Cerebrospinal Fluid Cortisol Levels Research Articles

High CSF cortisol levels are associated with frontal lobe and hippocampal atrophy across patients on the Alzheimer’s disease spectrum

AbstractBackgroundMultiple studies have linked high cerebrospinal fluid (CSF) cortisol levels, a frequently used biomarker of stress, with the Alzheimer’s disease (AD) pathophysiology. However, the relationship between CSF cortisol levels and AD‐related brain atrophy is not fully understood. Thus, this study sought to determine the association between CSF cortisol levels and neuroimaging biomarkers of brain structure indexed by magnetic resonance imaging (MRI) in patients across the AD spectrum.MethodsParticipants with baseline measures of CSF cortisol and structural (high‐resolution T1‐weighted) MRI (n = 300) were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. The MRI scans were processed with FreeSurfer (v. 7.1.1), and the statistical analyses were performed using R (v. 4.1.1; R Core Team, 2021). We performed a region‐of‐interest (ROI) analysis using a generalized linear model (GLM), to assess the association between CSF cortisol levels and (1) volume of hippocampus, amygdala, subcortical and cortical segmentation, (2) cortical thickness and (3) surface area of cortical structures (Fig. 1). The ROI analysis was corrected by Bonferroni (p < 0.0005).ResultsCSF cortisol levels did not correlate with left hippocampal volume (p = 0.2; Fig. 2A) and mean global brain thickness (p = 0.002; Fig. 2C). However, we found a negative correlation with the volume of left fimbria (r = ‐0.20, p = 0.0003; Fig. 2B) and right superior frontal thickness (r = ‐0.21, p = 0.0003; Fig. 2D). In the regression model, only right superior frontal thickness showed significant association with CSF cortisol levels after adjusting for age (corrected R2 = 0.11, p < 0.0001). The other regions and parameters analyzed did not present significant correlations with CSF cortisol levels.ConclusionsThis cross‐sectional study found an association between elevated CSF cortisol levels and atrophy of left fimbria and right superior frontal in patients on the AD spectrum. Our findings suggest a particular vulnerability to cortisol in selected regions. To the best of our knowledge, this is the first study to assess the associations between CSF cortisol levels and ROIs from hippocampus and amygdala segmentation. Our results have potential implications for understating AD‐related brain atrophy and developing innovative therapeutic strategies.

Níveis dos hormônios do eixo hipotálamo-pituitária-adrenal no líquido cefalorraquidiano de pacientes com CCL e demência devido à doença de Alzheimer: uma revisão sistemática

ABSTRACT Underlying the neuropsychological manifestations of Alzheimer’s disease (AD), hypothalamic-pituitary-adrenal (HPA) axis dysregulation and subsequent hypercortisolemia have been proposed as major mechanisms driving AD progression from mild cognitive impairment (MCI) to the onset of dementia. Nonetheless, changes in cerebrospinal fluid (CSF) levels of HPA axis hormones remain controversial despite their potential in AD diagnosis and prognosis testing. Objective: This study aimed to review the evidence of the variation in CSF levels of CRH, ACTH, and cortisol in subjects with mild cognitive impairment (MCI) and AD compared with subjects without cognitive disorders. Methods: A systematic review was conducted in MEDLINE, EMBASE, and Web of Science databases on July 5, 2022. Results: Seventeen observational studies were included. The results from the compiled investigations showed that individuals with AD exhibit a significant elevation of CSF cortisol levels which appear to correlate with the presence of the ApoE-ε4 allele, being higher in those homozygous for this allele. The variation of CSF CRH and ACTH levels in AD, on the other hand, is still inconclusive. Moreover, most studies found no significant difference in CSF cortisol levels in individuals with MCI compared to healthy subjects and patients with AD. Conclusion: The findings gathered in this review disclose a significant elevation of CSF cortisol levels in AD. Future investigations are warranted to elucidate the potential use of CSF cortisol as a biomarker in AD-associated dementia.

Cerebrospinal Fluid Cortisol and Dehydroepiandrosterone Sulfate, Alzheimer's Disease Pathology, and Cognitive Decline.

