Cortisol Dysregulation Research Articles

Autonomous cortisol secretion promotes vascular calcification in vivo and in vitro under hyperaldosteronism.

Autonomous cortisol secretion (ACS) is not uncommon in patients with primary aldosteronism (PA). However, the cardiovascular burden of ACS due to its dysregulated cortisol secretion remains poorly understood. Thus, we examined the effects of ACS on vascular calcification in a hyperaldosteronism environment in vitro and in vivo. A total of 339 patients with PA with adrenal incidentaloma and low-dose dexamethasone suppression test data (cutoff level: cortisol > 1.8 μg/dL) from a prospectively maintained database were enrolled; abdominal aortic calcification (AAC) scores were quantitatively estimated. Human aortic smooth muscle cells (HAOSMCs) were used as in vitro model of vascular calcification. In this study, 65 of the 339 patients with PA had ACS; 274 did not. Patients with PA/ACS had a higher AAC score (1171.0 ± 2434.0 vs. 489.5 ± 1085.3, P = 0.012) than patients without ACS. ACS was independently associated with AAC score (β = 0.139, P = 0.004) in multivariate analysis, and post-suppression cortisol level was significantly correlated with the AAC score (P = 0.004). In the HAOSMC model, co-treatment with cortisol synergistically stimulated alkaline phosphatase activity and calcium deposition in a hyperaldosteronism environment. The stimulatory effect of cortisol was abolished by the mineralocorticoid receptor (MR) antagonist eplerenone, but not glucocorticoid receptor antagonist mifepristone, indicating a MR-dependent mechanism. In conclusion, the presence of ACS is associated with heavier vascular calcification in patients with PA. Aldosterone and cortisol synergistically activate HAOSMC calcification via MR signaling, via a process that can be attenuated by eplerenone.

Impact of Modern Lifestyle on Circadian Health and Its Contribution to Adipogenesis and Cancer Risk.

Recent research underscores a crucial connection between circadian rhythm disruption and cancer promotion, highlighting an urgent need for attention. Explore the molecular mechanisms by which modern lifestyle factors-such as artificial light exposure, shift work, and dietary patterns-affect cortisol/melatonin regulation and cancer risk. Employing a narrative review approach, we synthesized findings from Scopus, Google Scholar, and PubMed to analyze lifestyle impacts on circadian health, focusing on cortisol and melatonin chronobiology as molecular markers. We included studies that documented quantitative changes in these markers due to modern lifestyle habits, excluding those lacking quantitative data or presenting inconclusive results. Subsequent sections focused solely on articles that quantified the effects of circadian disruption on adipogenesis and tumor microenvironment modifications. This review shows how modern habits lead to molecular changes in cortisol and melatonin, creating adipose microenvironments that support cancer development. These disruptions facilitate immune evasion, chemotherapy resistance, and tumor growth, highlighting the critical roles of cortisol dysregulation and melatonin imbalance. Through the presented findings, we establish a causal link between circadian rhythm dysregulation and the promotion of certain cancer types. By elucidating this relationship, the study emphasizes the importance of addressing lifestyle factors that contribute to circadian misalignment, suggesting that targeted interventions could play a crucial role in mitigating cancer risk and improving overall health outcomes.

Depressive and Anxious Symptoms, Experimentally Manipulated Acute Social-Evaluative Threat, and Cortisol Reactivity.

Exposure to social-evaluative threat (SET) can elicit greater physiological responses, including cortisol, compared to non-SET stressors. An individual's level of depressive and anxious symptoms predicts variability in cortisol responses to stressors, and other research suggests that these individual differences may predict vulnerability to social evaluation. The current study integrates both lines of research, testing if there are different relationships between depressive and/or anxious symptoms and cortisol reactivity in the presence or absence of SET. Healthy undergraduate students ( N = 158, 65% female) were randomly assigned to deliver a speech in the presence (SET) or absence (non-SET) of two evaluators. Salivary cortisol was collected throughout, and self-reported depressive and anxious symptoms were assessed. We hypothesized that in the SET condition, higher levels of depressive and/or anxious symptoms would predict dysregulated cortisol responses compared to lower levels of symptoms and/or assignment to the non-SET group. In spite of inconclusive p values (which might be attributed to low statistical power), individuals with high depressive or high anxious symptoms appeared to have exaggerated cortisol responses in the SET condition, as indicated by more concave trajectories. This study suggests that both depression and anxiety could be associated with increased cortisol reactivity to SET.

