Targeting neuroendocrine abnormalities in Parkinson's disease with exercise.

Parkinson's Disease (PD) is a prevalent and complex age-related neurodegenerative condition for which there are no disease-modifying treatments currently available. The pathophysiological process underlying PD remains incompletely understood but increasing evidence points to multiple system dysfunction. Interestingly, the past decade has produced evidence that exercise not only reduces signs and symptoms of PD but is also potentially neuroprotective. Characterizing the mechanistic pathways that are triggered by exercise and lead to positive outcomes will improve understanding of how to counter disease progression and symptomatology. In this review, we highlight how exercise regulates the neuroendocrine system, whose primary role is to respond to stress, maintain homeostasis and improve resilience to aging. We focus on a group of hormones - cortisol, melatonin, insulin, klotho, and vitamin D - that have been shown to associate with various non-motor symptoms of PD, such as mood, cognition, and sleep/circadian rhythm disorder. These hormones may represent important biomarkers to track in clinical trials evaluating effects of exercise in PD with the aim of providing evidence that patients can exert some behavioral-induced control over their disease.

The Interrelated Multifactorial Actions of Cortisol and Klotho: Potential Implications in the Pathogenesis of Parkinson's Disease.

The pathogenesis of Parkinson's disease (PD) is complex, multilayered, and not fully understood, resulting in a lack of effective disease-modifying treatments for this prevalent neurodegenerative condition. Symptoms of PD are heterogenous, including motor impairment as well as non-motor symptoms such as depression, cognitive impairment, and circadian disruption. Aging and stress are important risk factors for PD, leading us to explore pathways that may either accelerate or protect against cellular aging and the detrimental effects of stress. Cortisol is a much-studied hormone that can disrupt mitochondrial function and increase oxidative stress and neuroinflammation, which are recognized as key underlying disease mechanisms in PD. The more recently discovered klotho protein, considered a general aging-suppressor, has a similarly wide range of actions but in the opposite direction to cortisol: promoting mitochondrial function while reducing oxidative stress and inflammation. Both hormones also converge on pathways of vitamin D metabolism and insulin resistance, also implicated to play a role in PD. Interestingly, aging, stress and PD associate with an increase in cortisol and decrease in klotho, while physical exercise and certain genetic variations lead to a decrease in cortisol response and increased klotho. Here, we review the interrelated opposite actions of cortisol and klotho in the pathogenesis of PD. Together they impact powerful and divergent mechanisms that may go on to influence PD-related symptoms. Better understanding of these hormones in PD would facilitate the design of effective interventions that can simultaneously impact the multiple systems involved in the pathogenesis of PD.

Evaluation and update of the expert consensus guidelines for the assessment of the cortisol awakening response (CAR).

The cortisol awakening response (CAR) is frequently assessed in psychobiological (stress) research. Obtaining reliable CAR data, however, requires careful attention to methodological detail. To promote best practice, expert consensus guidelines on the assessment of the CAR were published (Stalder et al., 2016, PNEC). However, it is unclear whether these highly cited guidelines have resulted in actual methodological improvements. To explore this, the PNEC editorial board invited the present authors to conduct a critical evaluation and update of current CAR methodology, which is reported here. (i) A quantitative evaluation of methodological quality of CAR research published in PNEC before and after the guidelines (2013-2015 vs. 2018-2020) was conducted. Disappointingly, results reveal little improvement in the implementation of central recommendations (especially objective time verification) in recent research. (ii) To enable an update of guidelines, evidence on recent developments in CAR assessment is reviewed, which mostly confirms the accuracy of the majority of the original guidelines. Moreover, recent technological advances, particularly regarding methods for the verification of awakening and sampling times, have emerged and may help to reduce costs in future research. (iii) To aid researchers and increase accessibility, an updated and streamlined version of the CAR consensus guidelines is presented. (iv) Finally, the response of the PNEC editorial board to the present results is described: potential authors of future CAR research to be published in PNEC will be required to submit a methodological checklist (based on the current guidelines) alongside their article. This will increase transparency and enable reviewers to readily assess the quality of the respective CAR data. Combined, it is hoped that these steps will assist researchers and reviewers in assuring higher quality CAR assessments in future research, thus yielding more reliable and reproducible results and helping to further advance this field of study.

