ObjectiveThis study aims to investigate the relationship between diurnal cortisol patterns, cognition and Alzheimer’s disease (AD) biomarkers in memory clinic patients.MethodMemory clinic patients ...were recruited from Karolinska University Hospital in Sweden (n=155). Diurnal cortisol patterns were assessed using five measures: awakening levels, cortisol awakening response, bedtime levels, the ratio of awakening to bedtime levels (AM/PM ratio) and total daily output. Cognition was measured in five domains: memory, working memory, processing speed, perceptual reasoning and overall cognition. AD biomarkers Aβ42, total tau and phosphorylated tau were assessed from cerebrospinal fluid (CSF). Cognition was measured at follow-up (average 32 months) in a subsample of participants (n=57).ResultsIn assessing the associations between cortisol and cognition, higher awakening cortisol levels were associated with greater processing speed at baseline. No relationship was found between diurnal cortisol patterns and change in cognition over time or CSF AD biomarkers in the total sample. After stratification by CSF Aβ42 levels, higher awakening cortisol levels were associated with worse memory performance in amyloid-positive participants. In amyloid-negative participants, higher bedtime cortisol levels and a lower AM/PM ratio were associated with lower overall cognition, greater awakening cortisol levels were associated with better processing speed, and a higher AM/PM ratio was associated with better perceptual reasoning. Additionally, higher awakening cortisol levels were associated with lower CSF Aβ42 levels in amyloid-positive participants, while higher bedtime cortisol levels and a lower AM/PM ratio were associated with higher CSF total tau in amyloid-negative participants.ConclusionsOur findings suggest that diurnal cortisol patterns are associated with cognitive function and provide new insights into the association between diurnal cortisol patterns and AD-related CSF biomarkers. Further research is needed to examine the complex relationship between cortisol, cognition and brain pathology.
Allostatic load (AL) is defined as the cumulative dysregulation of neuroendocrine, immunological, metabolic, and cardiovascular systems that increases the susceptibility to stress-related health ...problems. Several dementia and Alzheimer's disease (AD) risk factors have been identified, yet little is known about the role of AL and its associations with AD biomarkers (e.g., beta-amyloid (Aβ) or tau) and cognitive function among memory clinic patients. Hence, this study aims to assess the association between AL and AD biomarkers, cognitive performance, and cognitive decline after 3-years of follow-up.
Data from 188 memory clinic patients were derived from the Cortisol and Stress in AD (Co-STAR) study in Sweden. Participants underwent baseline assessments including blood tests for AL measures (including cortisol, thyroid stimulating hormone, cobalamin, homocysteine, leukocytes, glycated hemoglobin, albumin, high-density and low-density lipoprotein cholesterol, triglycerides, and creatinine), cerebrospinal fluid (CSF) sampling for AD biomarkers and neuropsychological tests including five cognitive domains. Linear regressions were conducted, adjusting for age, sex, and education.
Higher AL was associated with lower CSF Aβ1-42 levels (β = −0.175, p = 0.025), reflecting higher brain levels of Aβ1-42. Stratified analyses suggested a significant association among women but not men, although the AL-sex interaction was not statistically significant. AL was not significantly associated with T-tau level (β = −0.030, p = 0.682) and P-tau level (β = 0.091, p = 0.980). There were no significant associations between AL and cognition or cognitive decline after 3 years.
This study showed that higher AL was associated with increased brain amyloid accumulation. This suggests that AL may play a role in AD/dementia pathophysiology. Potential sex-related differences should be assessed in further larger studies.