Neurobiological Implications of Chronic Stress and Metabolic Dysregulation in Inflammatory Bowel Diseases.

Chronic stress is a significant factor affecting modern society, with profound implications for both physical and mental health. Central to the stress response is cortisol, a glucocorticoid hormone produced by the adrenal glands. While cortisol release is adaptive in acute stress, prolonged exposure to elevated levels can result in adverse effects. This manuscript explores the neurobiological implications of chronic stress and its impact on metabolic dysregulation, particularly in the context of inflammatory bowel diseases (IBDs). The hypothalamic-pituitary-adrenal (HPA) axis regulates cortisol production, which influences metabolism, immune response, and neurobiology. Elevated cortisol levels are associated with the development and exacerbation of metabolic disorders like IBD and contribute to neurodegenerative processes, including cognitive impairments and increased susceptibility to psychiatric conditions. The interaction between cortisol and its receptors, particularly glucocorticoid receptors, underscores the complexity of these effects. This review aims to elucidate the mechanisms through which chronic stress and cortisol dysregulation impact metabolic health and neurobiological function, providing insights into potential therapeutic strategies for mitigating these effects.

Neuroinflammation, cerebrovascular dysfunction and diurnal cortisol biomarkers in a memory clinic cohort: Findings from the Co-STAR study

Cortisol dysregulation, neuroinflammation, and cerebrovascular dysfunction are biological processes that have been separately shown to be affected in Alzheimer’s disease (AD). Here, we aimed to identify biomarker signatures reflecting these pathways in 108 memory clinic patients with subjective cognitive decline (SCD, N = 40), mild cognitive impairment (MCI, N = 39), and AD (N = 29). Participants were from the well-characterized Cortisol and Stress in Alzheimer’s Disease (Co-STAR) cohort, recruited at Karolinska University Hospital. Salivary diurnal cortisol measures and 41 CSF proteins were analyzed. Principal component analysis was applied to identify combined biosignatures related to AD pathology, synaptic loss, and neuropsychological assessments, in linear regressions adjusted for confounders, such as age, sex, education and diagnosis. We found increased CSF levels of C-reactive protein (CRP), interferon γ-inducible protein (IP-10), thymus and activation-regulated chemokine (TARC), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in MCI patients. Further, markers of cortisol dysregulation (flattened salivary cortisol awakening response and flattened cortisol slope) correlated with increased levels of placental growth factor (PlGF), IP-10, and chitinase 3-like 1 (YKL-40) in the total cohort. A biosignature composed of cortisol awakening response, cortisol slope, and CSF IL-6 was downregulated in AD patients. Moreover, biomarker signatures reflecting overlapping pathophysiological processes of neuroinflammation and vascular injury were associated with AD pathology, synaptic loss, and worsened processing speed. Our findings suggest an early dysregulation of immune and cerebrovascular processes during the MCI stage and provide insights into the interrelationship of chronic stress and neuroinflammation in AD.

Abstract P218: Resistant hypertension is associated with elevated 24-hour cortisol to cortisone ratios in black patients.

