Shireen Sindi

Chronic stress, cognitive functioning and mental health.

This review aims to discuss the evidence supporting the link between chronic stress, cognitive function and mental health. Over the years, the associations between these concepts have been investigated in different populations. This review summarizes the findings that have emerged from older populations as well as from populations suffering from pathological aging, namely Mild Cognitive Impairment and Alzheimers Disease. Although older adults are an interesting population to study in terms of chronic stress, other stress-related diseases can occur throughout the lifespan. The second section covers some of these stress-related diseases that have recently received a great deal of attention, namely burnout, depression, and post-traumatic stress disorder. Given that chronic stress contributes to the development of certain pathologies by accelerating and/or exacerbating pre-existing vulnerabilities that vary from one individual to the other, the final section summarizes data obtained on potential variables contributing to the association between chronic stress and cognition.

A transdisciplinary perspective of chronic stress in relation to psychopathology throughout life span development.

The allostatic load (AL) model represents an interdisciplinary approach to comprehensively conceptualize and quantify chronic stress in relation to pathologies throughout the life cycle. This article first reviews the AL model, followed by interactions among early adversity, genetics, environmental toxins, as well as distinctions among sex, gender, and sex hormones as integral antecedents of AL. We next explore perspectives on severe mental illness, dementia, and caregiving as unique human models of AL that merit future investigations in the field of developmental psychopathology. A complimenting transdisciplinary perspective is applied throughout, whereby we argue that the AL model goes beyond traditional stress-disease theories toward the advancement of person-centered research and practice that promote not only physical health but also mental health.

A clinical allostatic load index is associated with burnout symptoms and hypocortisolemic profiles in healthy workers

Chronic stress causes stress hormones to strain many biological systems in a process referred to as allostatic load (AL) that is measurable using an index of biomarkers. While the AL framework has been successfully applied in studies of workplace stress, few studies have investigated burnout, a debilitating condition sometimes characterized by blunted stress hormone levels. Using an AL index based on clinical norms, we hypothesized that higher AL indices would be associated with increased chronic stress, burnout symptoms, as well as hypoactive diurnal and reactive stress hormone levels. Fifteen neuroendocrine, immune, metabolic, and cardiovascular biomarkers were collected for 30 healthy participants from various professions and values were transformed into an AL index using clinical norms. Stress reactivity was assessed for salivary cortisol and α-amylase levels in response to the Trier Social Stress Test. Diurnal cortisol was measured at five time points (awakening, 30 min after awakening, 14:00 h, 16:00 h, and before bedtime) over two working days. We also administered questionnaires of chronic stress, burnout, and depression. Our results demonstrate that increased AL is associated with increased chronic stress, burnout symptoms, but not depressive symptoms. The High AL group demonstrated lower morning and stress reactive cortisol levels in comparison to the Low AL group, but no significant effects were detected for salivary α-amylase. These findings provide preliminary support for the utility of a new clinical AL index that is sensitive to physiological recalibrations intermittently observed in burnout research.

Sexual orientation and disclosure in relation to psychiatric symptoms, diurnal cortisol, and allostatic load.

Objectives Lesbian, gay, and bisexual (LGB) individuals—particularly those who have not disclosed their sexual orientation—are believed to experience increased chronic stress in comparison with heterosexuals. This interdisciplinary study assessed whether psychiatric symptoms (self-rated anxiety, depression, and burnout), stress hormone profiles (diurnal cortisol), and physiological dysregulations (allostatic load [AL]) would differ for a) LGBs versus heterosexuals and b) disclosed LGBs versus nondisclosed LGBs. Methods The study included 87 healthy participants (mean [SD] age = 24.6 [0.6] years; LGB n = 46, 43% women; and heterosexual n = 41, 49% women). Diurnal cortisol sampled at five time points was averaged for 2 days. AL indices were based on an algorithm incorporating 21 biomarkers representing neuroendocrine, immune/inflammatory, metabolic, and cardiovascular functioning. Psychological measures were assessed with well-validated questionnaires. Results Between-group results revealed no significant differences in symptoms of anxiety and burnout, nor among diurnal cortisol levels between sexual orientations. By contrast, gay/bisexual men unexpectedly had lower depressive symptoms (p = .003) and AL levels (p = .043) compared with heterosexual men. Within-group results revealed that disclosed LGBs had fewer psychiatric symptoms (p values < 0.01) and lower cortisol levels +30 minutes upon awakening (p = .004) compared with nondisclosed LGBs. Disclosure was not significantly related to AL levels. Conclusions LGBs did not manifest more stress-related problems than did heterosexuals. Life transitions like disclosing to one’s family and friends may be protective against psychopathologies and hyperactive cortisol awakening responses. Our novel findings underline the roles disclosure processes have on positive health and well-being for sexual minorities.

