Rita A. Popat

Effect of reproductive factors and postmenopausal hormone use on the risk of Parkinson disease

Objective: Parkinson disease (PD) is less common in women possibly because of hormonal or reproductive influences. The objective of this study was to evaluate the associations of reproductive factors and postmenopausal hormone use with the risk of PD among postmenopausal women. Methods: Incident cases (n = 178) and randomly selected age-matched controls (n = 189) who were members of the Kaiser Permanente Medical Care Program (KPMCP) of Northern California participated in the study conducted during the years 1994 to 1995. Statistical analyses were carried out using logistic regression. Results: The association of postmenopausal hormone use with PD risk depended on the type of menopause. Among women with history of a hysterectomy with or without an oophorectomy, estrogen use alone was associated with a 2.6-fold increased risk (adjusted odds ratio (OR) 2.6, 95% CI: 1.1 to 6.1) and significant trends in the risk of PD were observed with increasing duration of estrogen use, but disease risk was not influenced by recency of use. In contrast, among women with natural menopause, no increased risk of PD was observed with hormone use (estrogen alone or a combined estrogen-progestin regimen). Early age at final menstrual period (44 years or younger) was associated with reduction in risk (adjusted OR 0.5, 95% CI: 0.3 to 1.0). Age at menarche and parity were not associated with the risk of PD. Conclusion: Postmenopausal use of estrogen alone may increase the risk of Parkinson disease (PD) among women with a hysterectomy. Among women with natural menopause for whom the usual treatment is combined estrogen-progestin therapy, no increased risk of PD was observed.

Coffee, ADORA2A, and CYP1A2: the caffeine connection in Parkinson’s disease

Background and purpose:  In 1‐methyl‐4‐phenyl 1,2,3,6‐tetrahydropyridine animal models of Parkinson’s disease (PD), caffeine protects neurons by blocking the adenosine receptor A2A (ADORA2A). Caffeine is primarily metabolized by cytochrome P450 1A2 (CYP1A2). Our objective was to examine whether ADORA2A and CYP1A2 polymorphisms are associated with PD risk or modify the caffeine–PD association.

Effects of endogenous and exogenous estrogen exposures in midlife and late-life women on episodic memory and executive functions

Cognitive aging affects episodic memory and executive functions, and these vulnerable domains are postulated to be modulated by endogenous and exogenous estrogen exposures. In midlife and late-life women without dementia, estrogen effects on cognition can be examined through associations with concentrations of serum estrone and estradiol and through clinical trials of estrogen-containing hormone therapy. To this end, we reviewed published studies including at least 100 women (larger studies are less prone to publication bias) addressing associations between estrogen levels and performance on neuropsychological tests of episodic memory or executive functions (including working memory; seven studies), or that reported results of placebo-controlled clinical trials of hormone therapy with objective measures within these cognitive domains (eight studies). Results were considered separately for midlife and late-life (age≥65 years) women. There were no consistent associations between endogenous serum estrogen concentrations and episodic memory or executive functions in naturally menopausal midlife women or in older postmenopausal women. Clinical trial findings suggested no substantial impact of exogenous estrogens on episodic memory or executive functions over time frames of up to several years. A quantitative synthesis of clinical trial results supported the inference of absence of effect. This overall conclusion of no substantial effect on episodic memory or executive functions might reassure women concerned by potential adverse cognitive consequences of menopause or of relatively short-term midlife hormone therapy. There was no apparent window of opportunity during which exogenous hormones might benefit near-term cognition, but included studies provided limited power to identify such a window. Conclusions are tempered by small numbers of studies, imprecise estimates of long-term estrogen exposures, and narrow range of neuropsychological tests. Long-term (late-life) cognitive consequence of midlife estrogen exposures are poorly addressed by current data, as are cognitive consequences of surgical menopause and cognitive consequences of exogenous estrogens during the menopause transition. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.

Short- and long-term outcomes of necrotizing enterocolitis in infants with congenital heart disease.

