Associations and Potential Biological Pathways Between Physical Frailty and Epilepsy Incidence

BACKGROUND AND OBJECTIVES: Physical frailty has been longitudinally linked to multiple neurologic disorders but has not yet been extrapolated to epilepsy. The study aimed to investigate the prospective association between physical frailty and incident epilepsy and to explore potential biological processes associated with this relationship. METHODS: This prospective cohort study included 421,383 UK Biobank participants free of epilepsy, Parkinson disease, dementia, stroke, or migraine at baseline. Physical frailty status was assessed using a modified Fried frailty phenotype model based on 5 components (weight loss, exhaustion, low physical activity, slow gait speed, and low grip strength) that categorized participants as nonfrail, prefrail, or frail. Incident epilepsy was ascertained through linked health records. Cox proportional hazard models were conducted to calculate hazard ratios (HRs) and 95% CIs for the association between physical frailty and incident epilepsy. Hypothesis-driven mediation analyses were used to investigate potential biological pathways associated with the frailty-epilepsy association. RESULTS: During a mean follow-up of 13.2 years, 2,752 incident epilepsy cases were identified. Compared with nonfrail individuals, the multivariable-adjusted HRs (95% CIs) for incident epilepsy among those with prefrailty and frailty were 1.29 (1.19-1.40) and 1.81 (1.54-2.13), respectively. Among the 5 frailty components, slow gait speed (HR 1.46; 95% CI 1.29-1.65), low grip strength (HR 1.19; 95% CI 1.08-1.32), exhaustion (HR 1.18; 95% CI 1.06-1.32), and weight loss (HR 1.17; 95% CI 1.06-1.29) were associated with higher hazards of incident epilepsy. Biomarker analyses observed that blood biomarkers reflecting liver and kidney function, immune-inflammatory response, endocrine activity, and hematologic profiles were associated with both frailty and incident epilepsy and may collectively explain approximately 18.57% (95% CI 13.18%-26.83%) of the frailty-epilepsy association. In addition, several metabolically related biomarkers, involving lipoprotein particle size, amino acids, ketone bodies, total lipids, and triglycerides, were identified as potential contributors. DISCUSSION: Physical frailty was associated with a higher incidence of epilepsy in this prospective cohort. Biomarker analyses provided preliminary insights into biological domains potentially related to this association, including organ function, inflammation, endocrine regulation, hematologic status, and metabolic homeostasis.