David Q. Beversdorf

Accelerated Telomere Erosion Is Associated with a Declining Immune Function of Caregivers of Alzheimer’s Disease Patients

Caregivers of Alzheimer’s disease patients endure chronic stress associated with a decline of immune function. To assess the psychological and immunological changes of caregivers, we compared depressive symptoms, PBMC composition, in vitro activation-induced proliferation and cytokine production, and telomere length and telomerase activity of 82 individuals (41 caregivers and 41 age- and gender-matched controls). We found depressive symptoms were significantly higher in caregivers than in controls (p < 0.001). Correspondingly, caregivers had significantly lower T cell proliferation but higher production of immune-regulatory cytokines (TNF-α and IL-10) than controls in response to stimulation in vitro. We examined the impact of these changes on cellular replicative lifespan and found that caregivers had significantly shorter telomere lengths in PBMC than controls (6.2 and 6.4 kb, respectively, p < 0.05) with similar shortening in isolated T cells and monocytes and that this telomere attrition in caregivers was not due to an increase of shorter telomere possessing T cell subsets in PBMC. Finally, we showed that basal telomerase activity in PBMC and T cells was significantly higher in caregivers than in controls (p < 0.0001), pointing to an unsuccessful attempt of cells to compensate the excessive loss of telomeres in caregivers. These findings demonstrate that chronic stress is associated with altered T cell function and accelerated immune cell aging as suggested by excessive telomere loss.

Childhood Adversity Heightens the Impact of Later-Life Caregiving Stress on Telomere Length and Inflammation

Objective: To address the question of whether childhood abuse and other adversities have lasting, detectable consequences for inflammation and cell aging late in life, and whether the effects are large enough to be discernible beyond that of a major chronic stressor, dementia family caregiving. Previous research on the physical health consequences of childhood abuse and other adversities has been based on data from young or middle-aged adults. Method: In this community sample of 132 healthy older adults (mean age = 69.70 years; standard deviation = 10.14), including 58 dementia family caregivers and 74 noncaregivers, blood samples were analyzed for interleukin (IL)-6, tumor necrosis factor (TNF)-&agr;, and telomere length, a measure of cell aging. Depressive symptoms were assessed by the Center for Epidemiological Studies Depression Scale. Results: After controlling for age, caregiving status, gender, body mass index, exercise, and sleep, the presence of multiple childhood adversities was related to both heightened IL-6 (0.37 ± 0.03 log10 pg/mL versus 0.44 ± 0.03 log10 pg/mL) and shorter telomeres (6.51 ± 0.17 Kb versus 5.87 ± 0.20 Kb), compared with the absence of adversity; the telomere difference could translate into a 7- to 15-year difference in life span. Abuse was associated with heightened IL-6 and TNF-&agr; levels; for TNF-&agr;, this relationship was magnified in caregivers compared with controls. Moreover, abuse and caregiving status were associated significantly and independently with higher levels of depressive symptoms. Conclusions: Adverse childhood events are related to continued vulnerability among older adults, enhancing the impact of chronic stressors. Childhood adversities cast a very long shadow. BMI = body mass index; CES-D = Center for Epidemiological Studies Depression Scale; CRP = C-reactive protein; IL = interleukin; PBMCs = peripheral blood mononuclear cells; TNF = tumor necrosis factor.

Depressive symptoms, omega-6:omega-3 fatty acids, and inflammation in older adults.

Objective: To address how interactions between polyunsaturated fatty acid (PUFA) levels and depressive symptoms were related to proinflammatory cytokine synthesis. Depression and stress promote proinflammatory cytokine production. Dietary intakes of omega-3 (n-3) and omega-6 (n-6) PUFAs also influence inflammation; high n-6:n-3 ratios enhance proinflammatory cytokine production, although n-3 has anti-inflammatory properties. Methods: Blood samples from 43 older adults (mean age = 66.67 years, SD = 10.09) provided data on PUFAs and tumor necrosis factor (TNF)-&agr;, interleukin (IL)-6, and IL-6 soluble receptor (sIL-6r). Depressive symptoms were assessed by the Center for Epidemiological Studies Depression Scale. Results: Depressive symptoms and n-6:n-3 ratios worked together to enhance proinflammatory cytokines beyond the contribution provided by either variable alone, with substantial variance explained by their interaction: 13% for IL-6 and 31% for TNF-&agr;, whereas full models accounted for 18% and 40%, respectively. Although predicted cytokine levels were consistent across n-6:n-3 ratios with low depressive symptoms, higher n-6:n-3 ratios were associated with progressively elevated TNF-&agr; and IL-6 levels as depressive symptoms increased. Higher levels of sIL-6r were associated with higher n-6:n-3 ratios. Six individuals who met the criteria for major depressive disorder had higher n-6:n-3 ratios and TNF-&agr;, IL-6, and sIL-6r levels than those who did not meet the criteria; excluding these six individuals reduced the variance explained by the depressive symptoms and n-6:n-3 ratio interaction. Conclusions: Diets with high n-6:n-3 PUFA ratios may enhance the risk for both depression and inflammatory diseases. AA = arachidonic acid; BMI = body mass index; CES-D = Center for Epidemiological Studies Depression Scale; DHA = docosahexanoic acid; EPA = eicosapentaenoic acid; IL-6 = interleukin-6; sIL-6r = IL-6 soluble receptor; n-3 = omega-3; n-6 = omega-6; NF-&kgr;B = nuclear factor kappa B; PSQI = Pittsburgh Sleep Quality Index; PUFA = polyunsaturated fatty acid; TNF-&agr; = tumor necrosis factor-&agr;.