Background: RHTN is defined as blood pressure above goal despite using ≥3 antihypertensive medications. Patients with RHTN are at an increased risk for cardiovascular (CVD) compared to those with more easily controlled hypertension (HTN). Blacks With RHTN are at a specifically high risk for CVD. Mineralocorticoid receptor activation has been found as an important mechanism of RHTN. However, aldosterone levels are not different in blacks versus whites. The role of 24-hour cortisol-to-cortisone ratios in this group has not been investigated. Methods: We conducted a cross-sectional analysis of a large cohort of 2397 black and white patients with RHTN who were referred to the RHTN Clinic at the University of Alabama at Birmingham and who underwent 24-hour urine collection including cortisol and cortisone. Patients with HTN served as a control group. Results: Black patients with RHTN compared to whites had a trend to higher 24h cortisol levels (17.7±27.6 vs 16.9±14.9, p =0.70, significantly lower 24h cortisone levels (60.45±37.7 vs 75.3±40.0, p 0.000234), and significantly higher 24h cortisol-to-cortisone ratios (0.23±0.14 vs 0.20 ±0.10, p=0.027). They were younger (53.3±11.6 vs 59.4±12.9 years), more obese (BMI 34.9±7.6 vs 30.8±6.1 kg/m2, p<0.001), had earlier onset of HTN (35.6±12.5 vs 41.4±11.6 years of age, p<0.001), higher 24-hour urinary sodium excretion (188.2±92.5 vs 174.9±83.1 mmol, p=0.006) and lower potassium excretion (54.5 ±28.6 vs 65.5 ±30.5 mmol, p<0.001). Furthermore, they had a significantly higher rate of heart failure (p=0.000455) and diabetes (p=0.0006). Conclusion: Cortisol dysregulation and a higher cortisol-to-cortisone ratio as an index of 11beta HSD2 activity may play a role in black patients with RHTN and may be related to adverse outcomes in this population.

Prenatal treatment with corticosterone via maternal injection induces learning and memory impairments via delaying postsynaptic development in hippocampal CA1 neurons of rats.

Previously, we reported that prenatal exposure to high corticosterone induced attention-deficit hyperactivity disorder (ADHD)-like behaviors with cognitive deficits after weaning. In the present study, cellular mechanisms underlying cortisol-induced cognitive dysfunction were investigated using rat pups (Corti.Pups) born from rat mothers that were repetitively injected with corticosterone during pregnancy. In results, Corti.Pups exhibited the failure of behavioral memory formation in the Morris water maze (MWM) test and the incomplete long-term potentiation (LTP) of hippocampal CA1 neurons. Additionally, glutamatergic excitatory postsynaptic currents (EPSCs) were remarkably suppressed in Corti.Pups compared to normal rat pups. Incomplete LTP and weaker EPSCs in Corti.Pups were attributed to the delayed postsynaptic development of CA1 neurons, showing a higher expression of NR2B subunits and lower expression of PSD-95 and BDNF. These results indicated that the prenatal treatment with corticosterone to elevate cortisol level might potently downregulate the BDNF-mediated signaling critical for the synaptic development of hippocampal CA1 neurons during brain development, and subsequently, induce learning and memory impairment. Our findings suggest a possibility that the prenatal dysregulation of cortisol triggers the epigenetic pathogenesis of neurodevelopmental psychiatric disorders, such as ADHD and autism.

Placental Cortisol Dysregulation in Mothers with Experiences of Childhood Adversity: Potential Mechanisms and Clinical Implications.

Adverse childhood experiences (ACEs) are extremely prevalent in the United States population. Although ACEs occurs in childhood, exposure to them has been associated with adverse future pregnancy outcomes and an increased risk of poorer social determinants of health, which further drive the risk of negative pregnancy outcomes. In addition, maternal ACE exposure has been linked to poor infant and child outcomes, highlighting the intergenerational transmission of risk from mother to child. While alterations along the Maternal-Placental-Fetal Hypothalamic-pituitary-adrenal (HPA) axis is hypothesized to be involved, the exact biological pathway underlying this intergenerational passage of risk is mostly unknown. This present work will highlight what is known about pregnancy-related stress hormone physiology, discuss the potential mechanisms of action of ACEs on cortisol regulation, and suggest opportunities for further clinical and translational studies.