Timing is everything: anticipatory stress dynamics among cortisol and blood pressure reactivity and recovery in healthy adults.

Psychological states of anticipation modulate biological stress responsivity. While researchers generally investigate how subjective distress corresponds to the magnitude of stress reactivity, physiological recovery after acute stressors must also be considered when investigating disease vulnerabilities. This study assessed whether anticipatory stress would correspond to stress reactivity and recovery of salivary cortisol and blood pressure levels in response to a well-validated psychosocial stressor. Thirty participants (63% female; mean ± SEM age 45.4 ± 2.12 years) were exposed to the Trier Social Stress Test (TSST) consisting of a public speech and mental arithmetic. Ten salivary cortisol samples and systolic and diastolic blood pressure recordings were collected at time points spanning 50 min before and up to 50 min after stress exposure. These data were transformed into parameters representing stress reactivity (area under the curve) and stress recovery (percent change). The Primary Appraisal Secondary Appraisal scale assessed anticipatory stress before exposure to the TSST. Our results revealed that increased anticipatory stress predicted increased stress reactivity for cortisol (p = 0.009) but not blood pressure. For stress recovery, increased anticipatory stress predicted greater decrements of cortisol concentration (p = 0.015) and blood pressure (p = 0.039), even when controlling for total systemic “output” by incorporating baseline activity. This efficient shutdown of stress responses would have otherwise been ignored by solely investigating reactive increases. These findings underscore the importance of measuring multiple dynamic parameters such as recovery when investigating physiological stress response patterns as a function of psychosocial factors.

Aging and Alzheimer’s Disease

Publisher Summary This chapter discusses aging and Alzheimers disease. The possibility that aging-associated alterations of neuroendocrine systems contribute to the pathophysiology of behavioral changes and disorders of later life has long intrigued clinicians and investigators. This possibility was largely an inference from the substantial aging-associated reduction in concentrations of several important hormones such as estrogen, testosterone, growth hormone, and thyroid stimulating hormone (TSH). However, establishing causality for decreased neuroendocrine activity in the pathophysiology of such later-life behavioral problems as impaired cognition and depression has proved difficult. For example, attempts to treat major neuropsychiatric disorders of later life with gonadal hormones have been largely disappointing. Furthermore, the direction in which several behaviorally relevant neuroendocrine systems are altered in late life is inconsistent with the assumption that aging is always associated with reduced neuroendocrine activity.

Advances in the therapy of Alzheimer’s disease: targeting amyloid beta and tau and perspectives for the future

Worldwide multidisciplinary translational research has led to a growing knowledge of the genetics and molecular pathogenesis of Alzheimer’s disease (AD) indicating that pathophysiological brain alterations occur decades before clinical signs and symptoms of cognitive decline can be diagnosed. Consequently, therapeutic concepts and targets have been increasingly focused on early-stage illness before the onset of dementia; and distinct classes of compounds are now being tested in clinical trials. At present, there is a growing consensus that therapeutic progress in AD delaying disease progression would significantly decrease the expanding global burden. The evolving hypothesis- and evidence-based generation of new diagnostic research criteria for early-stage AD has positively impacted the development of clinical trial designs and the characterization of earlier and more specific target populations for trials in prodromal as well as in pre- and asymptomatic at-risk stages of AD.