Beta-adrenergic Modulation of Cognitive Flexibility during Stress

Stress-induced activation of the locus ceruleus-norepinephrine (LC-NE) system produces significant cognitive and behavioral effects, including enhanced arousal and attention. Improvements in discrimination task performance and memory have been attributed to this stress response. In contrast, for other cognitive functions that require cognitive flexibility, increased activity of the LC-NE system may produce deleterious effects. The aim of the present study was to determine the effect of pharmacological modulation of the LC-NE system on stress-induced impairments in cognitive flexibility performance in healthy individuals. Cognitive performance, plus psychological and physiological parameters for 16 adults without any history of anxiety disorders, was assessed during four test sessions: stress and no-stress, with each condition tested after administration of propranolol and placebo. The Trier Social Stress Test, a public-speaking and mental arithmetic stressor, was presented to participants for the stress sessions, whereas a similar, but nonstressful, control task (reading, counting) was utilized for the no-stress sessions. Tests of cognitive flexibility included lexical-semantic and associative problem-solving tasks (anagrams, Compound Remote Associates Test). Visuo-spatial memory and motor processing speed tests served as control tasks. Results indicate that (1) stress impaired performance on cognitive flexibility tasks, but not control tasks; (2) compared to placebo, cognitive flexibility improved during stress with propranolol. Therefore, psychological stress, such as public speaking, negatively impacts performance on tasks requiring cognitive flexibility in normal individuals, and this effect is reversed by beta-adrenergic antagonism. This may provide support for the hypothesis that stress-related impairments in cognitive flexibility are related to the noradrenergic system.

Chronic stress, daily stressors, and circulating inflammatory markers.

OBJECTIVES Acute laboratory stressors elicit elevations in serum levels of interleukin-6 (IL-6) and C-reactive protein (CRP). Chronic stressors, such as family dementia caregiving, promote a state of chronic low-grade elevation in circulating inflammatory markers. The recurrent daily stressors associated with chronic stress may lead to repeated and sustained activation of the physiological stress systems. The present study evaluated the possibility that greater exposure and reactivity to daily stressors fueled increased levels of circulating inflammatory markers among family dementia caregivers, compared with noncaregiving controls. METHODS This cross-sectional study included 53 caregivers and 77 noncaregiving controls. A semistructured interview assessed the occurrence of daily stressors in the past 24 h. A blood sample provided data on two inflammatory markers, C-reactive protein (CRP) and interleukin-6 (IL-6). RESULTS Caregivers were more likely to experience multiple stressors in the past 24 h than noncaregiving controls. The occurrence of multiple daily stressors was associated with greater serum IL-6 and CRP levels. The greater occurrence of daily stressors in the past 24 h partially mediated the relationship between dementia caregiving and CRP levels. CONCLUSION These results suggest that the cumulative effect of daily stressors promotes elevations in inflammatory markers. Greater exposure to daily stressors may be a psychobiological mechanism leading to elevations in CRP levels among family dementia caregivers.

Noradrenergic modulation of cognitive flexibility in problem solving.

Stress causes impaired performance on tests of creativity. Drugs that block beta-adrenergic receptors improve test performance in patients with test anxiety. Furthermore, catecholamine precursors (L-DOPA) reduce the flexibility of semantic networks. Our study investigated the effect of noradrenergic system modulation on cognitive flexibility in problem solving. Eighteen normal subjects undertook three problem solving tasks (number series, shape manipulation and anagrams) 45 min after propranolol, placebo and ephedrine. On the task that appeared to rely most heavily on cognitive flexibility (anagrams), subjects who were most able to solve these problems demonstrated significantly shorter solution times (logarithmic scores) after propranolol than after ephedrine. This suggested that the noradrenergic system exerts a modulatory effect on cognitive flexibility in problem solving.