Smaller Cortisol Awakening Responses Are Associated with Greater Visual Dependence in Postural Control.

There are known links between the hypothalamic-pituitary-adrenal (HPA) axis and systems responsible for regulating posture. Our aim was to explore directly, for the first time, whether an aspect of circadian HPA axis activity (the cortisol awakening response: CAR) was associated with greater visual dependency in postural control. For measurement of the CAR, electronically monitored saliva samples were collected by participants following morning awakening in their home environment. On the afternoons of the same days, postural sway was measured in the laboratory by exposing participants to static (control) and moving visual stimuli whilst standing still and upright on a force platform. Visual dependence was assessed as the increase in postural sway (path length) during exposure to the moving compared with the static condition. The 44 measurement days were derived from four days for each of eleven healthy participants (mean ± SD age: 51.18 ± 3.3 years). As expected, postural sway was greater when exposed to moving versus static cues. Mixed regression modelling showed that participants with smaller four day average CARs had greater deterioration in postural sway when presented with moving stimuli. These data are the first to document associations between the CAR and visual dependency in postural sway.

The cortisol awakening response predicts a same-day index of executive function in healthy young adults.

The cortisol awakening response (CAR) is associated with various aspects of cognition, including executive function, in older adult and clinical samples. However, the association between these variables in the healthy functioning population is not well understood due to the limited number of appropriately controlled studies. This study explored the association between the CAR and a set shifting index of executive function in 55 (44 females) healthy participants aged 20.2 ± 3.0 years. Notoriously, assessment of the CAR from self-collected saliva samples within the domestic setting is subject to sample timing error, so electronic monitoring of both awakening and sampling times were employed. Participants attended the laboratory in the afternoon of CAR assessment for testing on the Attention Switching Task of the CANTAB neuropsychological testing battery. A positive association was found between CAR magnitude and attention-switching performance in the afternoon of the same day. This was independent of known relevant CAR covariates, but only evident in CAR data collected without delay exceeding 8 min post-awakening. These findings offer insight into a potential role for the CAR in modulating cognitive functions associated with the pre-frontal cortex.

Salivary cortisol as a non-invasive window on the brain.

The validation of accurate and meaningful assessment of cortisol in saliva samples has proved revolutionary in stress research. Its many advantages have expanded the scope of investigation from traditional laboratory and clinical settings to include multidisciplinary and community-based research. These developments have given rise to a wealth insight into the links between stress and health. Here we highlight the potential of salivary cortisol as both a product and mediator of brain function, instrumental in disturbing brain health. However, the subtleties of salivary cortisol as a measure can be underestimated, leading to misinterpretation of findings. These issues are explored, with a particular emphasis on necessary methodological rigor. Notwithstanding great promise, there is undeniably more to learn so we conclude by making recommendations for future research including use of salivary cortisol in the development of integrative predictive models of stress-related risk factors and resilience across the life course.

Stress, the cortisol awakening response and cognitive function.

There is evidence that stress-induced disruption of the circadian rhythm of cortisol secretion, has negative consequences for brain health. The cortisol awakening response (CAR) is the most prominent and dynamic aspect of this rhythm. It has complex regulatory mechanisms making it distinct from the rest of the cortisol circadian rhythm, and is frequently investigated as a biomarker of stress and potential intermediary between stress and impaired brain function. Despite this, the precise function of the CAR within the healthy cortisol circadian rhythm remains poorly understood. Cortisol is a powerful hormone known to influence cognition in multiple and complex ways. Studies of the CAR and cognitive function have used varied methodological approaches which have produced similarly varied findings. The present review considers the accumulating evidence linking stress, attenuation of the CAR and reduced cognitive function, and seeks to contextualize the many findings to study populations, cognitive measures, and CAR methodologies employed. Associations between the CAR and both memory and executive functions are discussed in relation to its potential role as a neuroendocrine time of day signal that synchronizes peripheral clocks throughout the brain to enable optimum function, and recommendations for future research are provided.

Psychological stress reactivity and future health and disease outcomes: A systematic review of prospective evidence.

