Untargeted serum metabolomics reveals novel metabolite associations and disruptions in amino acid and lipid metabolism in Parkinson's disease.

BACKGROUND: Untargeted high-resolution metabolomic profiling provides simultaneous measurement of thousands of metabolites. Metabolic networks based on these data can help uncover disease-related perturbations across interconnected pathways. OBJECTIVE: Identify metabolic disturbances associated with Parkinson's disease (PD) in two population-based studies using untargeted metabolomics. METHODS: We performed a metabolome-wide association study (MWAS) of PD using serum-based untargeted metabolomics data derived from liquid chromatography with high-resolution mass spectrometry (LC-HRMS) using two distinct population-based case-control populations. We also combined our results with a previous publication of 34 metabolites linked to PD in a large-scale, untargeted MWAS to assess external validation. RESULTS: LC-HRMS detected 4,762 metabolites for analysis (HILIC: 2716 metabolites; C18: 2046 metabolites). We identified 296 features associated with PD at FDR<0.05, 134 having a log2 fold change (FC) beyond ±0.5 (228 beyond ±0.25). Of these, 104 were independently associated with PD in both discovery and replication studies at p<0.05 (170 at p<0.10), while 27 were associated with levodopa-equivalent dose among the PD patients. Intriguingly, among the externally validated features were the microbial-related metabolites, p-cresol glucuronide (FC=2.52, 95% CI=1.67, 3.81, FDR=7.8e-04) and p-cresol sulfate. P-cresol glucuronide was also associated with motor symptoms among patients. Additional externally validated metabolites associated with PD include phenylacetyl-L-glutamine, trigonelline, kynurenine, biliverdin, and pantothenic acid. Novel associations include the anti-inflammatory metabolite itaconate (FC=0.79, 95% CI=0.73, 0.86; FDR=2.17E-06) and cysteine-S-sulfate (FC=1.56, 95% CI=1.39, 1.75; FDR=3.43E-11). Seventeen pathways were enriched, including several related to amino acid and lipid metabolism. CONCLUSIONS: Our results revealed PD-associated metabolites, confirming several previous observations, including for p-cresol glucuronide, and newly implicating interesting metabolites, such as itaconate. Our data also suggests metabolic disturbances in amino acid and lipid metabolism and inflammatory processes in PD.

Proximity to residential and workplace pesticides application and the risk of progression of Parkinson's diseases in Central California.

BACKGROUND: Pesticide exposure has consistently been associated with Parkinson's disease (PD) onset. Yet, fewer epidemiologic studies have examined whether pesticides influence PD motor and non-motor symptom progression. OBJECTIVES: Using a geographic information system tool that integrates agricultural pesticide use reports and land use records to derive ambient exposures at residences and workplaces, we assessed associations between specific pesticides previously related to PD onset with PD symptom progression in two PD patient cohorts living in agricultural regions of California. METHODS: We calculated the pounds of pesticide applied agriculturally near each participant's residential or occupational addresses from 1974 to the year of PD diagnosis, using a geographic information system tool that links the California Pesticide Use Reports database to land use data. We examined 53 pesticides selected a priori as they have previously been associated with PD onset. We longitudinally followed two PD patient cohorts (PEG1 N = 242, PEG2 N = 259) for an average of 5.0 years (SD ± 3.5) and 2.7 years (SD ± 1.6) respectively and assessed PD symptoms using the movement disorder specialist-administered Unified Parkinson's disease Rating Scale part III (UPDRS), Mini-Mental State Examination (MMSE), and Geriatric Depression Scale (GDS). Weighted time-to-event regression models were implemented to estimate effects. RESULTS: Ten agricultural pesticides, including copper sulfate (pentahydrate), 2-methyl-4-chlorophenoxyacetic acid (MCPA) dimethylamine salt, tribufos, sodium cacodylate, methamidophos, ethephon, propargite, bromoxynil octanoate, monosodium methanearsonate (MSMA), and dicamba, were associated with faster symptom progression. Among these pesticides, residential or workplace proximity to higher amounts of copper sulfate (pentahydrate) and MCPA (dimethylamine salt) was associated with all three progression endpoints (copper sulfate: HRs = 1.22-1.36, 95 % CIs = 1.03-1.73; MCPA: HRs = 1.27-1.35, 95 % CIs = 1.02-1.70). CONCLUSIONS: Our findings suggest that pesticide exposure may not only be relevant for PD onset but also PD progression phenotypes. We have implicated ten specific pesticide active ingredients in faster PD motor and non-motor decline.

Immune system disruptions implicated in whole blood epigenome-wide association study of depression among Parkinson's disease patients.

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.

