Pyrethroid pesticide exposures may be associated with the onset of depression in later life via disruption of dopaminergic, serotonergic, and neurological functioning. We sought to investigate the association between living near agricultural pyrethroid pesticide applications and depression measures in central California, using two waves (PEG 1&2, total N = 1,654) of a case control study of Parkinson's disease (PD). At enrollment, participants self-reported history of use of depression medications and dates of MD-diagnosed depression and anxiety. Participants also completed a Geriatric Depression Scale-Short Form upon enrollment. We used the California Pesticide Use Registry to assign estimated ambient pyrethroid pesticide exposures at participant's home addresses over the 5 years before the index date (date of outcome, or an age-matched year for participants without the outcome). We used logistic and linear regression to evaluate associations between living near any pyrethroid applications over the 5-year index period and measures of depression and anxiety. We also evaluated modification by study wave and PD status. We observed associations of pyrethroids with depression, depression medications, and anxiety (adjusted odds ratio [aOR] depression = 1.54, 95% confidence interval [CI] 1.14, 2.07; aOR depression medications = 1.68, 95% CI 1.25, 2.25; aOR anxiety = 1.60, 95% CI 1.17, 2.18). However, we observed no associations with mild/moderate depressive symptoms according to the GDS score at enrollment (aOR = 1.04, 95% CI 0.77, 1.42). We did not observe a consistent modification of the pyrethroid-depression associations by study wave and PD status. Ambient pyrethroid pesticide exposures may be associated with measures of depression in later life.

Although Parkinson's Disease (PD) is typically described in terms of motor symptoms, depression is a common feature. We explored whether depression influences blood-based genome-wide DNA methylation (DNAm) in 692 subjects from a population-based PD case-control study, using both a history of clinically diagnosed depression and current depressive symptoms measured by the geriatric depression scale (GDS). While PD patients in general had more immune activation and more accelerated epigenetic immune system aging than controls, the patients experiencing current depressive symptoms (GDS≥5) showed even higher levels of both markers than patients without current depressive symptoms (GDS<5). For PD patients with a history of clinical depression compared to those without, we found no differences in immune cell composition. However, a history of clinical depression among patients was associated with differentially methylated CpGs. Epigenome-wide association analysis (EWAS) revealed 35 CpGs associated at an FDR≤0.05 (569 CpGs at FDR≤0.10, 1718 CpGs at FDR≤0.15). Gene set enrichment analysis implicated immune system pathways, including immunoregulatory interactions between lymphoid and non-lymphoid cells (p-adj = 0.003) and cytokine-cytokine receptor interaction (p-adj = 0.004). Based on functional genomics, 25 (71%) of the FDR≤0.05 CpGs were associated with genetic variation at 45 different methylation quantitative trait loci (meQTL). Twenty-six of the meQTLs were also expression QTLs (eQTLs) associated with the abundance of 53 transcripts in blood and 22 transcripts in brain (substantia nigra, putamen basal ganglia, or frontal cortex). Notably, cg15199181 was strongly related to rs823114 (SNP-CpG p-value = 3.27E-310), a SNP identified in a PD meta-GWAS and related to differential expression of PM20D1, RAB29, SLC41A1, and NUCKS1. The entire set of genes detected through functional genomics was most strongly overrepresented for interferon-gamma-mediated signaling pathway (enrichment ratio = 18.8, FDR = 4.4e-03) and T cell receptor signaling pathway (enrichment ratio = 13.2, FDR = 4.4e-03). Overall, the current study provides evidence of immune system involvement in depression among Parkinson's patients.

Background

Increasing evidence connects the gut microbiome to Parkinson's disease (PD) etiology, but little is known about microbial contributions to PD progression and its clinical features.

Objective

We aim to explore the association between the gut microbiome with PD, and the microbial association with PD-specific clinical features.

Methods

In a community-based case-control study of 96 PD patients and 74 controls, microbiome data were obtained from 16S rRNA gene sequencing of fecal samples, and analyzed for microbial diversity, taxa abundance, and predicted functional pathways that differed in PD patients and controls, and their association with PD-specific features (disease duration, motor subtypes, L-DOPA daily dose, and motor function).