BACKGROUND: Acute psychological stress activates the sympatho-adrenal medullary (SAM) system and hypothalamo-pituitary adrenal (HPA) axis. The relevance of this stress reactivity to long-term health and disease outcomes is of great importance. We examined prospective studies in apparently healthy adults to test the hypothesis that the magnitude of the response to acute psychological stress in healthy adults is related to future health and disease outcomes. METHODS: We searched Medline Complete, PsycINFO, CINAHL Complete and Embase up to 15 Aug 2019. Included studies were peer-reviewed, English-language, prospective studies in apparently healthy adults. The exposure was acute psychological stress reactivity (SAM system or HPA axis) at baseline. The outcome was any health or disease outcome at follow-up after ≥1 year. RESULTS: We identified 1719 papers through database searching and 1 additional paper through other sources. Forty-seven papers met our criteria including 32,866 participants (range 30-4100) with 1-23 years of follow-up. Overall, one third (32 %; 83/263) of all reported findings were significant and two thirds (68 %; 180/263) were null. With regard to the significant findings, both exaggerated (i.e. high) and blunted (i.e. low) stress reactivity of both the SAM system and the HPA axis at baseline were related to health and disease outcomes at follow-up. Exaggerated stress reactivity at baseline predicted an increase in risk factors for cardiovascular disease and decreased telomere length at follow-up. In contrast, blunted stress reactivity predicted future increased adiposity and obesity, more depression, anxiety and PTSD symptoms, greater illness frequency, musculoskeletal pain and regulatory T-Cell percentage, poorer cognitive ability, poorer self-reported health and physical disability and lower bone mass. CONCLUSION: Exaggerated and blunted SAM system and HPA axis stress reactivity predicted distinct physical and mental health and disease outcomes over time. Results from prospective studies consistently indicate stress reactivity as a predictor for future health and disease outcomes. Dysregulation of stress reactivity may represent a mechanism by which psychological stress contributes to the development of future health and disease outcomes.

The cortisol awakening response predicts response inhibition in the afternoon of the same day.

The cortisol awakening response (CAR) is the rapid increase of cortisol levels 30-45 min after awakening in the morning. Numerous studies have indicated the relationship between the CAR and cognition. However, little is known about daily variation in the CAR and cognitive function in healthy adults. The aim of the present study was to investigate whether the CAR predicted the response inhibition function on the same day in both behaviour and the dynamic time course of brain processing. The saliva samples of 47 healthy men were collected at three time points: immediately on awakening, 30 min and 45 min post-awakening in the morning. Participants performed a Go/NoGo task while electroencephalograms (EEG) were recorded in the afternoon of the same day. The results showed that a greater CAR was associated with a stronger N2. In the sub-group of CAR responders (n = 33) the CAR was negatively related to the false alarm rate of NoGo-trials. Our findings suggested that the CAR was predictive of the function of response inhibition in both the earlier cognitive step (i.e., conflict monitoring) and the behavioural performance of response inhibition on the same day in healthy men.

Physical fitness and prior physical activity are both associated with less cortisol secretion during psychosocial stress.

BACKGROUND: Evidence linking fitness and decreased psychosocial stress comes from studies of athletes and typically relies upon self-report measures. Furthermore, there is little evidence regarding the impact of physical activity (PA) prior to a stressor. The aims of this study were to determine whether fitness and prior PA influence cortisol concentrations during psychosocial stress. METHODS: Seventy-five non-athletic participants took part in a submaximal walk prior to the Trier Social Stress Test for Groups (TSST-G). During the walk, fitness was assessed using heart rate (HR). A further 89 participants took part in the TSST-G without the walk. Stress responsiveness was assessed using salivary cortisol collected at 10-min intervals on seven occasions. RESULTS: Hierarchical multiple regression revealed that average walking HR accounted for 9% of the variance in cortisol secretion (P = .016), where a higher HR was associated with higher cortisol secretion. Between-subjects ANCOVA revealed that the walking group had a significantly lower cortisol secretion than the non-walking group (P = .009). CONCLUSIONS: These findings indicate that fitter individuals have reduced cortisol secretion during psychosocial stress. They also indicate that prior PA can reduce cortisol concentrations during psychosocial stress and are suggestive of a role of PA in reducing the impact of stress on health.

Salivary diurnal cortisol profiles in patients suffering from chronic breathlessness receiving supportive and palliative care services: A cross-sectional study.