IntroductionElevated cortisol levels have been reported in Alzheimer’s disease (AD) and may accelerate the development of brain pathology and cognitive decline. Dehydroepiandrosterone sulfate (DHEAS) has anti-glucocorticoid effects and it may be involved in the AD pathophysiology.ObjectivesTo investigate associations of cerebrospinal fluid (CSF) cortisol and DHEAS levels with (1) cognitive performance at baseline; (2) CSF biomarkers of amyloid pathology (as assessed by CSF Aβ levels), neuronal injury (as assessed by CSF tau), and tau hyperphosphorylation (as assessed by CSF p-tau); (3) regional brain volumes; and (4) clinical disease progression.Materials and MethodsIndividuals between 49 and 88 years (n = 145) with mild cognitive impairment or dementia or with normal cognition were included. Clinical scores, AD biomarkers, brain MRI volumetry along with CSF cortisol and DHEAS were obtained at baseline. Cognitive and functional performance was re-assessed at 18 and 36 months from baseline. We also assessed the following covariates: apolipoprotein E (APOE) genotype, BMI, and education. We used linear regression and mixed models to address associations of interest.ResultsHigher CSF cortisol was associated with poorer global cognitive performance and higher disease severity at baseline. Cortisol and cortisol/DHEAS ratio were positively associated with tau and p-tau CSF levels, and negatively associated with the amygdala and insula volumes at baseline. Higher CSF cortisol predicted more pronounced cognitive decline and clinical disease progression over 36 months. Higher CSF DHEAS predicted more pronounced disease progression over 36 months.ConclusionIncreased cortisol in the CNS is associated with tau pathology and neurodegeneration, and with decreased insula and amygdala volume. Both CSF cortisol and DHEAS levels predict faster clinical disease progression. These results have implications for the identification of patients at risk of rapid decline as well as for the development of interventions targeting both neurodegeneration and clinical manifestations of AD.

Preoperative Cerebrospinal Fluid Cortisol and the Risk of Postoperative Delirium: A Prospective Study of Older Hip Fracture Patients

Background: Ageing, depression, and neurodegenerative disease are common risk factors for delirium in the elderly. These risk factors are associated with dysregulation of the hypothalamic-pituitary-adrenal axis, resulting in higher levels of cortisol under normal and stressed conditions and a slower return to baseline. Objectives: We investigated whether elevated preoperative cerebrospinal fluid (CSF) cortisol levels are associated with the onset of postoperative delirium. Methods: In a prospective cohort study CSF samples were collected after cannulation for the introduction of spinal anesthesia of 75 patients aged 75 years and older admitted for surgical repair of acute hip fracture. Delirium was assessed with the confusion assessment method (CAM) and the Delirium Rating Scale-Revised-98 (DRS-R98). Because the CAM and DRS-R98 were available for time of admission and 5 postoperative days, we used generalized estimating equations and linear mixed modeling to examine the association between preoperative CSF cortisol levels and the onset of postoperative delirium. Results: Mean age was 83.5 (SD 5.06) years, and prefracture cognitive decline was present in one-third of the patients (24 [33%]). Postoperative delirium developed in 27 (36%) patients. We found no association between preoperative CSF cortisol levels and onset or severity of postoperative delirium. Conclusions: These findings do not support the hypothesis that higher preoperative CSF cortisol levels are associated with the onset of postoperative delirium in elderly hip fracture patients.

Transcriptome analysis of normal-appearing white matter reveals cortisol- and disease-associated gene expression profiles in multiple sclerosis