Non-invasive automatic screening for Alzheimer’s disease has the potential to improve diagnostic accuracy while lowering healthcare costs. Previous research has shown that patterns in speech, ...language, gaze, and drawing can help detect early signs of cognitive decline. In this paper, we describe a highly multimodal system for unobtrusively capturing data during real clinical interviews conducted as part of cognitive assessments for Alzheimer’s disease. The system uses nine different sensor devices (smartphones, a tablet, an eye tracker, a microphone array, and a wristband) to record interaction data during a specialist’s first clinical interview with a patient, and is currently in use at Karolinska University Hospital in Stockholm, Sweden. Furthermore, complementary information in the form of brain imaging, psychological tests, speech therapist assessment, and clinical meta-data is also available for each patient. We detail our data-collection and analysis procedure and present preliminary findings that relate measures extracted from the multimodal recordings to clinical assessments and established biomarkers, based on data from 25 patients gathered thus far. Our findings demonstrate feasibility for our proposed methodology and indicate that the collected data can be used to improve clinical assessments of early dementia.
Background
Cortisol, one of the most important mediators of stress in humans, is often found increased in Alzheimer’s disease (AD) patients and correlates with disease severity. Stress response and ...inflammation are two systems that are tightly associated to one another. Several lines of evidence suggest that cortisol can promote inflammation. However, less is known on the interaction of cortisol with neuroinflammation in the context of AD, and to the best of our knowledge there are no human studies that have systematically explored the association of these two systems in AD patients so far. The aim of this study was to investigate levels of cerebrospinal fluid (CSF) biomarkers of neuroinflammation and their relationship to salivary cortisol in a memory clinic cohort.
Method
A total of 108 memory clinic patients with subjective cognitive decline (SCI, n = 40), mild cognitive impairment (MCI, n = 39) and AD (n = 29), from the Karolinska University Hospital in Stockholm, Sweden, were included in this study. Salivary cortisol was collected at six timepoints during the day on two days, to quantify awakening cortisol, cortisol awakening response (CAR), bedtime cortisol and total cortisol. CSF levels of 37 neuroinflammation and cerebrovascular dysfunction biomarkers were determined by a multiplex immunoassay. Associations among cortisol and neuroinflammation markers were assessed by linear regression models adjusting for age and diagnosis. ANCOVA tests were used to compare biomarker levels between the diagnostic groups.
Result
Awakening cortisol was significantly elevated in the AD group compared to the SCI and MCI participants. Higher IP‐10 and placental growth factor (PlGF) levels were associated with decreased CAR independent of age and diagnosis. Thymus and activation‐regulated chemokine (TARC), CRP, intracellular adhesion molecule 1 (ICAM‐1) and vascular cell adhesion molecule 1 (VCAM‐1) levels were upregulated in MCI participants compared to SCI and AD.
Conclusion
We provide evidence that the HPA axis is altered in AD. Moreover, salivary cortisol is associated to neuroinflammation in an age and diagnosis independent manner. Finally, neuroinflammatory and vascular dysfunction regulators are increased in CSF during MCI stages followed by a drop in their levels in AD participants, presumably reflecting a more active role of neuroinflammation at an early state.
Abstract Introduction Several sleep disturbance parameters as well as abnormal cortisol secretion levels are increasingly acknowledged as risk factors for Alzheimer’s disease (AD). Currently, the ...mechanisms between sleep disturbances and AD, and the interplay with abnormal cortisol levels, are still not understood. This study examines how self-reported sleep disturbances are associated with structural brain measures and diurnal cortisol dysregulation in a cohort of memory clinic patients. Methods The study was based on a cohort of 146 memory clinic patients diagnosed with either mild cognitive impairment or subjective cognitive impairment. The Karolinska Sleep Questionnaire (KSQ) was used to measure self-reported sleep. Neuroimaging (MRI or CT) was used to quantify structural brain measures using four visual rating scales (Scheltens, Pasquier, Koedam, and Fazekas scales). Salivary cortisol was sampled to measure diurnal cortisol patterns through five computed measures of awakening, bedtime, total, AM/PM cortisol ratio, and cortisol awakening response. Results Some associations were found between sleep, structural brain measures and cortisol. Increased apnea index (based on the KSQ) was associated with greater odds of posterior brain atrophy (OR=1.20, p=0.015) measured by the Koedam visual rating scale. Further, increased apnea index was associated with reduced awakening cortisol (β=-0.03; p=0.045, and an increased daytime sleepiness index (based on the KSQ) was associated with both reduced awakening cortisol (β=-0.03; p=0.025) and a reduced AM/PM cortisol ratio (β=-0.04; p=0.021). Conclusion In a memory clinic cohort, self-reported apnea disturbances are associated with a neuroimaging correlate of increased posterior atrophy and lower awakening cortisol, while daytime sleepiness index is associated with lower awakening cortisol and a reduced AM/PM cortisol ratio. These findings add insights into the early identification of modifiable AD risk factors an¬d their mechanisms. Support (if any)
Background
Chronic stress has been studied as a potential lifestyle risk factor for Alzheimer's disease (AD). Prolonged stress can lead to alterations in diurnal patterns of cortisol. This study aims ...to investigate the relationship between diurnal cortisol patterns, cognition, and AD biomarkers in memory clinic patients.
