Cognitive function in old age but not mood is dependent on a ER22/23EK variation in the glucocorticoid receptor gene. The Leiden 85-plus Study (original) (raw)
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Cortisol levels during human aging predict hippocampal atrophy and memory deficits
Nature Neuroscience, 1998
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.
High cortisol levels are associated with cognitive impairment no-dementia (CIND) and dementia
Clinica Chimica Acta, 2013
Background: This study aimed to compare serum cortisol concentrations in cognitively healthy elderly and in subjects with cognitive impairment no dementia (CIND) and dementia, besides to evaluate these concentrations according to apolipoprotein E genotype (APOE). Methods: Three-hundred and nine elderly enrolled in the Pietà Study (Brazil) were divided in 3 groups: control (n = 158), CIND (n = 92) and dementia (n = 59) and had concentrations of morning serum cortisol measured. Hormone concentrations were measured by chemiluminescence and APOE genotypes were determined by PCR followed by restriction fragment length polymorphism (RFLP). Results: Medians of cortisol concentrations (μg/dl) for the groups were 12.14 (interquartile range-IQR 6.34) for control, 13.65 (IQR 5.88) for CIND and 14.47 (IQR 7.35) for dementia. Significant differences were observed for control vs. CIND (P = 0.003), control vs. dementia (P = 0.001), but not for CIND vs. dementia (P = 0.269). No association was observed between cortisol concentrations and APOE genotype among the groups (P = 0.348). Conclusions: The elevation in cortisol concentrations is associated with dementia, independently of APOE genotypes. Further studies are required to understand if elevation of cortisol is an initial event and how hippocampal damage and the loss of hypothalamus-pituitary-adrenal (HPA) axis inhibition may affect its concentrations.
2006
Depression and cognitive decline have been associated with changes in circulating cortisol concentrations. Cortisol exerts its functions through mineralocorticoid (MR) and glucocorticoid (GR) receptors. However, data on the influence of variations in the MR and GR genes on depressive symptoms and cognitive functioning in older adults are scarce. Therefore, we explored the impact of MR-215G/C, MR-I180V, GR-ER22/23EK, GR-N363S, and GR-BclI polymorphisms on these end points in the population-based Leiden 85-plus Study. This prospective study includes 563 participants aged 85 years and older, with a mean follow-up of 4.2 years. In this study, high morning cortisol levels (per 1 SD cortisol) associated with impairments in global cognitive functioning (p ¼ 0.002) at baseline (age 85). These impairments were mainly attributable to lower attention (p ¼ 0.057) and slower processing speed (p ¼ 0.014). Similar effects were also observed during follow-up (age 85-90), where participants with higher cortisol levels (per 1 SD cortisol) had impaired global cognitive functioning (p ¼ 0.003), as well as impairments in attention (p ¼ 0.034) and processing speed (p ¼ 0.013). Changes in depressive symptoms were observed for the MR-I180V single-nucleotide polymorphism (SNP), where during follow-up the prevalence of depressive symptoms was higher in the 180V-allele carriers (p ¼ 0.049) compared to noncarriers. Dependent on these polymorphisms, no differences in overall and in specific domains of cognitive functioning were observed. In conclusion, the MR-I180V SNP has a specific effect on depressive symptoms, independent from cognitive functioning, and other polymorphisms in the MR and GR genes. In contrast, these genetic variants in the MR and GR genes do not influence cognitive functioning in old age.
The Association Between Serum Cortisol and Cognitive Decline In Older Persons
American Journal of …, 2010
OBJECTIVE: To investigate whether serum cortisol levels are associated with cognitive performance and cognitive decline in elderly persons and whether this association differs by age, sex, and depression status.DESIGN: Data from the Longitudinal Aging Study Amsterdam, with repeated measurements of cognitive performance after 3 and 6 years.PARTICIPANTS: A total of 1,154 persons, aged 65-88 years.MEASUREMENTS: Serum concentrations of total cortisol (CRT) and corticosteroid binding globulin (CBG) were measured at baseline, and from these free cortisol index (CRT/CBG) was computed. At baseline and 3 and 6 years of follow-up, global cognitive functioning, verbal memory performance, and speed of information processing were assessed.RESULTS: After adjustment for demographics, health, and life style variables, a significant association between high levels of free cortisol and poorer performance on verbal learning (B = -0.32; 95% confidence interval: -0.64 to -0.01) was found in both women and men. Additional adjustment for depression did not change this association. In women, but not in men, high levels of free cortisol (B = -0.85; 95% confidence interval: -1.40 to -0.31) were associated with slower speed of information processing. The associations between cortisol and cognitive performance were the same for the younger and the older old and for depressed and nondepressed persons. Higher levels of cortisol were not associated with cognitive decline over a period of 6 years.CONCLUSION: Our study provides further evidence that high levels of cortisol measured during the day are associated with lower memory function and speed of information processing but not with decline in cognitive functioning over 6 years of time.