OBJECTIVE. Congenital heart disease is a significant risk factor for necrotizing enterocolitis in the term infant. We compared the short- and long-term necrotizing enterocolitis–specific outcomes of infants with congenital heart disease with those of neonates without congenital heart disease. PATIENTS AND METHODS. A retrospective study of 202 patients with necrotizing enterocolitis treated at our center from May 1999 to August 2007 was conducted. Infants with necrotizing enterocolitis were grouped according to the presence (n = 76) or absence (n = 126) of congenital heart disease. Demographic and necrotizing enterocolitis–specific outcomes were recorded. The groups were compared by nonparametric and χ2 analyses. Univariate and multivariate odds ratios were determined for each outcome. RESULTS. The average birth weight and gestational age of the 2 groups were not significantly different. The initial necrotizing enterocolitis severity, as determined by Bell stage, was less for necrotizing enterocolitis subjects with congenital heart disease compared with those without congenital heart disease. When controlling for birth weight and gestational age, the congenital heart disease group had decreased risk of perforation, need for a bowel operation, strictures, need for a stoma, sepsis, and short bowel syndrome compared with the non–congenital heart disease group. Although not statistically significant, subjects with congenital heart disease had a trend toward decreased risk of death from necrotizing enterocolitis, recurrent necrotizing enterocolitis, and need for peritoneal drainage. CONCLUSIONS. Infants with congenital heart disease and necrotizing enterocolitis have decreased risk of major short- and long-term negative outcomes associated with necrotizing enterocolitis compared with neonates without congenital heart disease. Differences in initial severity, range of age at diagnosis, and prognoses between subjects with necrotizing enterocolitis with and without cardiac disease suggest that necrotizing enterocolitis in the cardiac patient is a distinct disease process and should be labeled cardiogenic necrotizing enterocolitis.

Racial/Ethnic Differences in Gestational Diabetes Prevalence and Contribution of Common Risk Factors

BACKGROUND The White House, the American Heart Association, the Agency for Healthcare Research and Quality, and the National Heart, Lung and Blood Institute have all recently acknowledged the need to disaggregate Asian American subgroups to better understand this heterogeneous racial group. This study aims to assess racial/ethnic differences in relative contribution of risk factors of gestational diabetes mellitus (GDM) among Asian subgroups (Asian Indian, Chinese, Filipino, Japanese, Korean, and Vietnamese), Hispanics, non-Hispanic blacks, and non-Hispanic whites. METHODS Pregnant women in 2007-2012 were identified through California state birth certificate records and linked to the electronic health records in a large mixed-payer ambulatory care organisation in Northern California (n = 24 195). Relative risk and population attributable fraction (PAF) for specific racial/ethnic groups were calculated to assess the contributions of advanced maternal age, overweight/obesity (Centers for Disease Control and Prevention (CDC) standards and World Health Organization (WHO)/American Diabetes Association (ADA) body mass index cut-offs for Asians), family history of type 2 diabetes, and foreign-born status. RESULTS GDM was most prevalent among Asian Indians (19.3%). Relative risks were similar across all race/ethnic groups. Advanced maternal age had higher PAFs in non-Hispanic whites (22.5%) and Hispanics (22.7%). Meanwhile family history (Asian Indians 22.6%, Chinese 22.9%) and foreign-borne status (Chinese 40.2%, Filipinos 30.2%) had higher PAFs in Asian subgroups. Overweight/obesity was the most important GDM risk factor for non-Hispanic whites, Hispanics, Asian Indians, and Filipinos when the WHO/ADA cut-off points were applied. Advanced maternal age was the only risk factor studied that was modified by race/ethnicity, with non-Hispanic white and Hispanic women being more adversely affected than other racial/ethnic groups. CONCLUSIONS Overweight/obesity, advanced maternal age, family history of type 2 diabetes, and foreign-borne status are important risk factors for GDM. The relative contributions of these risk factors differ by race/ethnicity, mainly due to differences in population prevalence of these risk factors.

Risk of Cardiovascular Disease Associated with a Restless Legs Syndrome Diagnosis in a Retrospective Cohort Study from Kaiser Permanente Northern California.