Method
Participants diagnosed with subjective cognitive impairment (SCI), mild cognitive impairment (MCI), or AD dementia were recruited from Karolinska University Hospital memory clinic in Sweden (n=155). Baseline cognition was measured using five cognitive domains (memory, working memory, processing speed, perceptual reasoning, overall cognition), operationalized as average z‐scores. Diurnal cortisol patterns were assessed using five salivary cortisol measures: awakening levels, cortisol awakening response, bedtime levels, the ratio of awakening to bedtime cortisol levels (AM/PM ratio), and total daily output. AD biomarkers Aβ42, total tau (T‐Tau), and phosphorylated tau (P‐Tau) were measured from cerebrospinal fluid. Cognition was measured at follow‐up (average 32 months) in a subsample of participants (n=57).
Result
Awakening cortisol levels were significantly higher in AD dementia compared with SCI. Greater cortisol awakening response was associated with better memory performance (OR= 1.57, 95% CI: 1.10 – 2.23), while a greater AM/PM ratio (OR= 2.21, 95% CI: 1.15 – 4.25) and lower bedtime cortisol levels (OR= .64, 95% CI: .40 – 1.01) were associated with better overall cognition. Cortisol measures were not associated with cognitive decline during follow‐up or with AD biomarkers in the full sample. However, in stratified analyses, higher awakening cortisol levels were associated with lower CSF Aβ42 in amyloid‐positive participants (b= ‐60.13; 95% CI ‐102.73 ‐ ‐17.52), while higher bedtime cortisol levels (b= .09; 95% CI .02 ‐ .17) and a lower AM/PM ratio (b= ‐.12; 95% CI ‐.23 ‐ ‐.02) were associated with higher CSF T‐Tau in amyloid‐negative participants.
Conclusion
This study shows that diurnal cortisol patterns are associated with cognitive performance in memory clinic patients. In people without amyloid pathology, cortisol may affect cognition through neurodegeneration‐related mechanisms, leading to the observed correlation with T‐Tau. Meanwhile, in amyloid‐positive participants, the greater pathology level may affect cortisol patterns. Further research should investigate the complex relationship between cortisol, cognition, and brain pathology.
•Cortisol & neuroinflammation interacted in their relation to neuroimaging correlates.•Greater angiogenesis marker levels associated with more severe white matter lesions.•Neuroinflammation ...interacted with beta-amyloid in relation to visual rating scales.•Some evidence was found for interaction between diurnal cortisol and beta-amyloid.
Neuroinflammation 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.
134 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.
Higher 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.
This 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.
Background
Neuroinflammation is considered a hallmark of the Alzheimer’s disease (AD) pathogenic process. Dysregulations in stress hormones (cortisol) may increase AD risk and are related to brain ...atrophy. This cross‐sectional study aims to examine interactions of cortisol patterns and neuroinflammation markers in their association with neuroimaging correlates.