Diurnal cortisol, neuroinflammation, and neuroimaging visual rating scales in memory clinic patients

BackgroundNeuroinflammation is a hallmark of the Alzheimer’s disease (AD) pathogenic process. Cortisol dysregulation may increase AD risk and is related to brain atrophy. This cross-sectional study aims to examine interactions of cortisol patterns and neuroinflammation markers in their association with neuroimaging correlates. Method134 participants were recruited from the Karolinska University Hospital memory clinic (Stockholm, Sweden). Four visual rating scales were applied to magnetic resonance imaging or computed tomography scans: medial temporal lobe atrophy (MTA), global cortical atrophy (GCA), white matter lesions (WML), and posterior atrophy. Participants provided saliva samples for assessment of diurnal cortisol patterns, and underwent lumbar punctures for cerebrospinal fluid (CSF) sampling. Three cortisol measures were used: the cortisol awakening response, total daily output, and the ratio of awakening to bedtime levels. Nineteen CSF neuroinflammation markers were categorized into five composite scores: proinflammatory cytokines, other cytokines, angiogenesis markers, vascular injury markers, and glial activation markers. Ordinal logistic regressions were conducted to assess associations between cortisol patterns, neuroinflammation scores, and visual rating scales, and interactions between cortisol patterns and neuroinflammation scores in relation to visual rating scales. ResultHigher levels of angiogenesis markers were associated with more severe WML. Some evidence was found for interactions between dysregulated diurnal cortisol patterns and greater neuroinflammation-related biomarkers in relation to more severe GCA and WML. No associations were found between cortisol patterns and visual rating scales. ConclusionThis study suggests an interplay between diurnal cortisol patterns and neuroinflammation in relation to brain structure. While this cross-sectional study does not provide information on causality or temporality, these findings suggest that neuroinflammation may be involved in the relationship between HPA-axis functioning and AD.

The Pathophysiology of Scoliosis Across the Spectrum of Human Physiological Systems

Scoliosis is a medical condition characterized by an abnormal lateral curvature of the spine. It can lead to various health issues, affecting mobility, respiratory function, and overall quality of life. There are several types of scoliosis, including idiopathic, congenital, neuromuscular, degenerative, and functional. The severity of scoliosis is measured by the degree of spinal curvature, typically expressed in degrees through a system known as the Cobb angle. Early detection and intervention are fundamental in managing scoliosis, as more severe forms may necessitate bracing or surgical intervention. Healthcare professionals must understand the different types of scoliosis and their unique characteristics to tailor appropriate treatment plans.Scoliosis can significantly impact various physiological systems, including the circulatory, digestive, endocrine, integumentary, lymphatic, muscular, nervous, and respiratory systems. In the circulatory system, scoliosis can cause hemodynamic changes, impaired venous return, cardiac strain, and pulmonary complications. In the digestive system, scoliosis can lead to gastric displacement, impaired intra-abdominal pressure, gastroesophageal reflux, and nutritional implications. The endocrine system can be affected by scoliosis, leading to neuroendocrine dysregulation, growth hormone abnormalities, cortisol dysregulation, and impact on thyroid function. Scoliosis can also affect the integumentary system, leading to pressure ulcers, altered skin sensation, and hygiene challenges. In the lymphatic system, scoliosis can cause lymphatic obstruction, impaired immune response, altered inflammatory responses, fibrosis, and secondary lymphedema. Scoliosis can affect the muscular system, leading to muscle imbalance, myofascial pain, respiratory muscle weakness, and mobility issues. The nervous system can also be impacted by scoliosis, leading to neural compression, central nervous system impact, neurological dysfunction, and coordination challenges. In the respiratory system, scoliosis can cause thoracic deformities, reduced lung compliance, ventilation-perfusion mismatch, respiratory muscle weakness, increased work of breathing (WOB), and an increased risk of respiratory infections.Recognizing and addressing the interplay between scoliosis and these physiological systems is integral for healthcare professionals to provide comprehensive care to individuals with scoliosis.Current research on scoliosis has made progress in diagnostic tools and techniques, including the use of imaging methods like MRI and X-ray, wearable sensors, and 3D reconstruction techniques for better evaluation of spinal motion and function, along with treatment strategies like Schroth exercises and braces, and management measures for respiratory and circulatory problems. However, there are limitations to current studies, such as the heterogeneity of scoliosis, compartmentalized approaches, limited longitudinal studies, reliance on retrospective data, and the need for standardized measures and diagnostic criteria. Future research prospects include advancements in genetic research, biomechanics, artificial intelligence and machine learning, longitudinal studies, non-invasive treatments, and multidisciplinary collaborations among researchers, clinicians, and technologists.