INTRODUCTION Recent cross-sectional studies suggest that restless legs syndrome (RLS) may be associated with an increased prevalence of cardiovascular disease (CVD) comorbidity or risk factors. We evaluated whether primary or secondary RLS was associated with an increased risk of incident cardiovascular disease in a retrospective cohort study within Kaiser Permanente Northern California (KPNC). METHODS We identified members of KPNC with primary RLS and secondary RLS between 1999 and 2008 by an algorithm that incorporated longitudinal clinical records related to the diagnosis and treatment of RLS and comorbidities. We then matched each RLS case with up to 50 individuals with no clinical records of RLS by age, sex, race/ethnicity, zip code, and membership duration. For the analyses we excluded any individual with coronary artery disease (CAD: angina, acute myocardial infarction, coronary revascularization procedure, CAD death), CVD (CAD plus stroke), and hypertension at baseline. New cardiovascular events were determined from clinical records. Follow-up ended at an outcome event, disenrollment from KPNC, or death, whichever occurred earliest. There were over 473,358 person-y of follow-up in this cohort analysis with a mean follow-up time of 3.91 y and range from 6 mo to 12 y. Survival analysis techniques, including survival curves and proportional hazard regression models, were used to assess the association between RLS status and CVD. RESULTS There were 7,621 primary RLS and 4,507 secondary RLS cases identified and included in the study. In general, primary RLS cases were younger and had less comorbidity than secondary RLS cases. During the follow-up period, CVD was diagnosed in 478 primary RLS cohort members, CAD was diagnosed in 310, and hypertension events were identified in 1,466. Diagnosis in secondary RLS cohort members was made during the follow-up period with 451, 338, and 598 CVD, CAD, and hypertension events, respectively. Subjects with primary RLS had a similar risk of incident CVD (hazard ratio (HR) = 0.95; 95% confidence interval (CI) = 0.86-1.04) and CAD (HR = 0.99; 95% CI = 0.89-1.13) to the comparison cohort, with a slight elevation in the risk of hypertension events (HR = 1.19; 95% CI = 1.12-1.25), after multivariable adjustment. Individuals classified as secondary RLS had a significant increased risk of CVD (HR = 1.33; 95% CI = 1.21-1.46), CAD (HR = 1.40; 95% CI = 1.25-1.56), and hypertension (HR = 1.28; 95% CI = 1.18-1.40). CONCLUSION Primary restless legs syndrome (RLS) was not associated with new-onset cardiovascular disease (CVD) or coronary artery disease (CAD) but was associated with a slight increased risk of hypertension. In contrast, secondary RLS was associated with an increased risk of CVD, CAD, and hypertension.

Association of DRD2 and DRD3 polymorphisms with Parkinson's disease in a multiethnic consortium

OBJECTIVE To examine genetic associations of polymorphisms in the dopamine receptor D2 (DRD2) and D3 (DRD3) genes with risk of Parkinsons disease (PD). METHODS The study included 1325 newly diagnosed patients with PD and 1735 controls from a consortium of five North American case-control studies. We collected risk factor information by in-person or telephone interview. Six DRD2 and two DRD3 polymorphisms were genotyped using a common laboratory. Odds ratios were estimated using logistic regression. RESULTS Among non-Hispanic whites, homozygous carriers of Taq1A DRD2 (rs1800497) polymorphism had an increased risk of PD compared to homozygous wildtype carriers (OR=1.5, 95% CI 1.0-2.3). In contrast, the direction of association for Taq1A polymorphism was opposite for African-Americans, showing an inverse association with PD risk (OR=0.10, 95% CI 0.2-0.7). Among white Hispanics who carried two alleles, the Ser9Gly DRD3 (rs6280) polymorphism was associated with a decreased risk of PD (OR=0.4, 95% CI 0.2-0.8). The inverse association of smoking with PD risk was not modified by any of the DRD2 or DRD3 polymorphisms. CONCLUSIONS DRD2 polymorphisms are unlikely to be true disease-causing variants; however, three DRD2 polymorphisms (including Taq1A) may be in linkage disequilibrium with possible disease associated variants in the DRD2-ANKK1-NCAM1-TTC12 gene cluster.

