Éilis J. O’Reilly

Coffee, Caffeine, and Risk of Depression Among Women

BACKGROUND Caffeine is the worlds most widely used central nervous system stimulant, with approximately 80% consumed in the form of coffee. However, studies that analyze prospectively the relationship between coffee or caffeine consumption and depression risk are scarce. METHODS A total of 50,739 US women (mean age, 63 years) free of depressive symptoms at baseline (in 1996) were prospectively followed up through June 1, 2006. Consumption of caffeine was measured from validated questionnaires completed from May 1, 1980, through April 1, 2004, and computed as cumulative mean consumption with a 2-year latency period applied. Clinical depression was defined as self-reported physician-diagnosed depression and antidepressant use. Relative risks of clinical depression were estimated using Cox proportional hazards regression models. RESULTS During 10 years of follow-up (1996-2006), 2607 incident cases of depression were identified. Compared with women consuming 1 or less cup of caffeinated coffee per week, the multivariate relative risk of depression was 0.85 (95% confidence interval, 0.75-0.95) for those consuming 2 to 3 cups per day and 0.80 (0.64-0.99; P for trend<.001) for those consuming 4 cups per day or more. Multivariate relative risk of depression was 0.80 (95% confidence interval, 0.68-0.95; P for trend=.02) for women in the highest (≥550 mg/d) vs lowest (<100 mg/d) of the 5 caffeine consumption categories. Decaffeinated coffee was not associated with depression risk. CONCLUSIONS In this large longitudinal study, we found that depression risk decreases with increasing caffeinated coffee consumption. Further investigations are needed to confirm this finding and to determine whether usual caffeinated coffee consumption can contribute to depression prevention.

Anti-Epstein–Barr virus antibodies as serological markers of multiple sclerosis: a prospective study among United States military personnel

Background: Elevated Epstein–Barr virus (EBV) antibody titers are risk factors for multiple sclerosis (MS), but the strength and consistency of this association are not well characterized. Objectives: The objectives of this study were to determine whether this association is confounded by vitamin D or modified by gender or race, and the usefulness of EBV nuclear antigen (EBNA) antibodies as a marker for MS. Methods: We conducted a prospective study among US military personnel. Antibody titers against EBV antigens were measured in serum samples from 222 individuals who developed MS and 444 age, sex, and race/ethnicity matched controls. Conditional logistic regression was used to estimate relative risks. Results: MS risk increased with increasing titers of anti-EBNA complex (p < 10−9) and anti-EBNA-1 (p = 5.8 × 10−9) titers. MS risk was 36-fold higher among individuals with anti-EBNA complex IgG titers ≥320 than among those with titers <20 (95% confidence interval [CI] 9.6–136), and 8-fold higher among those with anti-EBNA-1 ≥320 than among those with anti-EBNA-1 <20 (95% CI 2.6–23). These associations were consistent across gender and race/ethnicity groups and independent from 25-hydroxyvitamin D levels. Areas under the receiver operating characteristic (ROC) curves were 0.67 for EBNA complex and 0.65 for EBNA-1. Conclusions: Serum titers of pre-onset anti-EBNA antibodies are strong, robust markers of MS risk and could be useful in an MS risk score.

Smoking is a risk factor for early conversion to clinically definite multiple sclerosis.

Background Cigarette smoking increases the risk for development of multiple sclerosis and modifies the clinical course of the disease. In this study, we determined whether smoking is a risk factor for early conversion to clinically definite multiple sclerosis after a clinically isolated syndrome. Methods We included 129 patients with a clinically isolated syndrome, disseminated white-matter lesions on brain magnetic resonance imaging, and positive oligoclonal bands in the cerebrospinal fluid. The patients’ smoking status was obtained at the time of the clinically isolated syndrome. Results During a follow-up time of 36 months, 75% of smokers but only 51% of non-smokers developed clinically definite multiple sclerosis, and smokers had a significantly shorter time interval to their first relapse. The hazard ratio for progression to clinically definite multiple sclerosis was 1.8 (95% confidence interval, 1.2–2.8) for smokers compared with non-smokers (P = 0.008). Conclusions Smoking is associated with an increased risk for early conversion to clinically definite multiple sclerosis after a clinically isolated syndrome, and our results suggest that smoking is an independent but modifiable risk factor for disease progression of multiple sclerosis. Therefore, it should be considered in the counseling of patients with a clinically isolated syndrome.

