Andrea S. Vincent

Lifetime Adversity Leads to Blunted Stress Axis Reactivity: Studies from the Oklahoma Family Health Patterns Project

BACKGROUND Can stressful events in early life alter the response characteristics of the human stress axis? Individual differences in stress reactivity are considered potentially important in long-term health and disease; however, little is known about the sources of these individual differences. We present evidence that adverse experience in childhood and adolescence can alter core components of the stress axis, including cortisol and heart rate reactivity. METHODS We exposed 354 healthy young adults (196 women) to public speaking and mental arithmetic stressors in the laboratory. Stress responses were indexed by self-report, heart rate, and cortisol levels relative to measures on a nonstress control day. Subjects were grouped into those who had experienced 0, 1, or 2 or more significant adverse life events, including Physical or Sexual Adversity (mugged, threatened with a weapon, experienced a break-in or robbery or raped or sexually assaulted by a relative or nonrelative) or Emotional Adversity (separation from biological mother or father for at least 6 months before age 15). RESULTS Experience of adversity predicted smaller heart rate and cortisol responses to the stressors in a dose-dependent fashion (0 > 1 > 2 or more events) (F values = 5.79 and 8.11, p values < .004) for both men and women. This was not explained by differences in socioeconomic status, the underlying cortisol diurnal cycle, or subjective experience during the stress procedure. CONCLUSIONS The results indicate a long-term impact of stressful life experience on the reactivity of the human stress axis.

Cortisol responses to mental stress, exercise, and meals following caffeine intake in men and women

Caffeine elevates cortisol secretion, and caffeine is often consumed in conjunction with exercise or mental stress. The interactions of caffeine and stress on cortisol secretion have not been explored adequately in women. We measured cortisol levels at eight times on days when healthy men and women consumed caffeine (250 mg x 3) and underwent either mental stress or dynamic exercise protocols, followed by a midday meal, in a double blind, placebo-controlled, crossover design. Men and women had similar cortisol levels at the predrug baselines, but they responded differently to mental stress and exercise. The cortisol response to mental stress was smaller in women than in men (p=.003). Caffeine acted in concert with mental stress to further increase cortisol levels (p=.011), the effect was similar in men and women. Exercise alone did not increase cortisol, but caffeine taken before exercise elevated cortisol in both men and women (ps<.05). After a postexercise meal, the women had a larger cortisol response than the men, and this effect was greater after caffeine (p<.01). Cortisol release in response to stress and caffeine therefore appears to be a function of the type of stressor and the sex of the subject. However, repeated caffeine doses increased cortisol levels across the test day without regard to the sex of the subject or type of stressor employed (p<.00001). Caffeine may elevate cortisol by stimulating the central nervous system in men but may interact with peripheral metabolic mechanisms in women.

Blood Pressure Response to Caffeine Shows Incomplete Tolerance After Short-Term Regular Consumption

Abstract—Caffeine acutely raises blood pressure (BP). The clinical significance of this effect depends on whether BP responses persist in persons who consume caffeine on a daily basis. Accordingly, the ability of caffeine to raise BP after 5 days of regular daily intake was tested in a randomized controlled trial. Individual differences in tolerance formation were then examined. Men (n=49) and women (n=48) completed a double-blind, crossover trial conducted over 4 weeks. During each week, subjects abstained for 5 days from dietary caffeine and instead used capsules totaling 0 mg, 300 mg, and 600 mg of caffeine per day in 3 divided doses. On day 6, in the laboratory, they used capsules with either 0 mg or 250 mg of caffeine at 9:00 am and 1:00 pm. Systolic/diastolic BP increases as a result of 250 mg of caffeine remained significant (P <0.006/0.001) at all levels of previous daily consumption. Individual difference comparisons found that although half the subjects had complete loss of systolic and diastolic BP responses to the challenge doses, the other half showed no loss in BP response, even after using 600 mg of caffeine per day for the previous 5 days (F >7.90, P <0.001). The sexes did not differ in degree of tolerance formation. Daily caffeine consumption failed to eliminate the BP response to repeated challenge doses of caffeine in half of the healthy adults who were tested. Caffeine may therefore cause persistent BP effects in persons who are regular consumers, even when daily intake is at moderately high levels.