Stochastic Epigenetic Mutations Influence Parkinson's Disease Risk, Progression, and Mortality.

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.

Ambient Pyrethroid Pesticide Exposures in Adult Life and Depression in Older Residents of California's Central Valley.

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.

[Social representation of Alzheimer's disease for family caregivers: stressful and rewarding]. / Representação social da doença de Alzheimer para familiares cuidadores: desgastante e gratificante.

OBJECTIVE: To understand the content of Social Representation (SR) of family caregivers of Alzheimer's disease patients. METHOD: Interviews were conducted with 26 caregivers and analyzed by the ALCESTE software. RESULTS: The SR content was structured in two thematic axes called Daily Life and Care and Medical and Emotional Concepts and Outcomes. The first axis creates images related to the routine of interaction with the sick person, and contains a description of care procedures, experiences, and practices applied every day. The second is composed of subjective and conceptual aspects that make up the social representation of Alzheimer's disease, with meanings related to the emotional, medical, and biological contexts. CONCLUSION: Due to the importance of topics related to patients' dependence and the personal and emotional consequences of the disease, overload is the main content of the SR of Alzheimer's disease for caregivers, and the understanding of these SR by health professionals should support the planning of interventions addressing this group of individuals.

Social representation of Alzheimer's disease for family caregivers: stressful and rewarding / Representación social de la enfermedad de Alzheimer a familiares cuidadores: desgastador y gratificante / Representação social da doença de Alzheimer para familiares cuidadores: desgastante e gratificante

Abstract OBJECTIVE To understand the content of Social Representation (SR) of family caregivers of Alzheimer's disease patients. METHOD Interviews were conducted with 26 caregivers and analyzed by the ALCESTE software. RESULTS The SR content was structured in two thematic axes called Daily Life and Care and Medical and Emotional Concepts and Outcomes. The first axis creates images related to the routine of interaction with the sick person, and contains a description of care procedures, experiences, and practices applied every day. The second is composed of subjective and conceptual aspects that make up the social representation of Alzheimer's disease, with meanings related to the emotional, medical, and biological contexts. CONCLUSION Due to the importance of topics related to patients' dependence and the personal and emotional consequences of the disease, overload is the main content of the SR of Alzheimer's disease for caregivers, and the understanding of these SR by health professionals should support the planning of interventions addressing this group of individuals.

Resumen OBJETIVO Conocer el contenido de la Representación Social (RS) de los familiares cuidadores de pacientes con enfermedad de Alzheimer acerca de la enfermedad. MÉTODO Se llevaron a cabo entrevistas con 26 cuidadores, analizadas por el programa ALCESTE. RESULTADOS El contenido de la RS se estructuró en dos ejes temáticos denominados Cotidiano y Cuidado yConceptos y Repercusiones Médicas y Emocionales . El primer eje trae campos de imágenes relacionadas con la rutina del convivio con el familiar enfermo, conteniendo la descripción de los rituales del cuidado, las manifestaciones vividas y las prácticas utilizadas en el cotidiano. El segundo está compuesto de aspectos subjetivos y conceptuales que componen la representación social de la enfermedad de Alzheimer, con significados relacionados con el contexto emocional, médico y biológico. CONCLUSIÓN En virtud de la importancia de los temas relacionados con la dependencia del paciente y las repercusiones personales y emocionales de la enfermedad, la sobrecarga es el principal contenido de la enfermedad de Alzheimer para los cuidadores y el conocimiento de dichas RS por los profesionales sanitarios debe subsidiar la planificación de intervenciones dirigidas a ese grupo.

Resumo OBJETIVO Conhecer o conteúdo da Representação Social (RS) dos familiares cuidadores de pacientes com doença de Alzheimer sobre a doença. MÉTODO Foram realizadas entrevistas com 26 cuidadores, analisadas pelo programa ALCESTE. RESULTADOS O conteúdo da RS estruturou-se em dois eixos temáticos denominados Cotidiano e Cuidado eConceitos e Repercussões Médicas e Emocionais . O primeiro eixo traz campos de imagens relacionadas à rotina do convívio com o familiar doente, contendo a descrição dos rituais do cuidado, as manifestações vivenciadas e as práticas utilizadas no cotidiano. O segundo é composto por aspectos subjetivos e conceituais que compõem a representação social da doença de Alzheimer, com significados relacionados ao contexto emocional, médico e biológico. CONCLUSÃO Devido à importância dos temas relacionados à dependência do paciente e às repercussões pessoais e emocionais da doença, a sobrecarga é o principal conteúdo da RS da doença de Alzheimer para os cuidadores e o conhecimento dessas RS pelos profissionais de saúde deve subsidiar o planejamento de intervenções voltadas a esse grupo.