Poorer self-rated health is associated with elevated inflammatory markers among older adults

OBJECTIVE Self-rated health is a strong independent predictor of mortality after accounting for objective health status, behavioral risk factors, and sociodemographic characteristics. However, mechanisms underlying this association are largely unexplained. Inflammation has been associated with increased risk of morbidity and mortality in the elderly. The current study aimed to: (1) examine associations between self-rated health and serum inflammatory markers in older adults; (2) examine the relative strength of these associations for self-rated health versus self-rated change in recent health; (3) examine components of self-rated health that may underlie the association between inflammation and global self-rated health. METHODS Self-rated health, as measured by the RAND health survey, and serum interleukin (IL)-6 and C-reactive protein (CRP) were assessed among 250 generally healthy older adults (185 women, 65 men; average age=63.8±13.7 years). RESULTS A series of linear regression analyses demonstrated that poorer self-rated health was significantly associated with higher IL-6 and CRP. These relationships remained after controlling for age, body mass index, gender, and objective health conditions. These associations also remained after controlling for depressive symptoms, neuroticism, perceived change in health over the past year, and health behaviors (smoking, sleep quality, and physical activity). Analyses of RAND component measures demonstrated that poorer physical functioning was significantly associated with IL-6; the relationship between global self-rated health and both IL-6 and CRP remained after accounting for perceived physical functioning. CONCLUSIONS Poorer self-rated health is associated with elevated serum inflammatory markers among generally healthy older adults. The relationship of self-rated health with inflammatory markers is not secondary to depressive symptoms, neuroticism, or recent changes in perceived health. Subjective ratings of health provide important clinical information regarding inflammatory status, beyond traditional objective risk factors, even among generally healthy individuals.

Two-Year Evaluation of a Vocational Support Program for Adults on the Autism Spectrum

In this article the authors provide a description and evaluation of a vocational support program for adults with autism spectrum disorders (ASD). They followed 9 participants through 2 years of the program. Increases in employment rates and income were found for program participants, and 7 participants retained their initial job placements through the 2-year period. Employers rated program participants highly on a range of important job skills, although these individuals continued to experience social challenges in the workplace. Case notes offer further insight into the experiences of adults with ASD in the workplace. Overall, the results suggest that individuals on the autism spectrum can be successful in competitive, entry-level employment.

Outcomes of a Social and Vocational Skills Support Group for Adolescents and Young Adults on the Autism Spectrum.

Adolescents and young adults With autism spectrum disorders (ASD) frequently experience social isolation and vocational failure. Although social skills groups are vital, relatively feW model programs have been developed for this age group. This article revieWs the model and evaluation of the Aspirations program, an 8-Week social and vocational skills support group for adolescents and young adults With ASD. Self-report measures, including appraisal of peer relations and empathy, Were completed pre- and post-Aspirations. Data from structured observations Were also examined for changes in frequency of contributions made by group members over the course of the program. In addition, notes taken during staff meetings and feedback sessions With group members, and separately With their parents, Were revieWed for further evidence of the programs success. The results from these measures support the efficacy of the Aspirations program and provide insight into implementing a successful model for this population.

The effect of semantic and emotional context on written recall for verbal language in high functioning adults with autism spectrum disorder

OBJECTIVE Several deficits have been proposed to account for cognitive impairment in autism including an inability to comprehend the perspectives of others (“theory of mind”), an inability to process emotional information, and difficulty drawing together diverse information in context (“central coherence”). Because context (central coherence) and emotion can influence memory, a study was designed to show if autism spectrum disorder was associated with impaired utilisation of context and emotion in recall; and if impairments in theory of mind processing would influence recall in autism spectrum disorder. METHODS Ten high functioning subjects with autism spectrum disorder and 13 age and IQ matched controls were tested using recall tests. In the first coherence memory test, subjects listened to a series of word lists that were in varying degrees of syntactic and semantic (coherent) order and were asked to recall the words. In the second coherence memory test, subjects listened to stories consisting of sentences that were, or were not, in logical (coherent) order. In the emotional memory test, the subjects listened to sentences that were highly emotional or non-emotional. In the theory of mind test, the subjects listened to stories requiring varying levels of understanding of the perspectives of others. RESULTS There were no significant differences between groups in recall of coherent versus incoherent word lists, nor was there a significant difference between groups in recall of coherent versus incoherent stories. However, the control subjects recalled more of the emotional than non-emotional sentences, whereas the autism spectrum disorder group did not show such a difference. No significant difference existed in recall of stories requiring varying levels of understanding of the perspectives of others among subjects with autism spectrum disorder, and subjects with autism spectrum disorder did not differ from control subjects in the influence of theory of mind content on story recall. CONCLUSION The study shows that memory in high functioning adults with autism spectrum disorder is facilitated by emotional content to a lesser degree than it is facilitated by coherence. Therefore, impairments in emotional processing cannot be considered as simply an effect of the “weak central coherence” theory in autism spectrum disorder. Whereas the reasons for this emotional deficit are unknown, evidence of abnormalities of the limbic structures in autism spectrum disorder may provide an anatomical explanation.