Prenatal exposure to social adversity and infant cortisol in the first year of life

Exposure to social adversity has been associated with cortisol dysregulation during pregnancy and in later childhood; less is known about how prenatal exposure to social stressors affects postnatal cortisol of infants. In a secondary analysis of data from a longitudinal study, we tested whether a pregnant woman’s reports of social adversity during the third trimester were associated with their infant’s resting cortisol at 1, 6, and 12 months postnatal. Our hypothesis was that prenatal exposure to social adversity would be associated with elevation of infants’ cortisol. Measures included prenatal survey reports of social stressors and economic hardship, and resting cortisol levels determined from infant saliva samples acquired at each postnatal timepoint. Data were analyzed using linear mixed effects models. The final sample included 189 women and their infants (46.56% assigned female sex at birth). Prenatal economic hardship was significantly associated with infant cortisol at 6 months postnatal; reports of social stressors were not significantly associated with cortisol at any time point. Factors associated with hardship, such as psychological distress or nutritional deficiencies, may alter fetal HPA axis development, resulting in elevated infant cortisol levels. Developmental changes unique to 6 months of age may explain effects at this timepoint. More work is needed to better comprehend the complex pre- and post-natal physiologic and behavioral factors that affect infant HPA axis development and function, and the modifying role of environmental exposures.

Postpartum symptoms of anxiety, depression and stress: differential relationships to women’s cortisol profiles

PurposeWomen are at high risk of stress, anxiety, and depression during the postpartum but the ways in which these different types of psychological distress are related to cortisol regulation is not clear. We examined the distinct association of each type of distress with women’s average cortisol level, cortisol awakening response (CAR), cortisol decline across the day (diurnal slope), and overall amount of cortisol secretion across the day (AUCG).MethodsAt 6 months postpartum, a diverse group of 58 women completed measures of depression, anxiety, perceived stress, and life stressors. Each woman provided 4 salivary samples for cortisol assay from waking to bedtime on each of 2 consecutive days. Linear regressions were used to examine associations of stress, anxiety and depression to each of the 4 cortisol measures, controlling for number of stressful life events.ResultsDepressive symptoms were associated with less of a rise in the CAR (β = -.46, p = 0.01), steeper diurnal slope (β = .51, p = 0.006), and higher average cortisol level (β = .42, p = .01). Women who met the clinical cutoff for an anxiety disorder had lower overall cortisol output (β = -.29, p = 0.03). Stress was not related to any cortisol metric.ConclusionsFindings suggest that stress is less associated with cortisol alterations in the postpartum than are more severe types of psychological distress. Anxiety and depression may have distinct and opposite profiles of cortisol dysregulation. Results indicate that mental health assessment is critical even in the later postpartum so that interventions can be initiated to reduce emotional suffering and the risk of impaired cortisol regulation.

Daytime Sleepiness, Apnea, Neuroimaging Correlates and Cortisol Dysregulation in a Memory Clinic Cohort

Daytime Sleepiness, Apnea, Neuroimaging Correlates and Cortisol Dysregulation in a Memory Clinic Cohort

Life-course stress, cognition, and diurnal cortisol in memory clinic patients without dementia

