Environmentally Relevant Levels of Antiepileptic Carbamazepine Altered Intestinal Microbial Composition and Metabolites in Amphibian Larvae.

There is growing concern about the potential ecological risks posed by pharmaceutical residues in the aquatic environment. However, our understanding of the toxic effects of antiepileptic pharmaceuticals, such as carbamazepine (CBZ), on aquatic animal larvae is still limited. In this study, the tadpoles of the black-spotted pond frog (Pelophylax nigromaculatus) were exposed to environmentally relevant concentrations of CBZ (0.3 and 3.0 µg/L) for 30 days, and their growth, intestinal microbial composition, and metabolites were investigated to assess the potential toxic effects of CBZ in non-targeted aquatic organisms. Some tadpoles died during exposure, but there was no significant among-group difference in the survival and growth rates. CBZ exposure significantly altered the composition of tadpole intestinal microbiota. Relative abundances of some bacterial genera (e.g., Blautia, Prevotella, Bacillus, Microbacterium, etc.) decreased, while others (e.g., Paucibacter, etc.) increased in CBZ-exposed tadpoles. Interestingly, CBZ-induced alterations in some bacteria might not necessarily lead to adverse outcomes for animals. Meanwhile, small molecular intestinal metabolites related to energy metabolism, and antioxidant and anti-inflammatory activities were also altered after exposure. Taken together, environmentally relevant levels of CBZ might alter the metabolic and immune performances of amphibian larvae by modifying the abundance of some specific bacteria and the level of metabolites in their intestines, thereby potentially causing a long-term effect on their fitness.

Air Pollutants and Risk of Parkinson's Disease among Women in the Sister Study.

BACKGROUND: Air pollutants may contribute to the development of Parkinson's disease (PD), but empirical evidence is limited and inconsistent. OBJECTIVES: This study aimed to prospectively investigate the associations of PD with ambient exposures to fine particulate matter with aerodynamic diameter ≤2.5µm (PM2.5) and nitrogen dioxide (NO2). METHODS: We analyzed data from 47,108 US women from the Sister Study, enrolled from 2003-2009 (35-80 years of age) and followed through 2018. Exposures of interest included address-level ambient PM2.5 and NO2 in 2009 and their cumulative averages from 2009 to PD diagnosis with varying lag-years. The primary outcome was PD diagnosis between 2009 and 2018 (n=163). We used multivariable Cox proportional hazards and time-varying Cox models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: NO2 exposure in 2009 was associated with PD risk in a dose-response manner. The HR and 95% CI were 1.22 (95% CI: 1.03, 1.46) for one interquartile [4.8 parts per billion (ppb)] increment in NO2, adjusting for age, race and ethnicity, education, smoking status, alcohol drinking, caffeine intake, body mass index, physical activity, census region, residential area type, area deprivation index (ADI), and self-reported health status. The association was confirmed in secondary analyses with time-varying averaged cumulative exposures. For example, the multivariable adjusted HR for PD per 4.8 ppb increment in NO2 was 1.25 (95% CI: 1.05, 1.50) in the 2-year lag analysis using cumulative average exposure. Post hoc subgroup analyses overall confirmed the association. However, statistical interaction analyses found that the positive association of NO2 with PD risk was limited to women in urban, rural, and small town areas and women with ≥50th percentile ADI but not among women from suburban areas or areas with <50th percentile ADI. In contrast, PM2.5 exposure was not associated with PD risk with the possible exception for women from the Midwest region of the US (HRinterquartile-range=2.49, 95% CI: 1.20, 5.14) but not in other census regions. DISCUSSION: In this nationwide cohort of US women, higher level exposure to ambient NO2 is associated with a greater risk of PD. This finding needs to be independently confirmed and the underlying mechanisms warrant further investigation. https://doi.org/10.1289/EHP13009.

Polygenic risk score for Parkinson's disease and olfaction among middle-aged to older women.