Human Endogenous Retrovirus-K18 env as a risk factor in multiple sclerosis

Background The human endogenous retrovirus (HERV)-K18 Env is an Epstein-Barr virus (EBV)-associated superantigen. Given the evidence for a role of EBV in the etiology of multiple sclerosis (MS), HERV-K18 Env is a plausible candidate for association with MS. Objective To assess whether variation in HERV-K18 Env is a risk factor for MS. Methods We developed a single nucleotide polymorphism-based genotyping method to determine the distribution of the three alleles of HERV-K18 env. We then conducted a nested case-control study including 207 MS cases and 403 matched controls. Analyses were replicated in an independent series of 909 MS cases and 339 controls. Results Overall, there was a significant association between HERV-K18 env genotype and MS risk (χ2 P = 0.03). As compared with K18.2/K18.2 individuals, risk of MS was three fold higher among K18.3/K18.3 individuals (P = 0.03). An increase in MS risk among carriers of the K18.3 allele was also observed in the replication study, but did not reach statistical significance. In pooled analyses, K18.3/K18.3 individuals had a significantly increased risk of MS (relative risks [RR] comparing K18.3/K18.3 vs K18.2/K18.2 = 2.7; 95% confidence interval: 1.1–6.4). Conclusion Variation in EBV-associated superantigen HERV-K18 Env could influence the genetic susceptibility to MS.

Caffeine and alcohol intakes have no association with risk of multiple sclerosis

Background: The association between alcohol and caffeine intakes and risk of multiple sclerosis (MS) is unclear; no prospective studies have examined this relationship. Objective: We examined intakes of alcohol and caffeine in relation to risk of multiple sclerosis. Methods: Intakes of alcohol and caffeine were examined in relation to the risk of MS in two large cohorts of women, the Nurses’ Health Study (NHS; 92,275 women followed from 1980 to 2004) and Nurses’ Health Study II (NHS II; 95,051 women followed from 1991 to 2005). Their diet was assessed at baseline and every four years thereafter. During the follow-up, 282 cases of MS were confirmed with onset of symptoms after baseline. Twenty-four cases were missing information on alcohol intake, leaving a total of 258 cases for the alcohol analyses. Results: Neither total alcohol consumption, nor consumption of beer, wine, or liquor was related to MS risk. The multivariable-adjusted pooled relative risk (RR) found by comparing categories of alcohol intake to 0 gm/day was 1.07 (95% CI: 0.32–1.99) for 0.1–4.9 gm/day, 1.01 (0.32–1.99) for 5.0–14.9 gm/day, 1.21 (0.69–2.15) for 15.0–29.9 gm/day, and 0.80 (0.32–1.99) for 30+ gm/day; (p for trend=0.89). Caffeine intake was also not significantly associated with MS risk. The multivariable adjusted pooled RR comparing highest to lowest quintile of caffeine intake was 1.14; 95% CI: 0.79–1.66; p for trend=0.71. Consideration of caffeinated and decaffeinated coffee separately also yielded null results. Conclusion: These results do not support an association between alcohol and caffeine intakes and MS risk.