AimsTo examine associations of life-course stress with cognition and diurnal cortisol patterns in older adulthood, as well as potential mediation effects of diurnal cortisol patterns and perceived stress on the association between life-course stress and cognition. Methods127 participants without dementia were selected from a cohort of Swedish memory clinic patients. Cross-sectional associations between scores on two chronic stress questionnaires (perceived stress, stressful life events (SLEs)), five cognitive domains (overall cognition, memory, working memory, processing speed, perceptual reasoning), and two measures of diurnal cortisol patterns (total daily output, diurnal cortisol slope), as well as potential mediation effects of diurnal cortisol patterns and perceived stress on associations between life-course stress and cognition, were assessed using linear regressions. ResultsGreater lifetime exposure to SLEs was associated with worse memory, working memory, and processing speed performance, but not with diurnal cortisol patterns. A greater number of SLEs in late childhood was associated with worse working memory and processing speed, while a greater number of SLEs in non-recent adulthood were associated with better overall cognition and perceptual reasoning. Greater perceived stress was associated with a flattened diurnal cortisol slope, but not with cognition. No evidence for interplay between self-reported and physiological stress markers was found in relation to cognition, although there appeared to be a significant positive indirect association between economic/legal SLEs and the diurnal cortisol slope via perceived stress. ConclusionsThe associations between SLEs and cognition depend on the period during which SLEs occur, but seem independent of late-life cortisol dysregulation.

Growth hormone deficiency in the neurocritical patient

Growth hormone (GH) is synthesized in the anterior pituitary, but its production and release are controlled by two neurohormones found in the hypothalamus: somatostatin and growth hormone-releasing hormone (GHRH). GH supports bone growth, regeneration of neurons, astrocytes, endothelial cells, oligodendrocytes, and even neuronal myelination. It is also responsible for stimulating the growth and differentiation of cells from different tissues and cell types, thereby contributing to protein synthesis. Original research papers, case reports, and case series on GH deficiency among neurocritical patients were thoroughly examined in this review. After extensive study, 13 articles were selected for the analysis. Traumatic lesions are defined by distortion of the brain tissue and subsequent biochemical modifications, which can affect GH secretion. The majority of researchers identified fractures, trauma, and bleeding as the mechanical causes of GH deficiency, and subarachnoid haemorrhage (SAH) or traumatic brain injury (TBI) as the etiology. The dysregulation of certain other hormones, including ACTH, Cortisol, Gonadotropin, Prolactin, FSH, TSH, Testosterone, and Hydrocortisone is also related to GH insufficiency. Growth hormone deficiency can cause complications such as hypothyroidism, hypotension, hypoxia, adrenal insufficiency, electrolyte imbalance, hyperprolactinemia, depression, anxiety, concussions, seizures, vomiting, and loss of consciousness. According to previous studies, GH insufficiency is significantly affected by age, body mass index (BMI), pituitary dysfunction, and hypogonadism. GH treatment is widely used in patients with GH deficiency, as it has more benefits than harm. The GH dose should be individualized to minimize side effects and maximize clinical efficacy.

Cross-sectional analysis reveals COVID-19 pandemic community lockdown was linked to dysregulated cortisol and salivary alpha amylase in children.

The COVID-19 pandemic altered everyday life starting in March 2020. These alterations extended to the lives of children as their normal routines were disrupted by community lockdowns, online learning, limited in-person social contact, increased screen time, and reduced physical activity. Considerable research has investigated the physical health impact of COVID-19 infection, but far fewer studies have investigated the physiological impact of stressful pandemic-related changes to daily life, especially in children. The purpose of this study was to leverage an ongoing clinical trial to investigate physiological consequences associated with chronic stress of pandemic community lockdown on children. As a part of the clinical trial, children provided saliva samples. Saliva samples were analyzed for cortisol and salivary alpha amylase (sAA) content. This secondary cross-sectional analysis included 94 preadolescent children located within the Greater Boston, Massachusetts community. Children participated in the study either before, during, or following the pandemic community lockdown to form three groups for comparison. In response to chronic stress caused by the pandemic community lockdown, participants demonstrated dysregulation of fast-acting catecholamine response of the locus-coeruleus-norepinephrine system and slower-acting glucocorticoid response, resulting in an asymmetrical relationship of hypocortisolism (M = 0.78 ± 0.19 μg/mL, p < 0.001) paired with higher sAA (M = 12.73 ± 4.06 U/mL, p = 0.01). Results suggest that the abrupt COVID-19 disruption to daily life, including the stressful experience of community lockdown, had physiological effects on typically developing children. Further research is required to investigate mental health outcomes of children following the chronic stress of the pandemic community lockdown.

