Pre-clinical depressive symptoms are associated with a moderately increased risk of Parkinson’s disease, particularly among people with a high genetic susceptibility to PD, and metabolomic profiles account for a significant portion of this relationship.
Abstract
Accumulating evidence has suggested that depression is associated with an increased risk of Parkinson’s disease (PD), yet whether pre-clinical depressive symptoms in PD development and the potential mediating effects of metabolomic profiles remain unclear. We aimed to examine the association between depressive symptoms and PD risk, evaluate effect modification by genetic susceptibility, and assess metabolomic mediation. This prospective study included 451,922 PD-free participants from the UK Biobank. Depressive symptoms were collected by a 2-item Patient Health Questionnaire (range, 0–6; ≥3 indicates possible depressive disorder) at baseline. Identification of PD was based on medical records. PD-related polygenic risk score (PRS
PD
), which incorporates established genes for PD based on external GWAS meta-analyses, was tertiled as low, moderate, and high. Baseline plasma metabolites were quantified via NMR spectroscopy from blood samples. Data were analyzed using Cox regression. Over a median follow-up of 14.6 years, 3108 (0.7%) participants developed PD. Higher depressive symptom severity showed linear association with PD risk (hazard ratio [HR]: 1.11, 95% confidence interval: 1.07–1.15). Participants with possible depressive disorder had 36% higher PD risk (HR: 1.36, 1.15–1.61). Those with both possible depressive disorder and high genetic risk had the highest PD risk (HR 2.15, 1.74–2.65;
P
for interaction = 0.028). Metabolomic signature, incorporating fatty acids and lipoproteins, accounted for 15% (model-based proportion) of the depressive symptoms-PD association. Pre-clinical depressive symptoms are associated with a moderately increased risk of PD, particularly among people with a high genetic susceptibility to PD. Metabolomic profiles account for a significant portion of this relationship.
Major depressive disorder (MDD) is increasingly recognized as a systemic condition accompanied by metabolic disturbances, particularly in lipid metabolism. However, whether MDD is associated with the development of chronic pancreatitis (CP), a chronic inflammatory disease with substantial metabolic and nutritional consequences, remains unclear. We aimed to investigate the prospective association between MDD and incident CP and to assess the potential mediating role of circulating nuclear magnetic resonance (NMR)-based metabolic biomarkers.
In this prospective study of 273,524 UK Biobank participants, MDD was identified using hospital records and self-reports. Incident CP was ascertained through linked health records. Cox proportional hazards models were used to estimate associations, and mediation analyses based on NMR metabolomics were performed. A metabolomic signature was further derived using least absolute shrinkage and selection operator (LASSO) regression.
Over a median follow-up of 13.7 years, 411 incident CP cases were identified. MDD was independently associated with an increased risk of CP (HR 1.47, 95% CI 1.10–1.96). Exploratory mediation analyses suggested that lipid-related metabolites accounted for part of the observed association, including triglycerides in HDL particles (HDL-TG; 5.10%), triglycerides in LDL particles (LDL-TG; 4.19%), and fatty acid unsaturation (7.61%). A 51-metabolite signature explained 20.80% (95% CI 13.20–27.20%) of the association. The association was stronger in participants aged ≤60 years (
P
-interaction = 0.014).
Major depressive disorder was associated with a higher risk of CP, and exploratory mediation analyses suggested that lipid related metabolomic alterations may account for part of this association. These findings highlight metabolic dysregulation as a potential biological correlate of the observed MDD–CP association.
Wei-Zhen Yang, Chang-Gan Chen, Jun-Peng Li et al.· Frontiers in Nutrition· 0 citations
Multiple lipid species, particularly phosphatidylethanolamines (PEs) and triglycerides (TGs), were significantly associated with depressive symptoms after FDR correction in longitudinal models, supporting further mechanistic and biomarker investigations.
Ç. Dağlı, N. Armstrong, P. Patel et al.· medRxiv· 0 citations
Psychiatric multimorbidity marks a sustained elevation in AD risk, potentially through overlapping inflammatory and metabolic pathways, potentially through overlapping inflammatory and metabolic pathways.