INTRODUCTION: Olfactory impairment and Parkinson's disease (PD) may share common genetic and environmental risk factors. This study investigates the association of a PD polygenic risk score (PRS) with olfaction, and whether the associations are modified by environmental exposures of PM2.5, NO2, or smoking. METHODS: This analysis included 3358 women (aged 50-80) from the Sister Study with genetic data and results from the Brief Smell Identification Test (B-SIT) administered in 2018-2019. PD PRS was calculated using 90 single nucleotide polymorphisms. Olfactory impairment was defined with different B-SIT cutoffs, and PD diagnosis was adjudicated via expert review. We report odds ratios (ORs) and 95% confidence intervals (CIs) from multivariable logistic regression. RESULTS: As expected, PD PRS was strongly associated with the odds of having PD (OR highest vs. lowest quartile = 3.79 (1.64, 8.73)). The highest PRS quartile was also associated with olfactory impairment, with OR ranging from 1.24 (0.98, 1.56) for a B-SIT cutoff of 9 to 1.42 (1.04, 1.92) for a cutoff of 6. For individual B-SIT items, the highest PRS quartile was generally associated with lower odds of correctly identifying the odorant, albeit only statistically significant for pineapple (0.72 (0.56, 0.94), soap (0.76 (0.58, 0.99)) and rose (0.70 (0.54, 0.92)). The association of PD PRS with olfactory impairment was not modified by airborne environmental exposures or smoking. CONCLUSION: These preliminary data suggest that high PD genetic susceptibility is associated with olfactory impairment in middle-aged and older women.

Ambient Air Pollutants and Olfaction among Women 50-79 Years of Age from the Sister Study.

BACKGROUND: Poor olfaction is common in older adults and may have profound adverse implications on their health. However, little is known about the potential environmental contributors to poor olfaction. OBJECTIVE: We investigated ambient fine particulate matter [PM ≤2.5µm in aerodynamic diameter (PM2.5)] and nitrogen dioxide (NO2) in relation to poor olfaction in middle-aged to older women. METHODS: The Sister Study is a nationwide cohort of 50,884 women in the United States with annual average air pollutant exposures estimated based on participants' residences from enrollment (2003-2009) through 2017. This analysis was limited to 3,345 women, 50-79 years of age as of January 2018, who completed the Brief Smell Identification Test (B-SIT) in 2018-2019. Poor olfaction was defined as a B-SIT score of ≤9 in the primary analysis. We conducted multivariable logistic regressions, accounting for covariates and study sampling design. RESULTS: Overall, we found little evidence for associations of air pollutants with poor olfaction. The odds ratio (OR) and 95% confidence interval (CI) of poor olfaction for each interquartile range (IQR) increment of air pollutants in 2006 were 1.03 (95% CI: 0.91, 1.17) for PM2.5 (per 3.3 µg/m3) and 1.08 (95% CI: 0.96, 1.22) for NO2 (per 5.7 ppb). Results were similar in the analyses using the most recent (2017) or the cumulative average (2006-2017) air pollutant exposure data. Secondary analyses suggested potential association in certain subgroups. The OR per IQR was 1.35 (95% CI: 1.11, 1.65) for PM2.5 among younger participants (<54.2 years of age) and 1.87 (95% CI: 1.29, 2.71) for NO2 among current smokers. DISCUSSION: This study did not find convincing evidence that air pollutants have lasting detrimental effects on the sense of smell of women 50-79 years of age. The subgroup analyses are exploratory, and the findings need independent confirmation. https://doi.org/10.1289/EHP12066.

Parkinson's Disease Case Ascertainment in the Sister Study: A Cohort for Environmental Health Research.