Advances in the prevention of Alzheimer's Disease

Alzheimers disease (AD), the leading cause of dementia, has reached epidemic proportions, with major social, medical and economical burdens. With no currently available curative treatments, both the World Health Organization and the G8 Dementia Summit recently identified dementia and AD prevention as a major public health priority. Dementia and AD have a wide range of risk factors (genetic, vascular/metabolic and lifestyle-related), which often co-occur and thus interact with each other. Previous intervention efforts aimed at preventing dementia and AD focused on the management of single risk factors, with relatively modest findings. Also, the effect of risk factors depends on age at exposure, indicating that the timing of preventive interventions needs to be carefully considered. In view of the complex multifactorial nature of AD, as well as its long pre-clinical (asymptomatic) phase, interventions simultaneously targeting multiple risk factors and disease mechanisms at an early stage of the disease are most likely to be effective. Three large European multidomain prevention trials have been launched with the goal of preventing cognitive decline, dementia and AD in older adults with different risk profiles. Pharmacological trials are also shifting towards prevention of Alzheimer dementia, by targeting at-risk individuals prior to the onset of cognitive symptoms. The current review will summarize and discuss the evidence on risk and protective factors from observational studies, ongoing lifestyle-related and pharmacological randomized controlled trials (RCTs), as well as future directions for dementia and AD prevention.

The Stroke RiskometerTM App: Validation of a data collection tool and stroke risk predictor

Background The greatest potential to reduce the burden of stroke is by primary prevention of first-ever stroke, which constitutes three quarters of all stroke. In addition to population-wide prevention strategies (the ‘mass’ approach), the ‘high risk’ approach aims to identify individuals at risk of stroke and to modify their risk factors, and risk, accordingly. Current methods of assessing and modifying stroke risk are difficult to access and implement by the general population, amongst whom most future strokes will arise. To help reduce the burden of stroke on individuals and the population a new app, the Stroke Riskometer™, has been developed. We aim to explore the validity of the app for predicting the risk of stroke compared with current best methods. Methods 752 stroke outcomes from a sample of 9501 individuals across three countries (New Zealand, Russia and the Netherlands) were utilized to investigate the performance of a novel stroke risk prediction tool algorithm (Stroke Riskometer™) compared with two established stroke risk score prediction algorithms (Framingham Stroke Risk Score [FSRS] and QStroke). We calculated the receiver operating characteristics (ROC) curves and area under the ROC curve (AUROC) with 95% confidence intervals, Harrels C-statistic and D-statistics for measure of discrimination, R2 statistics to indicate level of variability accounted for by each prediction algorithm, the Hosmer-Lemeshow statistic for calibration, and the sensitivity and specificity of each algorithm. Results The Stroke Riskometer™ performed well against the FSRS five-year AUROC for both males (FSRS = 75·0% (95% CI 72·3%–77·6%), Stroke Riskometer™ = 74·0(95% CI 71·3%–76·7%) and females [FSRS = 70·3% (95% CI 67·9%–72·8%, Stroke Riskometer™ = 71·5% (95% CI 69·0%–73·9%)], and better than QStroke [males–59·7% (95% CI 57·3%–62·0%) and comparable to females = 71·1% (95% CI 69·0%–73·1%)]. Discriminative ability of all algorithms was low (C-statistic ranging from 0·51–0·56, D-statistic ranging from 0·01–0·12). Hosmer-Lemeshow illustrated that all of the predicted risk scores were not well calibrated with the observed event data (P < 0·006). Conclusions The Stroke Riskometer™ is comparable in performance for stroke prediction with FSRS and QStroke. All three algorithms performed equally poorly in predicting stroke events. The Stroke Riskometer™ will be continually developed and validated to address the need to improve the current stroke risk scoring systems to more accurately predict stroke, particularly by identifying robust ethnic/race ethnicity group and country specific risk factors.

Allostatic load associations to acute, 3-year and 6-year prospective depressive symptoms in healthy older adults

Allostatic load represents the strain that chronic stress exerts on interconnected biological systems. Associated algorithms are related to numerous deleterious physical outcomes in older populations, and yet few studies have assessed associations to mental health outcomes like geriatric depression. Using data from the Douglas Hospital Longitudinal Study of Normal and Pathological Aging, we assessed whether using an allostatic load index derived from seven biomarkers could detect self-rated depressive symptoms in 58 healthy older adults followed longitudinally over a 6-year period. Our results revealed that increased allostatic load was associated with increased depressive symptoms on the same year of assessment. After 3 years, AL was prospectively associated with depressive symptoms, but entering age and sex as covariates attenuated this effect to a trend. Only age emerged as a significant predictor of depressive symptoms over 6 years. These findings suggest that increased AL in older age is only associated with depressive symptomatology acutely. Over longer periods of time, however, the physical and psychological sequelae of advanced age may contribute to increased depressive symptoms via pathways otherwise undetectable using allostatic load indices of sub-clinical physiological dysregulations.