Self-reported health (SRH) has been consistently shown to predict morbidity and mortality. However, the mechanisms underlying this association are poorly understood. The study by Cohen and colleagues reported in this issue of Psychosomatic Medicine fills this gap by examining a potential biological mechanism: alteration of immune system functioning. The study shows that SRH predicted common cold after experimentally controlled virus inoculation in healthy individuals. More specifically, SRH predicted the cold-related illness expression as measured by objective clinical signs, whereas it did not predict the infection rates as measured by predefined increases in specific antibodies. This editorial discusses the significance of this study and the possibility that inflammation, an innate immune response, is a link between SRH and common cold risk. Because the illness expression of cold is generally attributed to increased local inflammation and SRH has been found associated with increased systemic inflammation, it is possible that SRH is a correlate of a heightened systemic inflammatory state and thus leads to increased local inflammatory responses after an exposure to a cold virus. SRH was also associated with well-known risk factors for inflammation in this study, such as overweight, perceived stress, and social isolation. Because of the strong predictive value of SRH for future morbidity and mortality and the simple low-cost tools that enable its assessment, SRH has the potential to identify high-risk individuals in various public health settings. Future research is needed to address the translational applicability of these findings and to further the mechanistic investigation in high-risk groups including older adults.

Aim

To examine and compare the effects of subjective and objective social isolation on behavioral health in elderly adults.

Methods

A systematic search of PubMed was performed for original research articles from peer-reviewed journals examining one of the following topics: "Social isolation and sleep disturbance", "social isolation and depression", or "social isolation and fatigue in older adults". Studies were selected following the criteria established based on the aim of this review. Data were extracted from the articles by two independent reviewers. Due to the heterogeneity in study designs and outcome measures of the included studies, qualitative and narrative analyses were conducted.

Results

The set criteria were used to select a total of 16 studies for the review. Of the 16, 13 were cross-sectional studies. The characteristics of study populations were identified as follows. A total of 12 studies randomly selected subjects irrespective of pre-existing health conditions. Consequently, an unspecified number of the study subjects had chronic diseases in the studies compared. In addition, cultural and ethnic backgrounds of studies in this review were diverse, and included subjects living in North America, South America, Asia, Europe, and Oceania. Both subjective and objective types of social isolation increased behavioral symptoms, such as sleep disturbance, depressive symptoms, and fatigue in older adults. Furthermore, a few recent studies reported stronger effects of subjective social isolation than objective social isolation on sleep disturbance and depressive symptoms.

Conclusion

Social isolation affects behavioral health in older adults. Compared to the objective social isolation, subjective social isolation contributes more significantly to sleep disturbance and depression.

Objective

Although the interrelationships between sleep disturbance, inflammation, and depression have been found, molecular mechanisms that link these conditions are largely unknown. Kynurenine metabolism is hypothesized to be a key mechanism that links inflammation and depression. Inflammation activates the kynurenine pathway, leading to increases in 3-hydroxykynurenine (3HK) and quinolinic acid (QA), potentially neurotoxic metabolites, and decreases in kynurenic acid (KynA), a potentially neuroprotective compound. This relative neurotoxic shift in the balance of kynurenine metabolites has been associated with depression, but never been examined regarding sleep disturbance. We tested the association between sleep disturbance and this relative neurotoxic shift in 68 currently depressed, 26 previously depressed, and 66 never depressed subjects.

Methods

Sleep disturbance was assessed using the Pittsburgh Sleep Quality Index. Serum concentrations of kynurenine metabolites were measured using high performance liquid chromatography. Putative neuroprotective indices reflecting the relative activity of neuroprotective and neurotoxic kynurenine metabolites were calculated as KynA/QA and KynA/3HK (primary outcomes).

Results

Sleep disturbance was associated with reduced KynA/QA in the currently depressed group only (unadjusted beta -0.43, p<0.001). This association remained significant even after controlling for age, sex, analysis batch, body-mass index, and depressive symptoms in currently depressed subjects (adjusted beta -0.30, p=0.02). There was no significant association between sleep disturbance and KynA/3HK in any of the groups. Sleep disturbance was associated with increased C-reactive protein in currently depressed subjects only (unadjusted beta 0.38, p=0.007; adjusted beta 0.33, p=0.02).

Conclusion

These data support the hypothesis that altered kynurenine metabolism may molecularly link sleep disturbance and depression.

Study objectives

The objective of this study was to examine the associations between the temporal and severity characteristics of sleep disturbance and subsequent depression in community-dwelling older adults.

Design

A prospective cohort study with assessment of sleep disturbance and depression at baseline and across 2 years of follow-up.

Setting

Three urban communities in the United States.

Participants

Community-dwelling older adults in whom prior depression (n = 145), current depression (n = 68), or never mentally ill (n = 206) were diagnosed at the baseline assessment.

Measurements and results

Major depression at year 2, defined by the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders. Among patients with either a depression history or current depression at baseline, persistent sleep disturbance throughout year 1 was associated with persistent or recurrent depression at year 2, after adjustment for group status, antidepressant and hypnotic sedative use, severity of depressive symptoms, chronic medical burden, and sociodemographic variables (adjusted odds ratio = 5.20, 95% confidence interval [CI] = 1.16 to 23.29). Among those who were not depressed at year 1, persistent sleep disturbance throughout year 1 predicted depression recurrence during year 2 (adjusted hazards ratio = 16.05, CI = 1.21 to 213.06), independent of the severity of sleep disturbance. None of the older adults who were never mentally ill developed a depression.

Conclusions

Persistent sleep disturbance during a year-long period is associated with depression the following year. Among older adults with prior depression, identification of those with persistent sleep disturbance may optimize the efficacy of sleep related interventions to improve depression remission and/or prevent late-life depression.