Chronic breathlessness is a common source of psychological and physical stress in patients with advanced or progressive disease, suggesting that hypothalamic-pituitary-adrenal (HPA) axis dysregulation may be prevalent. The aim of this study was to measure the salivary diurnal cortisol profile in patients receiving supportive and palliative care for a range of malignant and non-malignant conditions and to compare the profile of those experiencing moderate-to-severe disability due to breathlessness against that of patients with mild/no breathlessness and that of healthy controls. Saliva samples were collected over two consecutive weekdays at 3, 6, and 12h after awakening in 49 patients with moderate-to-severe breathlessness [Medical Research Council (MRC) dyspnoea grade ≥3], 11 patients with mild/no breathlessness (MRC dyspnoea grade ≤2), and 50 healthy controls. Measures of breathlessness, stress, anxiety, depression, wellbeing and sleep were examined concomitantly. The diurnal cortisol slope (DCS) was calculated for each participant by regressing log-transformed cortisol values against collection time. Mean DCS was compared across groups using ANCOVA. Individual slopes were categorised into one of four categories: consistent declining, consistent flat, consistent ascending and inconsistent. Controlling for age, gender and socioeconomic status, the mean DCS was significantly flatter in patients with moderate-to-severe breathlessness compared to patients with mild/no breathlessness and healthy controls [F (2, 103)=45.64, p<0.001]. Furthermore, there was a higher prevalence of flat and ascending cortisol profiles in patients with moderate-to-severe breathlessness (23.4%) compared to healthy controls (0%). The only variable which correlated significantly with DCS was MRC dyspnoea grade (rs=0.29, p<0.05). These findings suggest that patients with moderate-to-severe breathlessness have evidence of HPA axis dysregulation and that this dysregulation may be related to the functional disability imposed by breathlessness.

Assessment of the cortisol awakening response: Real-time analysis and curvilinear effects of sample timing inaccuracy.

The cortisol awakening response (CAR) is typically measured in the domestic setting. Moderate sample timing inaccuracy has been shown to result in erroneous CAR estimates and such inaccuracy has been shown partially to explain inconsistency in the CAR literature. The need for more reliable measurement of the CAR has recently been highlighted in expert consensus guidelines where it was pointed out that less than 6% of published studies provided electronic-monitoring of saliva sampling time in the post-awakening period. Analyses of a merged data-set of published studies from our laboratory are presented. To qualify for selection, both time of awakening and collection of the first sample must have been verified by electronic-monitoring and sampling commenced within 15min of awakening. Participants (n=128) were young (median age of 20 years) and healthy. Cortisol values were determined in the 45min post-awakening period on 215 sampling days. On 127days, delay between verified awakening and collection of the first sample was less than 3min ('no delay' group); on 45days there was a delay of 4-6min ('short delay' group); on 43days the delay was 7-15min ('moderate delay' group). Cortisol values for verified sampling times accurately mapped on to the typical post-awakening cortisol growth curve, regardless of whether sampling deviated from desired protocol timings. This provides support for incorporating rather than excluding delayed data (up to 15min) in CAR analyses. For this population the fitted cortisol growth curve equation predicted a mean cortisol awakening level of 6nmols/l (±1 for 95% CI) and a mean CAR rise of 6nmols/l (±2 for 95% CI). We also modelled the relationship between real delay and CAR magnitude, when the CAR is calculated erroneously by incorrectly assuming adherence to protocol time. Findings supported a curvilinear hypothesis in relation to effects of sample delay on the CAR. Short delays of 4-6min between awakening and commencement of saliva sampling resulted in an overestimated CAR. Moderate delays of 7-15min were associated with an underestimated CAR. Findings emphasize the need to employ electronic-monitoring of sampling accuracy when measuring the CAR in the domestic setting.

Breathlessness and inflammation: potential relationships and implications.