Effect of High-Dose Cortisol on Memory Functions
Annals of the New York Academy of Sciences, 2006
Although research indicates that hightened glucocorticoid levels impair long-term memory functions and may inhibit traumatic memory retrieval in humans, the impact of acutely elevated glucocorticoid levels on learning and attentional functions is still unclear. Furthermore, the effect of glucocorticoids on executive functions as well as the recovery from long-term memory deficits is insufficiently studied. The present study examined memory functions in patients with acute exacerbation of neurological diseases (multiple sclerosis, acute optic neuritis), who were treated with a high dose of glucocorticoids. All patients demonstrated a reversible impairment of long-term memory functions, whereas measures of short-term memory, attentional functions, and alertness remained unaffected. These findings indicate a selective cognitive disturbance, providing further evidence that the memory deficits reflect a receptor-mediated effect of glucocorticoids on hippocampal function thereby supporting a potential association of stress-induced elevated cortisol levels and memory disturbances in trauma-related psychiatric disorders (psychogenic amnesia, PTSD).
Journal of Psychiatric Research, 2011
Many investigators have hypothesized that brain response to cortisol is altered in depression. However, neural activation in response to exogenously manipulated cortisol elevations has not yet been directly examined in depressed humans. Animal research shows that glucocorticoids have robust effects on hippocampal function, and can either enhance or suppress neuroplastic events in the hippocampus depending on a number of factors. We hypothesized that depressed individuals would show 1) altered hippocampal response to exogenous administration of cortisol, and 2) altered effects of cortisol on learning. In a repeated-measures design, 19 unmedicated depressed and 41 healthy individuals completed two fMRI scans. Fifteen mg oral hydrocortisone (i.e., cortisol) or placebo (order randomized and double-blind) was administered 1 h prior to encoding of emotional and neutral words during fMRI scans. Data analysis examined the effects of cortisol administration on 1) brain activation during encoding, and 2) subsequent free recall for words. Cortisol affected subsequent recall performance in depressed but not healthy individuals. We found alterations in hippocampal response to cortisol in depressed women, but not in depressed men (who showed altered response to cortisol in other regions, including subgenual prefrontal cortex). In both depressed men and women, cortisol's effects on hippocampal function were positively correlated with its effects on recall performance assessed days later. Our data provide evidence that in depressed compared to healthy women, cortisol's effects on hippocampal function are altered. Our data also show that in both depressed men and women, cortisol's effects on emotional memory formation and hippocampal function are related.
Persistence of abnormal cortisol levels in elderly persons after recovery from major depression
Journal of psychiatric …, 2009
Background Cortisol hypersecretion is characteristic of acute clinical depression, but little is known in fully recovered, non-treated elderly persons with a lifetime history of depression. This study was designed to examine patterns of diurnal cycle of cortisol in an elderly cohort without current depression or treatment for depression according to whether the person has or has not experienced a previous episode of depression or co-morbid depression with anxiety. Methods Cortisol secretion was evaluated in 162 community-dwelling elderly on a stressful and a non-stressful day (basal level). Past depression and anxiety disorders were assessed using a standardized psychiatric examination based on DSM-IV criteria (the Mini International Neuropsychiatric Interview). Results Antidepressant-free persons with a history of non-comorbid major depression (6.8 of the sample) showed basal cortisol % hypersecretion compared to those with depression and anxiety (8.6) or controls. Several hours after exposure to a stressful situation, % controls showed a sustained increase in cortisol secretion, which was not observed in persons with a history of depression. Persons with a history of depression with anxiety showed a similar cortisol secretion at baseline to controls but a heightened response to stressful situation; a pattern comparable to that observed in subjects with pure anxiety disorders (16.7). % Conclusion An abnormal HPA response persists even after effective treatment for depression. A history of co-morbid depression and anxiety gives rise to changes characteristic of anxiety alone. Our findings suggest that cortisol abnormalities may be trait markers for vulnerability to depression and for the differentiation of depression and depression with co-morbid anxiety.
Frontiers in Aging Neuroscience
ObjectiveElevated cortisol levels have been frequently reported in Alzheimer’s disease (AD) and linked to brain atrophy, especially of the hippocampus. Besides, high cortisol levels have been shown to impair memory performance and increase the risk of developing AD in healthy individuals. We investigated the associations between serum cortisol levels, hippocampal volume, gray matter volume and memory performance in healthy aging and AD.MethodsIn our cross-sectional study, we analyzed the relationships between morning serum cortisol levels, verbal memory performance, hippocampal volume, and whole-brain voxel-wise gray matter volume in an independent sample of 29 healthy seniors (HS) and 29 patients along the spectrum of biomarker-based AD.ResultsCortisol levels were significantly elevated in patients with AD as compared to HS, and higher cortisol levels were correlated with worse memory performance in AD. Furthermore, higher cortisol levels were significantly associated with smaller ...