| Title: | Genetic mechanisms, brain structures, and peripheral biomarkers mediate the relation between physical frailty and neuropsychiatric disorders |
| Journal: | Journal of Advanced Research |
| Published: | 19 Jun 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40543840/ |
| DOI: | https://doi.org/10.1016/j.jare.2025.06.046 |
Publication 16308
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
Abstract
INTRODUCTION: Physical frailty, which is characterized by multisystem functional decline, has emerged as a significant risk factor for adverse health outcomes. However, the relationship among physical frailty, brain function, and neuropsychiatric disorders, along with the underlying mechanisms, remains unclear.</p>
OBJECTIVES: To comprehensively investigate the association of physical frailty with brain function and neuropsychiatric disorders and explore the potential mechanism.</p>
METHODS: In the UK Biobank cohort study, physical frailty was assessed using the following five criteria: exhaustion, grip strength, physical activity, weight loss, and walking speed. We examined cross-sectional and longitudinal associations between mental health and cognition using regression and cross-lagged panel models. Cox proportional hazards models were used to assess longitudinal associations with neuropsychiatric disorders. We used Mendelian randomization (MR) to investigated potential causal relationships, whereas neuroimaging analyses identified frailty-related brain regions. Mediation analyses and structural equation modelling were used to explored the underlying mechanisms.</p>
RESULTS: Among 316,905 participants (median follow-up: 14.47 years), physical frailty showed significant cross-sectional and longitudinal associations with mental health deterioration and cognitive decline. Physical frailty increased the risks of all-cause dementia (HR = 2.14), Parkinson's disease (HR = 1.47), stroke (HR = 1.69), sleep disorder (HR = 2.63), anxiety disorder (HR = 2.37), major depressive disorder (MDD; HR = 2.88), and schizophrenia (HR = 3.76). The MR analysis suggested potential causal relationships between physical frailty and MDD (OR = 1.25) and anxiety disorder (OR = 1.30). Moreover, neuroimaging analyses highlighted a correlation between physical frailty and changes in the frontal cortex, as well as subcortical regions such as the thalamus, lateral ventricle, and hippocampus. Genetics, brain regions, and peripheral biomarkers (total cholesterol, GDF15, WFDC2) substantially mediate the relationship between frailty and neuropsychiatric disorders.</p>
CONCLUSION: This study provides comprehensive evidence linking physical frailty to brain dysfunction, suggesting that early frailty intervention is a potential strategy for preventing brain dysfunction and neuropsychiatric disorder.</p>
20 Authors
- Pei-Yang Gao
- Yan Fu
- Xiao-Yu He
- Dan-Dan Zhang
- Hao-Chen Chi
- Yi-Ming Huang
- Zhi-Bo Wang
- Wei Zhang
- Ya-Nan Ou
- Yi-Jun Ge
- Jia You
- Ling-Zhi Ma
- Yi-Xuan Qiang
- Bing Zhao
- Hai-Hong Yu
- Jianfeng Feng
- Lan Tan
- Wei Cheng
- Ya-Ru Zhang
- Jin-Tai Yu
1 Application
| Application ID | Title |
|---|---|
| 19542 | Identifying multi-level biomarkers and disease mechanisms for major mental disorders |
Enabling scientific discoveries that improve human health