Inter-individual differences in cortisol production by the hypothalamus–pituitary–adrenal (HPA) axis are thought to contribute to clinical and pathological heterogeneity of multiple sclerosis (MS). At the same time, accumulating evidence indicates that MS pathogenesis may originate in the normal-appearing white matter (NAWM). Therefore, we performed a genome-wide transcriptional analysis, by Agilent microarray, of post-mortem NAWM of 9 control subjects and 18 MS patients to investigate to what extent gene expression reflects disease heterogeneity and HPA-axis activity. Activity of the HPA axis was determined by cortisol levels in cerebrospinal fluid and by numbers of corticotropin-releasing neurons in the hypothalamus, while duration of MS and time to EDSS6 served as indicator of disease severity. Applying weighted gene co-expression network analysis led to the identification of a range of gene modules with highly similar co-expression patterns that strongly correlated with various indicators of HPA-axis activity and/or severity of MS. Interestingly, molecular profiles associated with relatively mild MS and high HPA-axis activity were characterized by increased expression of genes that actively regulate inflammation and by molecules involved in myelination, anti-oxidative mechanism, and neuroprotection. Additionally, group-wise comparisons of gene expression in white matter from control subjects and NAWM from (subpopulations of) MS patients uncovered disease-associated gene expression as well as strongly up- or downregulated genes in patients with relatively benign MS and/or high HPA-axis activity, with many differentially expressed genes being previously undescribed in the context of MS. Overall, the data suggest that HPA-axis activity strongly impacts on molecular mechanisms in NAWM of MS patients, but partly also independently of disease severity.

Associations between CSF cortisol and CSF norepinephrine in cognitively normal controls and patients with amnestic MCI and AD dementia.

This study evaluated the effects of Alzheimer disease (AD) on the relationship between the brain noradrenergic system and hypothalamic pituitary adrenocortical axis (HPA). Specifically, relationships between cerebrospinal fluid (CSF) norepinephrine (NE) and CSF cortisol were examined in cognitively normal participants and participants with AD dementia and amnestic mild cognitive impairment (aMCI). We hypothesized that there would a positive association between these 2 measures in cognitively normal controls and that this association would be altered in AD. Four hundred twenty-one CSF samples were assayed for NE and cortisol in controls (n=305), participants with aMCI (n=22), and AD dementia (n=94). Linear regression was used to examine the association between CSF cortisol and NE, adjusting for age, sex, education, and body mass index. Contrary to our hypothesis, CSF cortisol and NE levels were not significantly associated in controls. However, higher cortisol levels were associated with higher NE levels in AD and aMCI participants. Regression coefficients±standard errors for the change in cortisol per 100-pg/mL increase in NE are as follows: controls 0.0±0.2, P=1.0; MCI, 1.4±0.7, P=.14; and AD 1.1±0.4, P=.032. Analysis with MCI and AD participants combined strengthened statistical significance (1.2±0.3, P=.007). Enhanced responsiveness of the HPA axis to noradrenergic stimulatory regulation in AD and disruption of the blood brain barrier may contribute to these findings. Because brainstem noradrenergic stimulatory regulation of the HPA axis is substantially increased by both acute and chronic stress, these findings are also consistent with AD participants experiencing higher levels of acute and chronic stress.

Effects of Acute Confinement Stress-induced Hypothalamic-pituitary Adrenal Axis Activation and Concomitant Peripheral and Central Transforming Growth Factor-β1 Measures in Nonhuman Primates

Transforming growth factor-β1 (TGF-β1) is a multifunctional cytokine with anti-inflammatory, immunosuppressive, and neuroprotective properties. The hypothalamic-pituitary-adrenal axis and immune system exert bidirectional influences on each other, via cortisol and TGF-β1, but the exact nature of the interaction is not well characterized. The current study examined the effects, in bonnet macaques (Macaca radiata), of two consecutive acute confinement stress periods in an unfamiliar room while mildly restrained, first without and then with dexamethasone pretreatment (0.01 mg/kg intramuscular). Preceding the confinement studies, a non-stress control condition obtained contemporaneous levels of cortisol and TGF-β1 in both plasma and cerebrospinal fluid to match the confinement stress studies. Subjects were reared under either normative or variable foraging demand conditions. Since there were no rearing effects at baseline or for any of the conditions tested—either for cortisol or TGF-β—the study analyses were conducted on the combined rearing groups. The stress condition increased both plasma and cerebrospinal fluid cortisol levels whereas dexamethasone pretreatment decreased cortisol concentrations to below baseline levels despite stress. The stress condition decreased TGF-β1 concentrations only in cerebrospinal fluid but not in serum. Together, the data suggested that stress-induced reductions of a centrally active neuroprotective cytokine occur in the face of hypothalamic-pituitary-adrenal axis activation, potentially facilitating glucocortoid-induced neurotoxicity. Stress-induced reductions of neuroprotective cytokines prompt exploration of protective measures against glucocorticoid-induced neurotoxicity.