Caffeine Stimulation of Cortisol Secretion Across the Waking Hours in Relation to Caffeine Intake Levels

Objective: Caffeine increases cortisol secretion in people at rest or undergoing mental stress. It is not known whether tolerance develops in this response with daily intake of caffeine in the diet. We therefore tested the cortisol response to caffeine challenge after controlled levels of caffeine intake. Methods: Men (N = 48) and women (N = 48) completed a double-blind, crossover trial conducted over 4 weeks. On each week, subjects abstained for 5 days from dietary caffeine and instead took capsules totaling 0 mg, 300 mg, and 600 mg/day in 3 divided doses. On day 6, they took capsules with either 0 mg or 250 mg at 9:00 AM, 1:00 PM, and 6:00 PM, and cortisol was sampled from saliva collected at 8 times from 7:30 AM to 7:00 PM. Results: After 5 days of caffeine abstinence, caffeine challenge doses caused a robust increase in cortisol across the test day (p < .0001). In contrast, 5 days of caffeine intake at 300 mg/day and 600 mg/day abolished the cortisol response to the initial 9:00 AM caffeine dose, although cortisol levels were again elevated between 1:00 PM and 7:00 PM (p = .02 to .002) after the second caffeine dose taken at 1:00 PM. Cortisol levels declined to control levels during the evening sampling period. Conclusion: Cortisol responses to caffeine are reduced, but not eliminated, in healthy young men and women who consume caffeine on a daily basis. ANOVA = analysis of variance; C = caffeine; HPAC = hypothalamic-pituitary-adrenocortical axis; P = placebo; ACTH = adrenocorticotropin.

Greater Discounting of Delayed Rewards in Young Adults with Family Histories of Alcohol and Drug Use Disorders: Studies from the Oklahoma Family Health Patterns Project

BACKGROUND Increased discounting of delayed rewards may be a premorbid characteristic and possible risk factor for alcohol and other drug use disorders; however, previous studies have found no or minimal differences in delay discounting in individuals at risk for substance use disorders based on family history. It is possible that increased delay discounting may be more closely associated with antisocial traits, evident in a subset of individuals with positive family histories of alcohol and drug use disorders, and that previous studies were underpowered for detecting subtle to modest overall group differences. METHODS In this study, we compared 143 young adults with family histories of alcohol and other drug use disorders (FH+) and 155 young adults with no such histories (FH-) on delay discounting and subsequently examined how delay discounting was related to antisocial traits and other selected psychological and demographic variables. RESULTS The FH+ group discounted delayed rewards more than the FH- group. Subsequent analyses revealed that increased delay discounting was correlated with having more parents and grandparents with alcohol and drug use disorders, more antisocial traits, more depressive tendencies and lower IQs, and lower income. After controlling for all these relationships, more antisocial traits and lower IQ still predicted greater delay discounting, and subsequent analysis revealed that the greater delay discounting in the FH+ group was mediated by this groups greater number of individuals with antisocial traits. CONCLUSION FH+ individuals who discount delayed rewards more may be at increased risk for developing alcohol and other drug use disorders; however, additional descriptive studies and longitudinal studies are needed.

Copper Deficiency After Gastric Surgery: A Reason for Caution

Background:Acquired copper deficiency in adults leads to hematological and neurological manifestations that mimic vitamin B12 deficiency. A significant number of patients with copper deficiency syndrome have a history of gastric surgery, often remote. We sought to determine whether copper deficiency is present in a population of individuals with longstanding partial gastric resection. Methods:Serum copper, ceruloplasmin, and zinc levels were determined in 20 patients with a history of partial gastric resection and 50 controls, randomly selected from the Oklahoma City Veterans Affairs Medical Center electronic database. Results:Hypocupremia and symptoms of copper deficiency were detected in patients with partial gastric resection in contrast to controls (3/20 versus 0/50, P = 0.02). Serum copper and ceruloplasmin levels were significantly lower in individuals with partial gastric resection than in controls (P = 0.04 and P = 0.001, respectively). The mean interval between gastric surgery and testing was 20.7 years. Conclusions:Our results indicate that a significant number of individuals with longstanding history of partial gastric resection have undiagnosed hypocupremia. Screening for copper deficiency after gastric surgery may prevent the development of hematological and neurological complications in these patients.