BACKGROUND: Large prospective studies are essential for investigating the environmental causes of Parkinson's disease (PD), but PD diagnosis via clinical exams is often infeasible in such studies. OBJECTIVE: To present case ascertainment strategy and data collection in a US cohort of women. METHODS: In the Sister Study (n = 50,884, baseline ages 55.6±9.0), physician-made PD diagnoses were first reported by participants or their proxies. Cohort-wide follow-up surveys collected data on subsequent diagnoses, medication usage and PD-relevant motor and nonmotor symptoms. We contacted self-reported PD cases and their treating physicians to obtain relevant diagnostic and treatment history. Diagnostic adjudication was made via expert review of all available data, except nonmotor symptoms. We examined associations of nonmotor symptoms with incident PD, using multivariable logistic regression models and reported odds ratio (OR) and 95% confidence intervals (CI). RESULTS: Of the 371 potential PD cases identified, 242 diagnoses were confirmed. Compared with unconfirmed cases, confirmed cases were more likely to report PD diagnosis from multiple sources, medication usage, and motor and nonmotor features consistently during the follow-up. PD polygenic risk score was associated with confirmed PD (ORinter-quartile range = 1.74, 95% CI: 1.45-2.10), but not with unconfirmed cases (corresponding OR = 1.05). Hyposmia, dream-enacting behaviors, constipation, depression, unexplained weight loss, dry eyes, dry mouth, and fatigue were significantly related to PD risk, with ORs from 1.71 to 4.88. Only one of the eight negative control symptoms was associated with incident PD. CONCLUSION: Findings support our PD case ascertainment approach in this large cohort of women. PD prodromal presentation is likely beyond its well-documented profile.

Assessment of Self-reported Sense of Smell, Objective Testing, and Associated Factors in Middle-aged and Older Women.

Importance: Poor olfaction is common in older adults and signifies multiple adverse health outcomes, but it often goes unrecognized. Objective: To characterize the self-awareness of poor olfaction in women, including its prevalence, associated factors, reporting reliability, validity against an objective test, and factors associated with validity. Design, Setting, and Participants: These cross-sectional survey data and a case-control subsample were taken from the National Institute of Environmental Health Sciences' Sister Study. Of 41 118 participants (aged 41-85 years) who reported olfaction in 2014 through 2016, 3406 (aged 50-79 years) reported olfaction again in 2018 through 2019 and completed the 12-item Brief Smell Identification Test, version A, including 2353 women who self-reported poor olfaction in 2014 through 2016 and 1053 women who reported normal olfaction. Data analyses were performed between May 28, 2021, and December 23, 2021. Main Outcomes and Measures: Self-reported (yes/no) and objectively tested poor olfaction defined as a Brief Smell Identification Test score of 9 or lower. Multivariable logistic regressions were used to assess factors that might be associated with the prevalence and reporting accuracy of self-reported olfaction. In subsample analyses, the sampling strategy was accounted for to extrapolate data to eligible cohort samples. Results: Of the 41 118 women (mean [SD] age, 64.3 [8.7] years) included in the analysis, 3322 (8.1%) self-reported poor olfaction. Higher prevalence was associated with older age, not being married, current smoking status, frequent coffee drinking, overweight or obesity, less than optimal health, Parkinson disease, cognitive impairment, depression, anxiety, and seasonal allergy, whereas a lower prevalence was associated with non-Hispanic Black race and physical activity. In the subsample analyses, olfaction status reported 3 years apart showed a modest agreement (κ, 0.56; 95% CI, 0.51-0.61). The prevalence of objectively tested poor olfaction was 13.3% (95% CI, 11.5%-15.0%), and in contrast with self-reports, it was twice as high in non-Hispanic Black women as in non-Hispanic White women (24.5% vs 12.5%). Compared with objective tests, self-reports showed a low sensitivity (22.6%; 95% CI, 19.6%-25.6%), especially in non-Hispanic Black women (12.4%; 95% CI, 7.0%-17.8%). The specificity was uniformly high (>90%). Among participants who reported poor olfaction, higher odds of true vs false positives were associated with age older than 60 years (60-64 years old, 1.68; 95% CI, 1.51-1.87; 65-69 years old, 2.26; 95% CI, 2.03-2.51; 70-74 years old, 3.34; 95% CI, 3.00-3.73; ≥75 years old, 5.17; 95% CI, 4.43-6.03), non-Hispanic Black race (2.00; 95% CI, 1.70-2.36), no college education (1.34; 95% CI, 1.22-1.48), underweight (1.40; 95% CI, 1.04-1.88), fair or poor health (1.37; 95% CI, 1.22-1.54), and Parkinson disease (7.60; 95% CI, 5.60-10.32). Among those with objectively tested poor olfaction, lower odds of true positives vs false negatives were associated with Black race (0.46; 95% CI, 0.25-0.86). Conclusions and Relevance: In this case-control study, the self-awareness and reporting accuracy of poor olfaction in middle-aged and older women were low, particularly in non-Hispanic Black women. Given its potential health implications, awareness of this common sensory deficit should be raised.