INTRODUCTION
Alzheimer's Disease (AD) is a neurological condition that increases in severity from a gradual start. Previous studies have found an association between long sleep (LS) and AD. To slow its progression, it is important to recognize biomarkers associated with the early stages of both AD and LS.
METHODS
This study aimed to use two-sample Mendelian Randomization (MR) to identify blood and urine biomarkers associated with AD and LS. Thirty-five biomarkers from blood and urine were included as exposures in the MR analysis, while AD and LS were considered the outcomes. The AD dataset included 39,106 patients and 46,828 controls from Europe. Data on sleep duration were obtained from a GWAS in 34,184 cases and 305,742 controls of European ancestry. This study included 35 blood and urine biomarkers across 355,891 participants, including 318,953 white British, 23,582 non-white British, 6,019 African, and 7,338 South Asian participants from the UK Biobank.
RESULTS
Cystatin C, CRP, and Non-Albumin protein showed genetic association with AD and LS. The genetic association results after Bonferroni's correction are significant for Non-Albumin Protein in AD and LS.
DISCUSSION
This study provides further insight into the genetic associations and relationships among AD, LS, and other biomarkers; it also presents several potential candidates for AD and LS diagnosis and treatment. The opposing roles of C-reactive Protein, Cystatin C, and Non-Albumin protein in AD and LS warrant a greater exploration of their differential functions at various ages and in specific brain microenvironments in future studies.
CONCLUSION
This study provides a theoretical basis for the diagnosis and treatment of AD and LS. More experiments are needed in the future to verify this prediction.
Jian-Ran Ma, Zhen Wei, Chunshu Rong et al.· Current Alzheimer Research· 0 citations
Combining peripheral plasma NfL levels with standard clinical phenotypes provides an objective, quantifiable, and non-invasive tool for early risk stratification of affective disorders in PD.
Guidong Liu, Yan-Qin Geng, Hanwen Zhang et al.· Frontiers in Aging Neuroscie...· 0 citations
BACKGROUND
Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine involved in metabolic and inflammatory pathways. We examined the associations of plasma GDF15 with incident brain disorders and explored potential mediating pathways and causality.
METHODS
UK Biobank participants were followed for a median of 14 years. Plasma GDF15 was measured at baseline. Cox proportional hazards models assessed associations with incident brain disorders, including all-cause dementia (ACD), Alzheimer's disease (AD), Parkinson's disease (PD), anxiety, depression, sleep disorders, stroke, and epilepsy. Mediation analyses evaluated biochemical and hematological pathways, and one-sample Mendelian randomization (MR) was used to assess potential causal effects.
RESULTS
Higher GDF15 levels were associated with increased risks of overall brain disorders and all examined subtypes. In continuous analyses (per 1-unit increase in log2-transformed GDF15), hazard ratios (95% CIs) were 1.54 (1.48-1.60) for overall brain disorders, 1.98 (1.80-2.17) for ACD, 1.84 (1.60-2.10) for AD, 1.37 (1.18-1.59) for PD, 1.26 (1.16-1.37) for anxiety, 1.38 (1.29-1.49) for depression, 1.40 (1.26-1.55) for sleep disorders, 1.92 (1.81-2.05) for stroke, and 1.71 (1.46-2.01) for epilepsy (all P < 0.001). Lipid- and inflammation-related markers appeared to partially mediate these associations. High-density lipoprotein cholesterol (HDL-C) accounted for an estimated 7.51% of the association with depression and 11.47% with sleep disorders, while neutrophil count showed relatively larger mediation estimates across multiple outcomes. MR analyses did not support a direct causal effect of GDF15.
CONCLUSION
Plasma GDF15 is associated with a broad range of incident brain disorders and may act partly through lipid- and inflammation-related pathways, particularly HDL-C and neutrophil count.
Xin-Ru Guo, Songyu Wu, Zhouyang Sun et al.· Progress in Neuro-psychophar...· 0 citations
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