The role of sleep quality in the pathogenesis and management of Type 2 diabetes

With a growing prevalence of both Type 2 diabetes and sleep disturbances in the population, emerging evidence suggests a potential link between sleep quality and diabetes. This review explores the role of sleep quality in Type 2 diabetes, including its association with glycemic control and the potential of sleep interventions in management. The review clarifies underlying mechanisms connecting sleep disturbances to diabetes, encompassing cortisol, melatonin, ghrelin, and leptin dysregulation. Sleep quality affects emotional well-being, contributing to stress-related insulin resistance. Exploring the intricate connection between sleep quality and glycemic control uncovers intricate patterns involving HbA1c levels and intriguing gender disparities. However, the obstacle of patient adherence underscores the necessity for nuanced strategies, including personalized approaches. The implications for diabetes management and public health resonate through adaptable care during challenging circumstances, evidence-based population health strategies, and proactive prevention efforts. Adaptable care methods, rooted in telehealth and individualized support, ensure uninterrupted diabetes management. Early intervention and prevention programs can forestall prediabetes progression, necessitating proactive public health initiatives. This review showcases the links between sleep quality and Type 2 diabetes, revealing a landscape where sleep interventions hold potential, but also emphasizing the need for holistic, patient-centered approaches in diabetes management.

Sleep disturbances, cortisol, and neuroimaging correlates among memory clinic patients

AbstractBackgroundSleep disturbances are increasingly acknowledged as a preclinical marker for Alzheimer’s disease (AD), however, the mechanisms underlying the association between sleep disturbances and dementia remain unclear. Sleep disturbances may affect AD through brain morphology changes and vascular damage, as sleep disturbances are known to be linked with altered grey‐ and white‐matter integrity. Moreover, sleep and brain changes may be linked with cortisol levels. Sleep disturbances have been proposed to parallel cortisol dysregulation, and older individuals with preclinical AD have altered awakening cortisol, a feature that is intensified among people also suffering from sleep disturbances.MethodThe study is based on 146 memory clinic patients from the Karolinska University Hospital memory clinic (Sweden). Participants are in the age range 47‐86 years and diagnosed with either subjective cognitive impairment or mild cognitive impairment. Self‐reported sleep disturbances are measured by the Karolinska Sleep Questionnaire. Brain imaging (MRI or CT) was used to semi‐quantify brain atrophy using four visual rating scales: Medial Temporal Atrophy, Global Cortical Atrophy, Koedam (posterior brain atrophy) and Fazekas (white‐matter lesions) scales. Lastly, saliva cortisol has been sampled 6 times daily to measure diurnal cortisol patterns.ResultOrdinal logistic regressions show significant associations between sleep disturbances and brain parameters. Insufficient sleep (OR = 1.30, p = 0.048) is associated with greater odds of white‐matter lesions, and apnea (OR = 1.26, p = 0.036) and snoring (OR = 1.38, p = 0.045) are associated with greater odds of posterior brain atrophy. Increased daytime sleepiness is associated with both reduced awakening cortisol (β = ‐0.03, p = 0.025) and a flattened cortisol curve (β = ‐0.04, p = 0.019). Apnea is associated with reduced awakening cortisol (β = ‐0.06, p = 0.013). However, cortisol was not found to significantly interact with sleep in predicting brain outcomes.ConclusionThese results show that various sleep disturbance parameters (short sleep duration, apnea, and snoring) are associated with neuroimaging correlates, while daytime sleepiness and apnea are associated with markers of dysregulated cortisol patterns. The results suggest that neuroimaging correlates and cortisol measures may clarify the mechanisms underlying the associations between sleep disturbance and cognitive impairment, and the combination of objective sleep measures and neuroimaging markers in future studies may further reveal the mechanisms.