Diffusion Tensor Imaging of the Olfactory System in Older Adults With and Without Hyposmia.

Objectives: To compare gray matter microstructural characteristics of higher-order olfactory regions among older adults with and without hyposmia. Methods: Data from the Brief Smell Identification Test (BSIT) were obtained in 1998-99 for 265 dementia-free adults from the Health, Aging, and Body Composition study (age at BSIT: 74.9 ± 2.7; 62% White; 43% male) who received 3T diffusion tensor imaging in 2006-08 [Interval of time: mean (SD): 8.01 years (0.50)], Apolipoprotein (ApoEε4) genotypes, and repeated 3MS assessments until 2011-12. Cognitive status (mild cognitive impairment, dementia, normal cognition) was adjudicated in 2011-12. Hyposmia was defined as BSIT ≤ 8. Microstructural integrity was quantified by mean diffusivity (MD) in regions of the primary olfactory cortex amygdala, orbitofrontal cortex (including olfactory cortex, gyrus rectus, the orbital parts of the superior, middle, and inferior frontal gyri, medial orbital part of the superior frontal gyrus), and hippocampus. Multivariable regression models were adjusted for total brain atrophy, demographics, cognitive status, and ApoEε4 genotype. Results: Hyposmia in 1998-99 (n = 57, 21.59%) was significantly associated with greater MD in 2006-08, specifically in the orbital part of the middle frontal gyrus, and amygdala, on the right [adjusted beta (p value): 0.414 (0.01); 0.527 (0.01); respectively]. Conclusion: Older adults with higher mean diffusivity in regions important for olfaction are more likely to have hyposmia up to ten years prior. Future studies should address whether hyposmia can serve as an early biomarker of brain microstructural abnormalities for older adults with a range of cognitive functions, including those with normal cognition.

Self-Reported Versus Objectively Assessed Olfaction and Parkinson's Disease Risk.

BACKGROUND: Poor olfaction is a prodromal symptom of Parkinson's disease (PD); however, self-reported sense of smell is often dismissed as unreliable. OBJECTIVE: To assess self-reported and objectively assessed sense of smell, independently and jointly, in relation to future risk for PD. METHODS: We conducted a prospective analysis using data from 2,424 participants, ages 71-82 at baseline, from the Health, Aging, and Body Composition study. Exposures were self-reported poor sense of smell or taste and the objectively measured 12-item Brief Smell Identification Test score. The outcome was incident PD, analyzed using Cox proportional hazard models adjusted for age, sex, race, and cognitive function. RESULTS: After approximately 10 years of follow-up, both self-reported and objectively tested poor sense of smell were independently associated with a higher risk of developing PD: the hazard ratios (95% confidence interval) were 2.8 (1.3, 5.9) and 4.0 (2.1, 7.5), respectively. When analyzed jointly, compared with participants who reported and tested normal, the hazard ratio was 2.2 (1.0, 4.6) for those reported poor sense of smell but tested normal, 3.6 (1.9, 6.9) for reported normal but tested poor, and 7.8 (3.2, 19.4) for both reported and tested poor. We did not find significant interactions between self-reported and objectively tested sense of smell in predicting PD risk. CONCLUSION: This study provides preliminary evidence that self-reported poor sense of smell or taste should not be simply dismissed as useless in predicting risk of PD. Future studies should confirm our finding and evaluate whether structured questionnaires may further improve the predictability.