Reliability and validity of two self-administered questionnaires for screening restless legs syndrome in population-based studies

BACKGROUND A reliable and valid questionnaire for screening restless legs syndrome (RLS) is essential for determining accurate estimates of disease frequency. In a 2002 NIH-sponsored workshop, experts suggested three mandatory questions for identifying RLS in epidemiologic studies. We evaluated the reliability and validity of this RLS-NIH questionnaire in a community-based sample and concurrently developed and evaluated the utility of an expanded screening questionnaire, the RLS-EXP. METHODS The study was conducted at Kaiser Permanente of Northern California and the Stanford University Sleep Clinic. We evaluated test-retest reliability in a random sample of subjects with prior physician-assigned RLS (n=87), subjects with conditions frequently misclassified as RLS (n=31), and healthy subjects (n=9). Validity of both instruments was evaluated in a random sample of 32 subjects, and in-person examination by two RLS specialists was used as the gold standard. RESULTS For the first three RLS-NIH questions, the kappa statistic for test-retest reliability ranged from 0.5 to 1.0, and sensitivity and specificity was 86% and 45%, respectively. For the subset of five questions on RLS-EXP that encompassed cardinal features for diagnosing RLS, kappas were 0.4-0.8, and sensitivity and specificity were 81% and 73%, respectively. CONCLUSIONS Sensitivity of RLS-NIH is good; however, the specificity of the instrument is poor when examined in a sample that over-represents subjects with conditions that are commonly misclassified as RLS. Specificity can be improved by including separate questions on cardinal features, as used in the RLS-EXP, and by including a few questions that identify RLS mimics, thereby reducing false positives.

Early surgical intervention or watchful waiting for the management of asymptomatic mitral regurgitation: a systematic review and meta-analysis

BACKGROUND Discordance between studies drives continued debate regarding the best management of asymptomatic severe mitral regurgitation (MR). The aim of the present study was to conduct a systematic review and meta-analysis of management plans for asymptomatic severe MR, and compare the effectiveness of a strategy of early surgery to watchful waiting. METHODS A systematic review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Studies were excluded if they: (I) lacked a watchful waiting cohort; (II) included symptomatic patients; or (III) included etiologies other than degenerative mitral valve disease. The primary outcome of the study was all-cause mortality at 10 years. Secondary outcomes included operative mortality, repair rate, repeat mitral valve surgery, and development of new atrial fibrillation. RESULTS Five observational studies were eligible for review and three were included in the pooled analysis. In asymptomatic patients without class I triggers (symptoms or ventricular dysfunction), pooled analysis revealed a significant reduction in long-term mortality with an early surgery approach [hazard ratio (HR) =0.38; 95% confidence interval (CI): 0.21-0.71]. This survival benefit persisted in a sub-group analysis limited to patients without class II triggers (atrial fibrillation or pulmonary hypertension) [relative risk (RR) =0.85; 95% CI: 0.75-0.98]. Aggregate rates of operative mortality did not differ between treatment arms (0.7% vs. 0.7% for early surgery vs. watchful waiting). However, significantly higher repair rates were achieved in the early surgery cohorts (RR =1.10; 95% CI: 1.02-1.18). CONCLUSIONS Despite disagreement between individual studies, the present meta-analysis demonstrates that a strategy of early surgery may improve survival and increase the likelihood of mitral valve repair compared with watchful waiting. Early surgery may also benefit patients when instituted prior to the development of class II triggers.

Effect of non‐steroidal anti‐inflammatory medications on the risk of amyotrophic lateral sclerosis

Inflammatory processes may be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). We examined the association of non‐steroidal anti‐inflammatory drugs (NSAIDs) with the risk of ALS in case‐control study of incident cases (n = 111) conducted within the Kaiser Permanente Medical Care Program of Northern California during the years 1996–2000. Controls (n = 258) randomly selected from the same population were frequency matched by age and gender to the ALS cases. Information regarding use of NSAIDs (non‐aspirin and aspirin) and three classes of ‘control’ medications was collected by in‐person structured interview. Subjects who used medication at least twice a week for at least a month were classified as ‘ever users’. Multivariable logistic regression models were adjusted for age, gender, history of osteoarthritis/rheumatoid arthritis and pain, and other medication use. Overall, there was no association between NSAID use and ALS; however, some sex differences were noted for non‐aspirin NSAID use. Among men, non‐aspirin NSAID use was associated with a two‐fold increased risk of ALS (adjusted odds ratio (OR) 2.0, 95% confidence interval (CI) 1.0–3.9), whereas among women, non‐aspirin NSAID use was not associated with increased ALS risk (adjusted OR 0.5, 95% CI 0.2–1.2). ALS risk was not associated with aspirin use or with ‘control’ medications. This study did not find any evidence to suggest that NSAID use reduces the risk of ALS. The observed sex differences with non‐aspirin NSAID use could be due to chance or an unmeasured confounder.