55 CORTISOL DIURNAL RHYTHM AND INFLAMMATION IN DELIRIUM AFTER HIP FRACTURE

Introduction: Delirium is a serious and common condition affecting older people. The pathophysiology is incompletely understood and there are no specific treatments. Current hypotheses suggest involvement of exaggerated cortisol release in response to stressors, and amagnified central nervous system (CNS) inflammatory response to peripheral insults. The aim of this collaborative research project was to test the hypotheses that delirium is associated with increased cortisol, increased pro-inflammatory and reduced anti-inflammatory cytokines in cerebrospinal fluid (CSF). Methods: Participants with acute hip fracture were recruited at the Royal Infirmary of Edinburgh and Oslo University Hospital. Theywere assessed for delirium pre-operatively, and at regular intervals for two weeks post-operatively. CSF was collected at the spinal anaesthetic performed for their fracture repair. Cortisol was measured by Enzyme-linked immunosorbent assay, and a highsensitivity panel of cytokines by Luminex assay (Interleukin(IL)-1 , IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IFN, GM-CSF and TNF). Group comparisonswerewith Kruskal–Wallis or Student’s t-test, and logistic regression analysis was used to adjust for potential confounders. Results: Delirium was diagnosed in 68/148 participants (46%) in the cortisol assay and 38/76 (50%) in the cytokine assay. CSF cortisol was higher in those with prevalent delirium (median 36.5nmol/L, IQR26.3–53.1) than incident (30.0nmol/L (16.8–39.2)) or never delirium (27.2nmol/L (18.8–39.3)), p=0.023. CSF cortisol level above the median was still associated with delirium after adjusting for confounders. There were no differences observed in the levels of most cytokines between groups, but IL-5 was low in those with pre-operative delirium. Conclusions: These findings support the hypothesis that delirium is associated with exaggerated cortisol release, but provide little evidence of an exaggerated CNS inflammatory response. Prolonged high cortisol increases neuronal vulnerability to damage or death from various insults. Whether high cortisol is a cause or consequence of delirium merits further detailed investigation.

Utility of cerebrospinal fluid cortisol level in acute bacterial meningitis.

Background: Meningitis remains a serious clinical problem in developing as well as developed countries. Delay in diagnosis and treatment results in significant morbidity and mortality. The role and levels of intrathecal endogenous cortisol is not known. Objective: To study the cerebrospinal fluid (CSF) cortisol levels and to evaluate its role as a diagnostic and therapeutic marker in acute bacterial meningitis. Materials and Methods: Thirty patients with acute bacterial meningitis with no prior treatment were evaluated. Cortisol levels were compared with 20 patients with aseptic (viral) meningitis and 25 control subjects. Results: Mean CSF cortisol level was 13.85, 3.47, and 1.05 in bacterial meningitis, aseptic meningitis, and controls, respectively. Mean CSF cortisol level in bacterial meningitis was significantly higher as compared to controls (P < 0.001). There was significant difference in CSFcortisol levels in bacterial and aseptic meningitis (P < 0.001). Conclusions: Cortisol levels in CSF are highly elevated in patients with acute bacterial meningitis. This suggests that intrathecalcortisol may serve as a valuable, rapid, relatively inexpensive diagnostic marker in discriminatingbetween bacterial and aseptic meningitis. This helps in earlier institution of appropriate treatment and thereby decreasing morbidity and mortality.

Estimation of cerebrospinal fluid cortisol level in tuberculous meningitis.