Method
188 participants were recruited from the Karolinska University Hospital memory clinic (Stockholm, Sweden), and underwent magnetic resonance imaging or computed tomography. Four visual rating scales were applied to the scans: medial temporal lobe atrophy (MTA), global cortical atrophy (GCA), white matter lesions (Fazekas), and posterior atrophy (Koedam). Additionally, participants provided saliva to assess diurnal cortisol patterns, and underwent lumbar punctures for cerebrospinal fluid (CSF) sampling. Five cortisol measures were used: awakening levels, bedtime levels, cortisol awakening response (CAR), total daily output, and the ratio of awakening to bedtime levels (AM/PM ratio). Nineteen CSF neuroinflammation markers were categorized into five composite scores (mean z‐scores): proinflammatory cytokines (Interleukin (IL‐)6, IL‐8, IL‐15, IL‐12/IL‐23 p40, CC chemokine ligand (CCL)4, CXC chemokine ligand 10), other cytokines (IL‐5, IL‐16, CCL17), angiogenesis markers (Vascular endothelial growth factor (VEGF), VEGF‐D, VEGF‐receptor 1, Placental growth factor), vascular injury markers (Serum amyloid A, C‐reactive protein, Vascular cell adhesion molecule‐1, Intercellular adhesion molecule‐1), and glial activation markers (YKL‐40, CCL2). Ordinal logistic regressions were conducted to assess associations between cortisol patterns, neuroinflammation scores, and visual rating scales, and interactions between cortisol patterns and neuroinflammation composite scores in predicting visual rating scales.
Result
Higher levels of angiogenesis markers were associated with greater odds of more severe white matter lesions. Furthermore, awakening cortisol levels, bedtime levels, CAR, and total daily output independently interacted with ‘other cytokines’ scores to predict MTA, CAR and total daily output independently interacted with ‘proinflammatory cytokines’ scores to predict white matter lesions, and the AM/PM ratio interacted with angiogenesis markers to predict GCA. No associations were found between cortisol patterns and visual rating scales.
Conclusion
This study provides evidence for potential interplay between diurnal cortisol patterns and neuroinflammation. While this study does not provide information on causality, these findings suggest that neuroinflammation is involved in the pathway between chronic stress and AD.
Background
Sleep 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.
Method
The 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.
Result
Ordinal 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.
Conclusion
These 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.
Background
Various lifestyle and physiological dementia risk factors have been identified. However, little is still known about the role of stress‐related risk factors. Chronic psychological stress ...affects several systems, such as the immune and cardiovascular systems, and increases the risk for physical, behavioral and mental disorders and reduced cognitive function. The goal of this study is to assess whether allostatic load (AL), a composite biomarker measure of chronic stress, is associated with AD biomarkers and cognitive function among memory clinic patients.
Methods
Data were derived from the Co‐STAR study at Karolinska University Hospital Memory Clinic, Sweden. Participants underwent baseline assessments including blood tests for AL measures, and cerebrospinal fluid sampling for AD biomarkers (Ab1‐42, total Tau (T‐tau), phosphorylated Tau (P‐tau)), a neuropsychological test battery was performed with measures for the following cognitive domains: general cognition, memory, working memory, processing speed and perceptual reasoning. Multiple linear regressions were conducted, adjusting for age, sex and education. P‐value <0.05 was used to identify significant associations.
Results
Higher AL was associated with lower CSF Ab1‐42 level (β = ‐0.175, p = 0.025) reflecting higher brain levels of Ab1‐42. Analyses stratified by sex showed that these associations were only present for women, but not for men. AL was not significantly associated with T‐tau level and P‐tau level. Multiple regression analyses showed that there were no significant association between AL and general cognitive functioning, processing speed, working memory, memory, and perceptual reasoning. AL modified the association between Ab1‐42 and perceptual reasoning; the non‐significant association was significant when additionally adjusted for AL (β = 0.157, p< 0.05).
Conclusion
This study identified a significant negative association between AL and Ab1‐42 among women, and AL modified the association between Ab1‐42 and perceptual reasoning. This suggests that AL may play a role in dementia pathophysiology. Further evidence is needed on whether specific subgroups in memory clinic samples are particularly vulnerable to the effects of high AL burden.
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