Coated‐platelet levels are influenced by smoking, aspirin, and selective serotonin reuptake inhibitors

Coated-platelets are a subpopulation of platelets observed upon dual-agonist stimulation with collagen and thrombin [1]. Unlike single-agonist activated platelets, coated-platelets support a robust prothrombinase activity and express high levels of several procoagulant proteins on their surface including factor V, fibrinogen, fibronectin, thrombospondin and von Willebrand factor [1]. Procoagulant proteins on coated-platelets are conjugated with serotonin via a transglutaminase-mediated reaction, and fibrinogen and thrombospondin bound to the platelet surface provide binding sites to stabilize serotonin-conjugated proteins [1]. The ability to produce coated-platelets varies dramatically among normal blood donors, ranging from 15% to 55% [1], although the basis for this wide variability is unknown. Prompted by the procoagulant potential of coated-platelets [1] and our previous unpublished observations, we have examined the effect of cigarette smoking,HMG-CoA reductase inhibitors (statins), selective serotonin reuptake inhibitors (SSRI) and antiplatelet agents on coated-platelet production in adults. Seventy subjects from the University of Oklahoma Health Sciences Center and Oklahoma City Veterans Administration Medical Center were enrolled in the study. The study was approved by the Institutional Review Board, and informed consent was obtained for all study subjects. The study population consisted of hospital volunteers, visitors and employees. Exclusion criteria included: concurrent diagnosis of dementia, stroke, transient ischemic attack (TIA), acute coronary syndrome (ACS), active infectious disease, bleeding diathesis or previous history of stroke, TIA or ACS within one year of enrollment. Smoking status, medications, gender and age were recorded at the time of enrollment. All individuals on antiplatelet medication reported daily use of aspirin ranging between 81.5 and 325 mg. Race was recorded through selfidentification for all study subjects. The subjects mean age was 64.8 ± 8.15 years (mean ± SD). The clinical characteristics of this study population including demographics, smoking status and use of aspirin, SSRI and statin medications are listed in Table 1. Blood was drawn, platelet-rich plasma was prepared, and coated-platelets were assayed as described [1,2]. Briefly, platelets were activated concurrently with thrombin and convulxin, a ligand for the collagen receptor glycoprotein VI, and the coated-platelet population was identified by its ability to bind biotinylated-fibrinogen [2]. Analysis was performed by flow cytometry, and coated-platelets were expressed as a percentage of all platelets [2]. Statistical analyses were performed using SAS (SAS System forWindows, version 8.2, SAS Institute Inc., Cary, NC, USA). Multiple-way ANOVAs were conducted to evaluate the effect of smoking, gender, race and use of aspirin, SSRIs and statins on coated-platelet synthesis. Regression analyses were used to evaluate relationships between coated-platelets levels and other independent variables (e.g. age). A P-value of < 0.05 was considered to be statistically significant. The subjects coated-platelet levels were 31.6% ± 13.2% (mean ± SD), with a range from 6.7% to 58.9%, consistent with previous published findings [1]. A six-way ANOVA was conducted to evaluate the effects of gender, race, smoking status, aspirin, statins and SSRIs on coated-platelets levels. All main effects and two-way interactions were considered. Nonsignificant interactions were excluded from the final model. Significant main effects were detected for smoking status [F(1, 62) = 6.3, P = 0.015], use of aspirin [F(1, 62) = 5.6, P = 0.022] and use of SSRIs [F(1, 62) = 4.2, P = 0.046]. Specifically, coated-platelet levels were significantly higher in individuals currently smoking when compared to individuals not smoking (32.6% ± 4.1%, n = 14 vs. 23.2% ± 3.1%, n = 56; adjusted mean ± 1SEM). Subjects taking aspirin had significantly lower coated-platelet levels than those not on aspirin (23.8% ± 4.0%, n = 22 vs. 32.0 ± 3.1, n = 48). Individuals using SSRIs had significantly lower coated-platelet levels when compared with persons not taking SSRIs (21.9% ± 5.6%, n = 5 vs. 33.9 ± 2.3, n = 65). The main effects for gender, race and statin use were not statistically significant for coated-platelet synthesis (P-values > 0.19). However, a significant interaction for coated-platelet potential was detected between race and statin use [F(1, 62) = 6.0, P = 0.018]. Specifically, coated-platelet Correspondence: Calin I. Prodan, 711 S.L. Young Blvd, PPOB Suite 215, Oklahoma City, OK 73104, USA. Tel.: +1 405 271 4113; fax: +1 405 271 5723; e-mail: calinprodan@ouhsc.edu