Background:Central nervous system (CNS) involvement in tuberculosis is around 5–10%. Of the various manifestations of CNS tuberculosis, meningitis is the most common (70–80%). Delay in diagnosis and treatment results in significant morbidity and mortality.Objective:To study the cerebrospinal fluid (CSF) cortisol levels in tubercular meningitis and compare the levels with controls.Methods:Cross-sectional, prospective, observational, hospital-based study done in 20 patients of tubercular meningitis, 20 patients of aseptic meningitis (AM) and 25 control subjects without any preexisting neurological disorders who have undergone lumbar puncture for spinal anesthesia.Results:Cortisol was detected in all 40 CSF samples of patients (100%). Mean CSF cortisol level was 8.82, 3.47 and 1.05 in tubercular meningitis, AM and controls, respectively. Mean CSF cortisol level in tubercular meningitis was significantly higher as compared to AM and controls (P < 0.0001).Conclusion:Cortisol level estimation in CSF is one of the rapid, relatively inexpensive diagnostic markers in early identification of tubercular meningitis along with CSF findings of elevated proteins, hypoglycorrhachia and lymphocytic pleocytosis. This aids in earlier institution of appropriate treatment and thereby decreasing morbidity and mortality. This is the first study on the estimation of CSF cortisol level in tuberculous meningitis.

Cerebrospinal fluid cortisol and cytokines in delirium after hip fracture

Introduction: Delirium is a serious and common condition affecting older people. The pathophysiology is incompletely understood and there are no specific treatments. Current hypotheses suggest involvement of exaggerated cortisol release in response to stressors, and amagnified central nervous system (CNS) inflammatory response to peripheral insults. The aim of this collaborative research project was to test the hypotheses that delirium is associated with increased cortisol, increased pro-inflammatory and reduced anti-inflammatory cytokines in cerebrospinal fluid (CSF). Methods: Participants with acute hip fracture were recruited at the Royal Infirmary of Edinburgh and Oslo University Hospital. Theywere assessed for delirium pre-operatively, and at regular intervals for two weeks post-operatively. CSF was collected at the spinal anaesthetic performed for their fracture repair. Cortisol was measured by Enzyme-linked immunosorbent assay, and a highsensitivity panel of cytokines by Luminex assay (Interleukin(IL)-1 , IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IFN, GM-CSF and TNF). Group comparisonswerewith Kruskal–Wallis or Student’s t-test, and logistic regression analysis was used to adjust for potential confounders. Results: Delirium was diagnosed in 68/148 participants (46%) in the cortisol assay and 38/76 (50%) in the cytokine assay. CSF cortisol was higher in those with prevalent delirium (median 36.5nmol/L, IQR26.3–53.1) than incident (30.0nmol/L (16.8–39.2)) or never delirium (27.2nmol/L (18.8–39.3)), p=0.023. CSF cortisol level above the median was still associated with delirium after adjusting for confounders. There were no differences observed in the levels of most cytokines between groups, but IL-5 was low in those with pre-operative delirium. Conclusions: These findings support the hypothesis that delirium is associated with exaggerated cortisol release, but provide little evidence of an exaggerated CNS inflammatory response. Prolonged high cortisol increases neuronal vulnerability to damage or death from various insults. Whether high cortisol is a cause or consequence of delirium merits further detailed investigation.

Utility of cerebrospinal fluid cortisol level in acute bacterial meningitis.

Background:Meningitis remains a serious clinical problem in developing as well as developed countries. Delay in diagnosis and treatment results in significant morbidity and mortality. The role and levels of intrathecal endogenous cortisol is not known.Objective:To study the cerebrospinal fluid (CSF) cortisol levels and to evaluate its role as a diagnostic and therapeutic marker in acute bacterial meningitis.Materials and Methods:Thirty patients with acute bacterial meningitis with no prior treatment were evaluated. Cortisol levels were compared with 20 patients with aseptic (viral) meningitis and 25 control subjects.Results:Mean CSF cortisol level was 13.85, 3.47, and 1.05 in bacterial meningitis, aseptic meningitis, and controls, respectively. Mean CSF cortisol level in bacterial meningitis was significantly higher as compared to controls (P < 0.001). There was significant difference in CSFcortisol levels in bacterial and aseptic meningitis (P < 0.001).Conclusions:Cortisol levels in CSF are highly elevated in patients with acute bacterial meningitis. This suggests that intrathecalcortisol may serve as a valuable, rapid, relatively inexpensive diagnostic marker in discriminatingbetween bacterial and aseptic meningitis. This helps in earlier institution of appropriate treatment and thereby decreasing morbidity and mortality.