Results

PD patients' gut microbiome showed lower species diversity (p = 0.04) and were compositionally different (p = 0.002) compared to controls but had a higher abundance of three phyla (Proteobacteria, Verrucomicrobiota, Actinobacteria) and five genera (Akkermansia, Enterococcus, Hungatella, and two Ruminococcaceae) controlling for sex, race, age, and sequencing platform. Also, 35 Metacyc pathways were predicted to be differentially expressed in PD patients including biosynthesis, compound degradation/utilization/assimilation, generation of metabolites and energy, and glycan pathways. Additionally, the postural instability gait dysfunction subtype was associated with three phyla and the NAD biosynthesis pathway. PD duration was associated with the Synergistota phylum, six genera, and the aromatic compound degradation pathways. Two genera were associated with motor function.

Conclusion

PD patients differed from controls in gut microbiome composition and its predicted metagenome. Clinical features were also associated with bacterial taxa and altered metabolic pathways of interest for PD progression.

Background

Stochastic epigenetic mutations (SEM) reflect a deviation from normal site-specific methylation patterns. Epigenetic mutation load (EML) captures the accumulation of SEMs across an individual's genome and may reflect dysfunction of the epigenetic maintenance system in response to epigenetic challenges.

Objective

We investigate whether EML is associated with PD risk and time to events (i.e., death and motor symptom decline).

Methods

We employed logistic regression and Cox proportional hazards regression to assess the association between EML and several outcomes. Our analyses are based on 568 PD patients and 238 controls from the Parkinson's disease, Environment and Genes (PEG) study, for whom blood-based methylation data was available.

Results

We found an association for PD onset and EML in all genes (OR = 1.90; 95%CI 1.52-2.37) and PD-related genes (OR = 1.87; 95%CI 1.50-2.32). EML was also associated with time to a minimum score of 35 points on the motor UPDRS exam (OR = 1.28; 95%CI 1.06-1.56) and time to death (OR = 1.29, 95%CI 1.11-1.49). An analysis of PD related genes only revealed five intragenic hotspots of high SEM density associated with PD risk.

Conclusion

Our findings suggest an enrichment of methylation dysregulation in PD patients in general and specifically in five PD related genes. EML may also be associated with time to death and motor symptom progression in PD patients.

Background

Studies of Parkinson's disease (PD) and the association with age at menarche or menopause have reported inconsistent findings. Mendelian randomization (MR) may address measurement errors because of difficulties accurately reporting the age these life events occur.

Objective

We used MR to assess the association between age at menopause and age at menarche with PD risk.

Methods

We performed inverse variant-weighted (IVW) MR analysis using external genome-wide association study (GWAS) summary data from the United Kingdom biobank, and the effect estimates between genetic variants and PD among two population-based studies (Parkinson's disease in Denmark (PASIDA) study, Denmark, and Parkinson's Environment and Gene study [PEG], United States) that enrolled 1737 female and 2430 male subjects of European ancestry. We, then, replicated our findings for age at menopause using summary statistics from the PD consortium (19 773 women), followed by a meta-analysis combining all summary statistics.

Results

For each year increase in age at menopause, the risk for PD decreased (odds ration [OR], 0.84; 95% confidence interval [CI], 0.73-0.98; P = 0.03) among women in our study, whereas there was no association among men (OR, 0.98; 95% CI, 0.85-1.11; P = 0.71). A replication using summary statistics from the PD consortium estimated an OR of 0.94 (95% CI, 0.90-0.99; P = 0.01), and we calculated a meta-analytic OR of 0.93 (95% CI, 0.89-0.98; P = 0.003). There was no indication for an association between age at menarche and PD (OR, 0.75; 95% CI, 0.44-1.29; P = 0.29).

Conclusions

A later age at menopause was associated with a decreased risk of PD in women, supporting the hypothesis that sex hormones or other factors related to late menopause may be neuroprotective in PD. © 2021 International Parkinson and Movement Disorder Society.