Both sleep disturbance and social isolation increase the risk for morbidity and mortality. Systemic inflammation is suspected as a potential mechanism of these associations. However, the complex relationships between sleep disturbance, social isolation, and inflammation have not been examined in a population-based longitudinal study. This study examined the longitudinal association between sleep disturbance and systemic inflammation, and the moderating effects of social isolation on this association. The CARDIA study is a population-based longitudinal study conducted in four US cities. Sleep disturbance - i.e., insomnia complaints and short sleep duration - was assessed in 2962 African-American and White adults at baseline (2000-2001, ages 33-45years). Circulating C-reactive protein (CRP) was measured at baseline and follow-up (2005-2006). Interleukin-6 (IL-6) and subjective and objective social isolation (i.e., feelings of social isolation and social network size) were measured at follow-up. Sleep disturbance was a significant predictor of inflammation five years later after full adjustment for covariates (adjusted betas: 0.048, P=0.012 for CRP; 0.047, P=0.017 for IL-6). Further adjustment for baseline CRP revealed that sleep disturbance also impacted the longitudinal change in CRP levels over five years (adjusted beta: 0.044, P=0.013). Subjective social isolation was a significant moderator of this association between sleep disturbance and CRP (adjusted beta 0.131, P=0.002). Sleep disturbance was associated with heightened systemic inflammation in a general population over a five-year follow-up, and this association was significantly stronger in those who reported feelings of social isolation. Clinical interventions targeting sleep disturbances may be a potential avenue for reducing inflammation, particularly in individuals who feel socially isolated.

Purpose

To evaluate the association between the rates of progressive visual field loss and the occurrence of depressive symptoms in patients with glaucoma followed over time.

Design

Prospective observational cohort study.

Participants

The study included 204 eyes of 102 patients with glaucomatous visual field defects on standard automated perimetry (SAP).

Methods

All patients had Geriatric Depression Scale (GDS) questionnaires and visual field tests obtained over a mean follow-up time of 2.2±0.6 years. Change in depressive symptoms was assessed by calculating the difference between GDS scores at the last follow-up visit from those at baseline. Rates of visual field loss were assessed by SAP. An integrated binocular visual field was estimated from the monocular SAP tests, and rates of change in mean sensitivity (MS) over time were obtained from linear mixed models. Regression models were used to investigate the association between progressive visual field loss and changes in depressive symptoms, adjusting for potentially confounding clinical and socioeconomic variables.

Main outcome measures

The association between rates of change in binocular SAP MS and change in GDS questionnaire scores.

Results

There was a significant correlation between change in the GDS scores during follow-up and change in binocular SAP sensitivity. Each 1 decibel (dB)/year change in binocular SAP MS was associated with a change of 2.0 units in the GDS scores during the follow-up period (P = 0.025). In a multivariable model adjusting for baseline disease severity, change in visual acuity, age, gender, race, Montreal Cognitive Assessment score, education, income, and comorbidity index, each 1 dB/year change in binocular SAP MS was associated with a change of 3.0 units in the GDS score (P = 0.019).

Conclusions

Faster visual field progression was associated with the occurrence of depressive symptoms in patients with glaucoma.

Unlabelled

One proposed mechanism for the association between social isolation and poor health outcomes is inflammation. Lonely or socially disconnected individuals show greater inflammatory responses, including up-regulation of pro-inflammatory gene expression, and people who are sensitive to cues of social disconnection (e.g., high levels of anxious attachment) exhibit greater inflammation in response to psychological stress. However, no studies have examined how sensitivity to social disconnection may influence pro-inflammatory responses to an inflammatory challenge. In the present study, we investigated the impact of sensitivity to social disconnection (a composite score comprised of loneliness, anxious attachment, fear of negative evaluation, and rejection sensitivity) on pro-inflammatory cytokines and gene expression in response to endotoxin, an inflammatory challenge, vs. placebo in a sample of one hundred and fifteen (n=115) healthy participants. Results showed that those who are more sensitive to social disconnection show increased pro-inflammatory responses (i.e., increased levels of tumor necrosis factor-alpha and interleukin-6) to endotoxin, as well as up-regulation of multiple genes related to inflammation. Furthermore, bioinformatics analyses revealed that those in the endotoxin group who are more sensitive to social disconnection exhibited a conserved transcriptional response to adversity (CTRA) regulatory profile, involving up-regulation of beta-adrenergic and pro-inflammatory transcription control pathways and down-regulation of antiviral transcription factors in response to endotoxin. These results may ultimately have implications for understanding the links between social isolation, inflammation, and health.

Clinical trials registration

ClinicalTrials.gov NCT01671150.

C-reactive Protein (CRP) measurements above 10 mg/L have been conventionally treated as acute inflammation and excluded from epidemiologic studies of chronic inflammation. However, recent evidence suggest that such CRP elevations can be seen even with chronic inflammation. The authors assessed 3,300 participants in The Coronary Artery Risk Development in Young Adults study, who had two or more CRP measurements between 1992/3 and 2005/6 to a) investigate characteristics associated with repeated CRP elevation above 10 mg/L; b) identify subgroups at high risk of repeated elevation; and c) investigate the effect of different CRP thresholds on the probability of an elevation being one-time rather than repeated. 225 participants (6.8%) had one-time and 103 (3.1%) had repeated CRP elevation above 10 mg/L. Repeated elevation was associated with obesity, female gender, low income, and sex hormone use. The probability of an elevation above 10 mg/L being one-time rather than repeated was lowest (51%) in women with body mass index above 31 kg/m(2), compared to 82% in others. These findings suggest that CRP elevations above 10 mg/L in obese women are likely to be from chronic rather than acute inflammation, and that CRP thresholds above 10 mg/L may be warranted to distinguish acute from chronic inflammation in obese women.