Cerebrospinal fluid cortisol and progesterone profiles and outcomes prognostication after severe traumatic brain injury.

Despite significant advances in the management of head trauma, there remains a lack of pharmacological treatment options for traumatic brain injury (TBI). While progesterone clinical trials have shown promise, corticosteroid trials have failed. The purpose of this study was to (1) characterize endogenous cerebrospinal fluid (CSF) progesterone and cortisol levels after TBI, (2) determine relationships between CSF and serum profiles, and (3) assess the utility of these hormones as predictors of long-term outcomes. We evaluated 130 adults with severe TBI. Serum samples (n=538) and CSF samples (n=746) were collected for 6 days post-injury, analyzed for cortisol and progesterone, and compared with healthy controls (n=13). Hormone data were linked with clinical data, including Glasgow Outcome Scale (GOS) scores at 6 and 12 months. Group based trajectory (TRAJ) analysis was used to develop temporal hormone profiles delineating distinct subpopulations. Compared with controls, CSF cortisol levels were significantly and persistently elevated during the first week after TBI, and high CSF cortisol levels were associated with poor outcome. As a precursor to cortisol, progesterone mediated these effects. Serum and CSF levels for both cortisol and progesterone were strongly correlated after TBI relative to controls, possibly because of blood-brain barrier disruption. Also, differentially impaired hormone transport and metabolism mechanisms after TBI, potential de novo synthesis of steroids within the brain, and the complex interplay of cortisol and pro-inflammatory cytokines may explain these acute hormone profiles and, when taken together, may help shed light on why corticosteroid trials have previously failed and why progesterone treatment after TBI may be beneficial.

Cerebrospinal fluid cortisol concentrations in healthy elderly are affected by both APOE and TOMM40 variants

Abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis have been reported in subjects with Alzheimer's disease (AD) and may include increased cerebrospinal fluid (CSF) cortisol concentrations. Moreover, presence of the APOE ɛ4 allele, which is an established risk factor for the development of AD, has been shown to associate with higher CSF cortisol levels, especially in AD sufferers. In this study, we examined whether TOMM40 variants, which have been reported to influence age of onset of AD, also had an effect on CSF cortisol levels, in healthy, cognitively intact individuals with or without APOE ɛ4. In our results, the increase in CSF cortisol associated with the presence of the APOE ɛ4 allele was only detected when a short TOMM40 poly-T variant, shown to associate with later age of onset of AD in ɛ4 carriers, was not present. These results are consistent with previous reports (e.g., Roses et al., 2009) suggesting that TOMM40 poly-T variants influence the effects of APOE alleles.

HPA Axis Dysregulation Associated to Apolipoprotein E4 Genotype in Alzheimer's Disease

The present work investigated the involvement of cortisol and its receptors, glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), in Alzheimer's disease (AD). Cortisol was measured in cerebrospinal fluid (CSF) samples from controls, mild cognitive impairment (MCI), progressive MCI evolving to AD, and AD. CSF cortisol levels do not seem to have a prognostic value, as increases in cortisol levels were found only in AD patients. GR expression was decreased while MR expression was increased in the frontal cortex of AD. When considering degeneration (ratio to synaptophysin and the post-synaptic marker PSD95), GR expression was similar between controls and AD, suggesting that GR loss was due to synaptic degeneration in AD. Increases in cortisol levels and MR expression were associated to an apolipoprotein E4 genotype. Cognitive status was negatively associated to CSF cortisol. In apolipoprotein E4 carriers, MR but not GR expression, negatively correlated to Mini-Mental Status Examination score and positively correlated to frontal cortex amyloid-β levels. It is concluded that there is a dysregulation of the hypothalamus-pituitary-adrenal axis in AD that seems to be consequence rather than cause of AD.