Habitual intake of flavonoid subclasses and risk of colorectal cancer in 2 large prospective cohorts

Background: Flavonoids inhibit the growth of colon cancer cells in vitro. In a secondary analysis of a randomized controlled trial, the Polyp Prevention Trial, a higher intake of one subclass, flavonols, was statistically significantly associated with a reduced risk of recurrent advanced adenoma. Most previous prospective studies on colorectal cancer evaluated only a limited number of flavonoid subclasses and intake ranges, yielding inconsistent results. Objective: In this study, we examined whether higher habitual dietary intakes of flavonoid subclasses (flavonols, flavones, flavanones, flavan-3-ols, and anthocyanins) were associated with a lower risk of colorectal cancer. Design: Using data from validated food-frequency questionnaires administered every 4 y and an updated flavonoid food composition database, we calculated flavonoid intakes for 42,478 male participants from the Health Professionals Follow-Up Study and for 76,364 female participants from the Nurses’ Health Study. Results: During up to 26 y of follow-up, 2519 colorectal cancer cases (1061 in men, 1458 in women) were documented. Intakes of flavonoid subclasses were not associated with risk of colorectal cancer in either cohort. Pooled multivariable adjusted RRs (95% CIs) comparing the highest with the lowest quintiles were 1.04 (0.91, 1.18) for flavonols, 1.01 (0.89, 1.15) for flavones, 0.96 (0.84, 1.10) for flavanones, 1.07 (0.95, 1.21) for flavan-3-ols, and 0.98 (0.81, 1.19) for anthocyanins (all P values for heterogeneity by sex >0.19). In subsite analyses, flavonoid intake was also not associated with colon or rectal cancer risk. Conclusion: Our findings do not support the hypothesis that a higher habitual intake of any flavonoid subclass decreases the risk of colorectal cancer.

C-reactive protein, interleukin-6, soluble tumor necrosis factor α receptor 2 and incident clinical depression

BACKGROUND Despite an extensive literature on the role of inflammation and depression, few studies have evaluated the association between inflammatory biomarkers and depression in a prospective manner, and results are inconclusive. METHODS We conducted a prospective analysis of blood levels of CRP, IL-6 and TNFα-R2 in 4756 women participating in the Nurses׳ Health Study who donated blood in 1990 and were depression-free up to 1996. Participants were followed between 1996 and 2008 for reports of clinical diagnosis depression or antidepressant use. Additionally, we conducted cross-sectional analyses for CRP, IL-6 and TNFα-R2 and antidepressant use at time of blood draw. RESULTS After adjustment for body mass index, menopause status, use of anti-inflammatory drugs and other covariates, no significant associations between CRP, IL-6 and TNFα-R2 and incident depression were observed after a follow-up of 6-18 years. However, menopause status appears to modify the association between IL-6 and depression risk. In cross-sectional analyses, TNFα-R2 was associated with antidepressant use (OR=1.96, 95% CI=1.23-3.13, P-trend=0.001), but no significant associations were found for CRP and IL-6. LIMITATIONS Depression diagnosis was first assessed in 1996, 6 years after blood draw. However the biomarkers have high within-person correlations with measurements 4 years apart. CONCLUSIONS Blood levels of CRP, IL-6 and TNFα-R2 were not associated with incident depression over a follow-up of 6-18 years. In cross-sectional analyses, antidepressant use may be associated with higher levels of TNFα-R2 but no associations with depression or antidepressant use were observed in the prospective analysis.

Dietary flavonoid intake and risk of incident depression in midlife and older women