Coated‐platelets in ischemic stroke: differences between lacunar and cortical stroke

Background: Coated‐platelets are a subset of platelets with procoagulant potential observed upon dual agonist stimulation with collagen and thrombin. Objective: The goal was to investigate if coated‐platelet production differs between patients with lacunar ischemic stroke and non‐lacunar (cortical) ischemic stroke as compared with controls. Patients and methods: Blood samples from 60 patients with ischemic stroke (20 lacunar and 40 cortical) and 70 controls were analyzed for coated‐platelet production. Results: Coated‐platelet production was significantly lower in patients with lacunar stroke (21.8 ± 11.4%, mean ± 1 SD) as compared with either controls (31.6 ± 13.2%, P = 0.008) or patients with cortical stroke (39.4 ± 12.7%, P < 0.001). The increase in coated‐platelets for patients with cortical stroke as compared with controls was also significant (P = 0.008). Conclusions: Our results indicate a marked difference in coated‐platelet synthesis in lacunar vs. non‐lacunar stroke, thereby providing additional support for the existence of distinct pathological processes underlying these two subtypes of ischemic stroke. Further investigation of the role of coated‐platelets in stroke, taking into account these preliminary findings, is warranted.

Coated-platelet levels and progression from mild cognitive impairment to Alzheimer disease

Objectives: Coated-platelets are a subset of platelets produced by dual-agonist activation with collagen and thrombin. These platelets retain full-length amyloid precursor protein on their surface, are elevated in patients with amnestic as compared to nonamnestic mild cognitive impairment (MCI), and correlate with disease progression in Alzheimer disease (AD). Prompted by these findings, we investigated the association between coated-platelet production in amnestic MCI and rate of progression to AD. Methods: Coated-platelet levels were assayed in 74 patients with amnestic MCI who were subsequently followed longitudinally for up to 36 months in an outpatient dementia clinic. Levels are reported as percent of cells converted into coated-platelets. Subjects were categorized into tertiles of coated-platelet levels. The distributions of time to progression to AD were estimated for each tertile using cumulative incidence curves and compared statistically using a log-rank test. Cox proportional hazards regression was used to adjust for potential confounders. Results: The 24-month cumulative incidence of progression to AD was different among tertiles: 4% for the first tertile (lowest coated-platelet levels), 13% for the second tertile, and 37% for the third tertile (overall log-rank test, p = 0.02). The hazard rate of progression to AD for patients in the highest coated-platelet tertile was 5.1 times that for patients in the lowest tertile (p = 0.04), whereas the hazard rate for the middle tertile was similar to that for the lowest tertile (hazard rate ratio = 1.5, p = 0.7). Conclusions: Elevated coated-platelet levels in patients with amnestic MCI are associated with increased risk for progression to AD.

Use of a resting control day in measuring the cortisol response to mental stress: Diurnal patterns, time of day, and gender effects

In laboratory studies of individual differences in stress reactivity, cortisol responses are typically measured by comparing a prestress baseline with values obtained at the end of the stressor. In the present study, we measured cortisol in this manner on a stress day, but we also took samples on a second day when the volunteers rested in the lab at the same time of day and for the same duration. We compared stress responses as the difference from pre- to poststress and also poststress vs. rest day control. The latter method allowed a greater appreciation of how stress perturbed the underlying diurnal baseline. Although the effect of stress was statistically significant when measured as the change from pre- to poststress, the magnitude of the effect was 54% larger when measured against the time-of-day control from the rest day. In particular the diurnal control method provided a wider range of stress values that potentially provide a greater range of response values in carrying out analyses of individual differences.