Reduced cortisol levels in cerebrospinal fluid and differential distribution of 11β-hydroxysteroid dehydrogenases in multiple sclerosis: Implications for lesion pathogenesis

Relapses during multiple sclerosis (MS) are treated by administration of exogenous corticosteroids. However, little is known about the bioavailability of endogenous steroids in the central nervous system (CNS) of MS patients. We thus determined cortisol and dehydroepiandrosterone (DHEA) levels in serum and cerebrospinal fluid (CSF) samples from 34 MS patients, 28 patients with non-inflammatory neurological diseases (NIND) and 16 patients with other inflammatory neurological diseases (OIND). This revealed that MS patients – in sharp contrast to patients with OIND – show normal cortisol concentrations in serum and lowered cortisol levels in the CSF during acute relapses. This local cortisol deficit may relate to poor local activation of cortisone via 11β-hydroxysteroid dehydrogenase type 1 (11bHSD1) or to inactivation via 11bHSD2. Accordingly, 11bHSD2 was found to be expressed within active plaques, whereas 11bHSD1 was predominantly detected in surrounding “foamy” macrophages. Our study thus provides new insights into the impaired endogenous CNS cortisol regulation in MS patients and its possible relation to MS lesion pathogenesis. Moreover, an observed upregulation of 11bHSD1 in myelin-loaded macrophages in vitro suggests an intriguing hypothesis for the self-limiting nature of MS lesion development. Finally, our findings provide an attractive explanation for the effectivity of high- vs. low-dose exogenous corticosteroids in the therapy of acute relapses.

Cerebrospinal fluid cortisol levels are higher in patients with delirium versus controls

BackgroundHigh plasma cortisol levels can cause acute cognitive and neuropsychiatric dysfunction, and have been linked with delirium. CSF cortisol levels more closely reflect brain exposure to cortisol, but there are no studies of CSF cortisol levels in delirium. In this pilot study we acquired CSF specimens at the onset of spinal anaesthesia in patients undergoing hip fracture surgery, and compared CSF and plasma cortisol levels in delirium cases versus controls.FindingsDelirium assessments were performed the evening before or on the morning of operation with a standard battery comprising cognitive tests, mental status assessments and the Confusion Assessment Method. CSF and plasma samples were obtained at the onset of the operation and cortisol levels measured. Twenty patients (15 female, 5 male) aged 62 - 93 years were studied. Seven patients were diagnosed with delirium. The mean ages of cases (81.4 (SD 7.2)) and controls (80.5 (SD 8.7)) were not significantly different (p = 0.88). The median (interquartile range) CSF cortisol levels were significantly higher in cases (63.9 (40.4-102.1) nmol/L) than controls (31.4 (21.7-43.3) nmol/L; Mann-Whitney U, p = 0.029). The median (interquartile range) of plasma cortisol was also significantly higher in cases (968.8 (886.2-1394.4) nmol/L, than controls (809.4 (544.0-986.4) nmol/L; Mann Whitney U, p = 0.036).ConclusionsThese findings support an association between higher CSF cortisol levels and delirium. This extends previous findings linking higher plasma cortisol and delirium, and suggests that more definitive studies of the relationship between cortisol levels and delirium are now required.

PW01-217 - Gender differences in patients with alcohol dependence cortisol levels and stress-coping styles before and after alcohol withdrawal

Female and male alcohol dependent patients present an inhomogeneous group regarding to the drinking outcome. Stress, as well as stress-coping-styles are relevant predictive factors for the progress of alcohol dependence.MethodsSocial data, data of drinking behaviour, stress-styles and cortisol concentrations in plasma and cerebrospinal fluid (CSF) were measured in 130 patients with alcohol dependence (35F and 95M) before and after inpatient treatment.The age of onset alcohol dependence, the amount of alcohol consumption since last 3 months, the responsibility for education from children, living situation, and the practice of positive ore negative stress coping styles were investigated.ResultsFemale alcohol dependent patients show a significant higher age of onset for alcohol dependence (p=0.02) and have a significant lower consumption of alcohol in relation to male alcohol dependent patients (p=0.004).Moreover, female alcohol dependent patients are significant more frequent involved in education of children (p=0.04), and are living significant less alone (p=0.023).The cortisol levels in plasma and CSF between female and male alcohol dependent patients does not differ. However, female alcoholics show a significant higher score of negative stress-coping styles than male alcoholics (p= 0.023).ConclusionThere are significant psychosocial differences between female and male alcohol dependent patients. These gender specific differences relating to social stressors and handling with stress may be clinical relevant for treatment and outcome in alcohol-dependent patients.