PURPOSE OF REVIEW: Breathlessness and chronic inflammation both span a wide range of disease contexts and hold prognostic significance. The possibility of a causal relationship between the two has been hypothesized. The aims of this article are to review the intersections between breathlessness and inflammation in the literature, describe potential mechanisms connecting the two phenomena, and discuss the potential clinical implications of a causal relationship. RECENT FINDINGS: There is a very limited literature exploring the relationship between systemic inflammation and breathlessness in chronic obstructive pulmonary disease, heart failure, and cancer. One large study in cancer patients is suggestive of a weak association between self-reported breathlessness and inflammation. Studies exploring the relationship between inflammation and Medical Research Council Dyspnoea grade in chronic obstructive pulmonary disease patients have produced inconsistent findings. Although a causal relationship has not yet been proven, there is evidence to support the existence of potential mechanisms mediating a relationship. This evidence points to a role for the skeletal muscle and stress hormone systems. SUMMARY: There is much progress to be made in this area. Interventional studies, evaluating the impact of anti-inflammatory interventions on breathlessness, are needed to help determine whether a causal relationship exists. If proven, this relationship might have important implications for both the treatment and impact of breathlessness.

Use of Salivary Diurnal Cortisol as an Outcome Measure in Randomised Controlled Trials: a Systematic Review.

BACKGROUND: Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is associated with diverse adverse health outcomes, making it an important therapeutic target. Measurement of the diurnal rhythm of cortisol secretion provides a window into this system. At present, no guidelines exist for the optimal use of this biomarker within randomised controlled trials (RCTs). PURPOSE: The aim of this study is to describe the ways in which salivary diurnal cortisol has been measured within RCTs of health or behavioural interventions in adults. METHODS: Six electronic databases (up to May 21, 2015) were systematically searched for RCTs which used salivary diurnal cortisol as an outcome measure to evaluate health or behavioural interventions in adults. A narrative synthesis was undertaken of the findings in relation to salivary cortisol methodology and outcomes. RESULTS: From 78 studies that fulfilled the inclusion criteria, 30 included healthy participants (38.5 %), 27 included patients with physical disease (34.6 %) and 21 included patients with psychiatric disease (26.9 %). Psychological therapies were most commonly evaluated (n = 33, 42.3 %). There was substantial heterogeneity across studies in relation to saliva collection protocols and reported cortisol parameters. Only 39 studies (50 %) calculated a rhythm parameter such as the diurnal slope or the cortisol awakening response (CAR). Patterns of change in cortisol parameters were inconsistent both within and across studies and there was low agreement with clinical findings. CONCLUSIONS: Salivary diurnal cortisol is measured inconsistently across RCTs, which is limiting the interpretation of findings within and across studies. This indicates a need for more validation work, along with consensus guidelines.

Hair cortisol concentrations in relation to ill-being and well-being in healthy young and old females.

Hair cortisol concentration (HCC) provides a retrospective measure of long-term (i.e. over a period of months) cortisol secretion and has been shown to be elevated in relation to chronic stress conditions. However associations in healthy participants with subjective ill-being are less clear and associations with well-being have not been explored. The current study examined HCC in relation to independent comprehensive measures of ill-being (stress, depression, anxiety) and well-being (subjective happiness, life satisfaction, psychological well-being) in healthy young and old females (mean±SD: 19.5±2.2years and 78.6±6.7years respectively, total N=115). The data supported evidence of increased total cortisol secretion with increased age. No association between ill-being and HCC was found in either the young or older group of participants. A positive association between HCC and well-being was found in the older participant group which was independent of ill-being and potential confounds. These findings do not support associations between HCC and ill-being in healthy young or old females. However the results suggest that HCC is able to distinguish levels of well-being in healthy older females.

Relationship between post-awakening salivary cortisol and melatonin secretion in healthy participants.

We report the relationship between patterns of post-awakening salivary melatonin and cortisol secretion in healthy participants (n = 51; mean age 21.6 ± 5.0 years). Saliva samples were collected within the domestic setting, at 0-, 15-, 30-, and 45-min post-awakening on 2 consecutive typical weekdays. Analyses were undertaken on data with electronically verified sample timing accuracy (<5-min delay between awakening and the start of saliva sampling). Melatonin secretion declined linearly by an average of 29% within the first 45-min post-awakening. In contrast, there was a marked 112% surge in cortisol, characteristic of the cortisol awakening response. No day differences in melatonin or cortisol secretion were observed but melatonin concentrations were lower with later awakening. Despite contrasting post-awakening changes in these hormones, there was a lack of relationship between overall levels or patterns of melatonin and cortisol during this period.

The cortisol awakening response is associated with performance of a serial sequence reaction time task.