Higher circulating cortisol is associated with amyloidogenesis in post‐menopausal women: The Framingham Heart Study

AbstractBackgroundReports of a correlation between higher baseline cortisol and faster progression of Alzheimer’s disease (AD) in longitudinal cohorts and more advanced AD pathology in cross sectional studies raise the possibility that cortisol dysregulation contributes to AD pathogenesis. The current data, however, is less strong with regards to possible mechanisms underlying this relationship or the direction of influence between higher cortisol and AD severity. The goal of this study was to examine the associations between cortisol levels and incident cerebral amyloid and tau PET deposition.MethodsWe present a prospective cohort study of cognitively normal individuals derived from Framingham Heart Study (generation 3‐mean age 39.6±8.1 years, 48.5% women) who had measures of fasting morning plasma cortisol at baseline and PET measures of brain amyloid and tau 15±1.6 years later. Fasting cortisol levels were examined as tertitles (Cortisol level (min,max)‐ T1:3.92‐11.12; T2:11.13‐15.50; T3:15.76‐50.07). Linear regression was used to evaluate associations baseline plasma cortisol (in tertiles) with amyloid and tau deposition, adjusted for age, sex, and the duration between cortisol and PET imaging assessments. We assessed interactions by ApoE4 positivity, sex and menopausal status (women only).ResultsWe found no association between serum cortisol and amyloid/tau burden, and no significant interaction with age or ApoE4 status. However, the association between cortisol and amyloid retention interacted significantly with sex in our primary regions of interest (posterior cingulate cortex [PCC] β:0.059±0.027, p = 0.031; precuneus [PC] 0.071±0.025, 0.005, and whole brain [represented by FLR] 0.039±0.014, 0.006). Comparing the highest relative to the middle cortisol (the referent) tertiles among women, amyloid deposition was higher in PCC (β±SE: 0.059±0.027, p = 0.031), PC (0.071±0.025, 0.005), and FLR ROIs (0.039±0.014, p = 0.006). The same relationships did not hold in men or in relations to tau. Furthermore, the effect was only present in postmenopausal women, with the higher amyloid deposition in PC (β:0.103±0.040, p = 0.012) and FLR ROIs (0.071±0.020, 0.001) as well as superior temporal sulcus (secondary outcome). We did not observe any statistically significant association comparing bottom to the middle cortisol tertile.ConclusionAlthough future research is needed, the results suggest that serum cortisol may contribute to Alzheimer’s pathogenesis by driving amyloidogenesis in postmenopausal women.

The Role of Cortisol in Chronic Stress, Neurodegenerative Diseases, and Psychological Disorders.

Cortisol, a critical glucocorticoid hormone produced by the adrenal glands, plays a pivotal role in various physiological processes. Its release is finely orchestrated by the suprachiasmatic nucleus, governing the circadian rhythm and activating the intricate hypothalamic-pituitary-adrenal (HPA) axis, a vital neuroendocrine system responsible for stress response and maintaining homeostasis. Disruptions in cortisol regulation due to chronic stress, disease, and aging have profound implications for multiple bodily systems. Animal models have been instrumental in elucidating these complex cortisol dynamics during stress, shedding light on the interplay between physiological, neuroendocrine, and immune factors in the stress response. These models have also revealed the impact of various stressors, including social hierarchies, highlighting the role of social factors in cortisol regulation. Moreover, chronic stress is closely linked to the progression of neurodegenerative diseases, like Alzheimer's and Parkinson's, driven by excessive cortisol production and HPA axis dysregulation, along with neuroinflammation in the central nervous system. The relationship between cortisol dysregulation and major depressive disorder is complex, characterized by HPA axis hyperactivity and chronic inflammation. Lastly, chronic pain is associated with abnormal cortisol patterns that heighten pain sensitivity and susceptibility. Understanding these multifaceted mechanisms and their effects is essential, as they offer insights into potential interventions to mitigate the detrimental consequences of chronic stress and cortisol dysregulation in these conditions.