conner, Himali, Maillard, DeCarli, Beiser, Vasan, and Seshadri; Statistical analysis: Conner, Himali, and Maillard. Obtained funding: DeCarli, Vasan, and Seshadri. Study supervision: Seshadri.
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Jiménez-Pavón et al. suggest that we should have considered physical activity or cardiorespiratory fitness as a factor that mediates the relation between cortisol and brain volumes in our study.1 We agree that physical activity may be associated with circulating levels of cortisol. However, there are reasons not to consider physical activity (or cardiorespiratory fitness) as a mediating factor in an analysis linking cortisol levels to brain-related outcomes. The biological framework connecting physical activity, cortisol, and the brain suggests that cortisol is on the pathway between physical activity and brain morphology rather than physical activity being an intermediary between cortisol and brain outcomes.2 Consequently, it would make more sense to examine the mediating effect of cortisol on the relation between physical activity (or cardiorespiratory fitness) and brain volumes, rather than assessing the mediating effect of physical activity in the link between cortisol and brain morphology. Such an approach is corroborated by the results presented in the reference cited by Jiménez-Pavón et al., which described an intervention to increase physical activity leading to a modulation of the levels of cortisol.3
It is neither appropriate to adjust for physical activity (an antecedent to cortisol in the biological pathway; thus possibly an overadjustment) while relating cortisol to brain volumes, nor to assess its mediating effect on the association of cortisol and brain morphology. However, we are open to the interesting idea of examining the mediating effect of cortisol on the association of physical activity with brain volumes.
Disclosure
The authors report no relevant disclosures. Contact [email protected] for full disclosures.
References
We concur with Barbosa et al. that the cross-sectional design of our study1 is a limitation. We also agree that measures (urinary or hair) of long-term exposure to cortisol would more appropriately reflect the cortisol status in an individual. These issues were acknowledged in the discussion section of our article.1
Cognitive impairment and dementia are clinical diagnoses. Consequently, other than examining measures of cognitive performance, we do not see how else we would have identified preclinical disease. The participants in our study were young (mean age 48.5 years),1 thus the likelihood of preclinical disease was extremely low. Furthermore, the study referenced by Barbosa et al.,2 which reported high cortisol levels in patients with cognitive impairment and Alzheimer disease years before clinical diagnosis, is in support of our hypothesis. In terms of the clinical significance of our findings, it depends on whether one only views extreme phenotypes (e.g. Cushing disease) as significant or not. Our findings suggested that, rather than thinking about elevated cortisol levels as harmful only when within extremes ranges, it might be more appropriate to consider that there is continuum of risk across the spectrum of cortisol levels. In the discussion section of our article, we specifically indicated that we did not focus on people with extreme cortisol phenotypes.1
Regarding the recommendation to use hair cortisol in epidemiologic studies of brain outcomes, we are not aware of such a “recommendation.” In the reference cited by the authors,3 there is no clear recommendation to exclusively use hair cortisol measures in epidemiologic studies of brain outcomes. While the debate on the methods used to assess the exposure to cortisol is interesting, it is beyond the scope of our article.
Disclosure
The authors report no relevant disclosures. Contact [email protected] for full disclosures.
References
In their very interesting article, Echouffo-Tcheugui et al.1 suggested that reduced brain volumes and poor cognitive measures could be a consequence of high cortisol levels. Given the cross-sectional design of the study, the inverse direction (i.e., high cortisol levels as a consequence of brain dysfunction) may also be considered. In addition, the absence of dementia was defined according to clinical criteria, which means that participants with preclinical neurodegenerative conditions may have been included. High cortisol levels have been reported in patients with cognitive impairment and Alzheimer disease years before clinical diagnosis.2 In this sense—the association of cortisol—memory and brain volumes demand a more critical analysis. Despite having statistical significance, the differences found regarding brain volume and cognitive performance were quite similar among cortisol tertiles. This information should raise a debate on whether these differences could be due to this study’s large sample size and how clinically meaningful they are. Further, single measures of serum cortisol may not reflect chronic hypercortisolism. Approximately only 10% of total serum cortisol is capable of crossing the blood-brain barrier and modulating brain function. Currently, hair cortisol, rather than urinary, has been recommended to assess long-term cortisol exposure in epidemiologic studies of brain function.3
Disclosure
The authors report no relevant disclosures. Contact [email protected] for full disclosures.
References
We read with interest the article by Echouffo-Tcheugui et al.1 on the association of serum cortisol with cognitive performance and brain structure integrity in young and middle-aged adults without dementia. They found higher serum cortisol was associated with impaired memory in asymptomatic young to middle-aged adults, but only associated with lower brain volumes in women. The authors highlighted the adjustment for potential confounders as 1 relevant strength; however, the role of physical activity (PA) or cardiorespiratory fitness (CRF) was not considered. PA and CRF have shown clear influences on both dimensions: the hypothalamic-pituitaryadrenal (HPA) axis,2 but also cognitive and structural brain parameters.3–4 Moreover, women usually showed lower levels of PA and CRF which could partially explain the particular association between cortisol and brain volumes. Therefore, the mediation role of PA or CRF should have been taken into account in the Framingham Heart Study. In fact, the role of PA/CRF on brain volume has been previously reported in the Framingham Heart Study cohort.5 It would be highly relevant if the authors could provide additional results about this mediation role based on existing data.
Disclosure
D. Jiménez-Pavón receieved a grant from the Spanish Ministry of Science and Innovation - MINECO (RYC-2014-16938). A. Carbonell-Baeza reports no relevant disclosures. Contact [email protected] for full disclosures.
References