There is emerging evidence of a relationship between the cortisol awakening response (CAR) and the neural mechanisms underlying learning and memory. The aim of this study was to determine whether the CAR is associated with acquisition, retention and overnight consolidation or improvement of a serial sequence reaction time task. Salivary samples were collected at 0, 15, 30 and 45 min after awakening in 39 healthy adults on 2 consecutive days. The serial sequence reaction time task was repeated each afternoon. Participants completed the perceived stress scale and provided salivary samples prior to testing for cortisol assessment. While the magnitude of the CAR (Z score) was not associated with either baseline performance or the timed improvement during task acquisition of the serial sequence task, a positive correlation was observed with reaction times during the stable performance phase on day 1 (r=0.373, p=0.019). Residuals derived from the relationship between baseline and stable phase reaction times on day 1 were used as a surrogate for the degree of learning: these residuals were also correlated with the CAR mean increase on day 1 (r=0.357, p=0.048). Task performance on day 2 was not associated with the CAR obtained on this same day. No association was observed between the perceived stress score, cortisol at testing or task performance. These data indicate that a smaller CAR in healthy adults is associated with a greater degree of learning and faster performance of a serial sequence reaction time task. These results support recognition of the CAR as an important factor contributing to cognitive performance throughout the day.

Assessment of the cortisol awakening response: Expert consensus guidelines.

The cortisol awakening response (CAR), the marked increase in cortisol secretion over the first 30-45 min after morning awakening, has been related to a wide range of psychosocial, physical and mental health parameters, making it a key variable for psychoneuroendocrinological research. The CAR is typically assessed from self-collection of saliva samples within the domestic setting. While this confers ecological validity, it lacks direct researcher oversight which can be problematic as the validity of CAR measurement critically relies on participants closely following a timed sampling schedule, beginning with the moment of awakening. Researchers assessing the CAR thus need to take important steps to maximize and monitor saliva sampling accuracy as well as consider a range of other relevant methodological factors. To promote best practice of future research in this field, the International Society of Psychoneuroendocrinology initiated an expert panel charged with (i) summarizing relevant evidence and collective experience on methodological factors affecting CAR assessment and (ii) formulating clear consensus guidelines for future research. The present report summarizes the results of this undertaking. Consensus guidelines are presented on central aspects of CAR assessment, including objective control of sampling accuracy/adherence, participant instructions, covariate accounting, sampling protocols, quantification strategies as well as reporting and interpreting of CAR data. Meeting these methodological standards in future research will create more powerful research designs, thus yielding more reliable and reproducible results and helping to further advance understanding in this evolving field of research.

The role of peer physical activity champions in the workplace: a qualitative study.

AIMS: Peer health champions have been suggested as an important component of multilevel workplace interventions to promote healthy behaviours such as physical activity (PA). There is accumulating quantitative evidence of their effectiveness but as yet little exploration of why and how champions influence peer behaviour. The current study explores the role of peer physical activity champions (PPACs) in influencing colleagues' PA behaviour from the perspectives of both champions and colleagues. METHODS: Seven months after the introduction of a workplace PA programme in 17 small- and medium-sized enterprises (SMEs), two focus groups were held with PPACs and four with programme participants. Data were analysed using inductive thematic analysis. RESULTS: Three overarching themes were developed: how PPACs encourage PA, valuable PPAC characteristics and sustaining motivation for the PPAC role. Both direct encouragement from PPACs and facilitation of wider PA supportive social networks within the workplace encouraged behaviour change. PA behaviour change is a delicate subject and it was important that PPACs provided enthusiastic and persistent encouragement without seeming judgemental. Being a PA role model was also a valuable characteristic. The PPACs found it satisfying to see positive changes in their colleagues who had become more active. However, colleagues often did not engage in suggested activities and PPACs required resilience to maintain personal motivation for the role despite this. CONCLUSION: Incorporating PPACs into SME-based PA interventions is acceptable to employees. It is recommended that PPAC training includes suggestions for facilitating social connections between colleagues. Sensitivity is required when initiating and engaging in conversations with colleagues about increasing their PA. Programmes should ensure PPACs themselves are provided with social support, especially from others in the same role, to help sustain motivation for their role. These findings will be useful to health-promotion professionals developing workplace health programmes.