Sequential analysis of biomarkers in cerebrospinal fluid and serum during invasive meningococcal disease

The aim of the present study was to determine the profile of different inflammatory molecules in serum and cerebrospinal fluid (CSF) during invasive meningococcal disease (IMD). Their relationship with IMD severity was also assessed. A cohort of 12 patients with IMD was investigated. Paired serum and CSF samples were obtained at the time of diagnostic and follow-up lumbar puncture and were examined using Luminex® analysis. IMD severity correlated with serum interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1ra) on admission. Furthermore, the CSF levels of IL-1β, IL-1ra, IL-6, IL-8, macrophage inflammatory protein-1β (MIP-1β), and monocyte chemoattractant protein-1 (MCP-1) were significantly higher than their respective serum levels. The strongest correlations were found between serum concentrations of IL-1β and IL-1ra, IL-6, IL-8, and MIP-1β, whereas the strongest correlations in CSF were found between endotoxin and IL-8, IL-17, MIP-1β, and MCP-1. As was expected, the concentrations of inflammatory molecules in both serum and CSF significantly decreased after antibiotic treatment. With regard to kinetics, a severe course of IMD correlated positively with rapid declines of CSF IL-6 and cortisol levels. Sequential multiple analyses revealed patterns of inflammatory responses that were associated with the severity of IMD, as well as with the compartmentalization and kinetics of the immune reaction.

Cortisol levels in cerebrospinal fluid correlate with severity and bacterial origin of meningitis

IntroductionOutcomes following bacterial meningitis are significantly improved by adjunctive treatment with corticosteroids. However, little is known about the levels and significance of intrathecal endogenous cortisol. The aim of this study was to assess cortisol as a biological and diagnostic marker in patients with bacterial meningitis.MethodsForty-seven consecutive patients with bacterial meningitis and no prior treatment were evaluated. For comparison, a group of 37 patients with aseptic meningitis and a group of 13 healthy control individuals were included.ResultsThe mean age of the bacterial meningitis patients was 42 years, and the mean Glasgow Coma Scale, Acute Physiology and Chronic Health Evaluation II, and Sequential Organ Failure Assessment scores on admission were 12, 13 and 4, respectively. Altogether, 40 patients (85%) were admitted to the intensive care unit, with a median (interquartile range) length of stay of 8 (4 to 15) days. A bacterial etiology was confirmed in 35 patients (74%). The median (interquartile range) cortisol concentration in cerebrospinal fluid (CSF) was 133 (59 to 278) nmol/l. CSF cortisol concentrations were positively correlated with serum cortisol levels (r = 0.587, P < 0.001). Furthermore, CSF cortisol levels correlated with Acute Physiology and Chronic Health Evaluation II score (r = 0.763, P < 0.001), Sequential Organ Failure Assessment score (r = 0.650, P < 0.001), Glasgow Coma Scale score (r = -0.547, P < 0.001) and CSF lactate levels (r = 0.734, P < 0.001). CSF cortisol was only weakly associated with intrathecal levels of IL-6 (r = 0.331, P = 0.02) and IL-8 (r = 0.296, P < 0.05). CSF cortisol levels in bacterial and aseptic meningitis significantly differed (P < 0.001). The CSF cortisol concentration of 46.1 nmol/l was found to be the optimal cutoff value for diagnosis of bacterial meningitis.ConclusionCSF cortisol levels in patients with bacterial meningitis are highly elevated and correlate with disease severity. Moreover, our findings also suggest that intrathecal cortisol may serve as a valuable marker in discriminating between bacterial and aseptic meningitis.