Background: The impact of dietary flavonoid intakes on risk of depression is unclear. Objective: We prospectively examined associations between estimated habitual intakes of dietary flavonoids and depression risk. Design: We followed 82,643 women without a previous history of depression at baseline from the Nurses’ Health Study [(NHS) aged 53–80 y] and the Nurses’ Health Study II [(NHSII) aged 36–55 y]. Intakes of total flavonoids and subclasses (flavonols, flavones, flavanones, anthocyanins, flavan-3-ols, polymeric flavonoids, and proanthocyanidins) were calculated from validated food-frequency questionnaires collected every 2–4 y. Depression was defined as physician- or clinician-diagnosed depression or antidepressant use and was self-reported in response to periodic questionnaires. Cox proportional hazards models were performed to examine associations. Results: A total of 10,752 incident depression cases occurred during a 10-y follow-up. Inverse associations between flavonol, flavone, and flavanone intakes and depression risk were observed. Pooled multivariable-adjusted HRs (95% CIs) were 0.93 (0.88, 0.99), 0.92 (0.86, 0.98), and 0.90 (0.85, 0.96) when comparing the highest (quintile 5) with the lowest (quintile 1) quintiles, respectively, with evidence of linear trends across quintiles (P-trend = 0.0004–0.08). In flavonoid-rich food-based analyses, the HR was 0.82 (95% CI: 0.74, 0.91) among participants who consumed ≥2 servings citrus fruit or juices/d compared with <1 serving/wk. In the NHS only, total flavonoids, polymers, and proanthocyanidin intakes showed significantly (9–12%) lower depression risks. In analyses among late-life NHS participants (aged ≥65 y at baseline or during follow-up), for whom we were able to incorporate depressive symptoms into the outcome definition, higher intakes of all flavonoid subclasses except for flavan-3-ols were associated with significantly lower depression risk; flavones and proanthocyanidins showed the strongest associations (HR for both: 0.83; 95% CI: 0.77, 0.90). Conclusions: Higher flavonoid intakes may be associated with lower depression risk, particularly among older women. Further studies are needed to confirm these associations.

Intakes of caffeine, coffee and tea and risk of amyotrophic lateral sclerosis: Results from five cohort studies

Caffeine is thought to be neuroprotective by antagonizing the adenosine A2A receptors in the brain and thereby protecting motor neurons from excitotoxicity. We examined the association between consumption of caffeine, coffee and tea and risk of amyotrophic lateral sclerosis (ALS). Longitudinal analyses based on over 1,010,000 males and females in five large cohort studies (the Nurses’ Health Study, the Health Professionals Follow-up Study, the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort Study, and the National Institutes of Health-AARP Diet and Health Study). Cohort-specific multivariable-adjusted risk ratios (RR) and 95% confidence intervals (CI) estimates of ALS incidence or death were estimated by Cox proportional hazards regression and pooled using random-effects models. Results showed that a total of 1279 cases of ALS were documented during a mean of 18 years of follow-up. Caffeine intake was not associated with ALS risk; the pooled multivariable-adjusted RR comparing the highest to the lowest quintile of intake was 0.96 (95% CI 0.81–1.16). Similarly, neither coffee nor tea was associated with ALS risk. In conclusion, the results of this large study do not support associations of caffeine or caffeinated beverages with ALS risk.

Serum urate at trial entry and ALS progression in EMPOWER

Abstract Our objective was to determine whether serum urate predicts ALS progression. A study population comprised adult participants of EMPOWER (n = 942), a phase III clinical trial to evaluate the efficacy of dexpramipexole to treat ALS. Urate was measured in blood samples collected during enrollment as part of the routine block chemistry. We measured outcomes by combined assessment of function and survival rank (CAFs), and time to death, by 12 months. Results showed that in females there was not a significant relation between urate and outcomes. In males, outcomes improved with increasing urate (comparing highest to lowest urate quartile: CAFS was 53 points better with p for trend = 0.04; and hazard ratio for death was 0.60 with p for trend = 0.07), but with adjustment for body mass index (BMI) at baseline, a predictor of both urate levels and prognosis, associations were attenuated and no longer statistically significant. Overall, participants with urate levels equal to or above the median (5.1 mg/dl) appeared to have a survival advantage compared to those below (hazard ratio adjusted for BMI: 0.67; 95% confidence interval 0.47–0.95). In conclusion, these findings suggest that while the association between urate at baseline and ALS progression is partially explained by BMI, there may be an independent beneficial effect of urate.