Differential thyroid–immune coupling across central and peripheral axes in Parkinson’s disease

In Parkinson’s disease (PD), peripheral immune alterations and chronic low-grade inflammation are present, and the thyroid plays a role in immune regulation. However, how immune status influences thyroid function, and at what level such effects emerge, remains unclear. This retrospective study included 396 patients with PD and 699 age- and sex-matched controls without thyroid disease. We examined serum thyroid indices, including thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), and the FT3/FT4 ratio. We also assessed inflammatory markers, including C-reactive protein (CRP), lymphocyte percentage, neutrophil percentage, and the neutrophil-to-lymphocyte ratio (NLR). We performed group comparisons, partial correlation analyses, interaction models, and segmented regression to assess thyroid–immune relationships. To assess generalizability, key associations were examined in an independent population-based cohort from the United States (NHANES). We found that inflammatory markers differed between groups: PD patients showed higher CRP, increased lymphocyte percentage, and reduced neutrophil percentage and NLR. Thyroid indices showed selective changes, with lower total T3, total T4, FT3, and the FT3/FT4 ratio in PD, whereas TSH and FT4 remained within their reference ranges. We further observed that the associations between thyroid indices and inflammatory markers differed by disease status. In controls, the FT3/FT4 ratio showed consistent associations with immune markers. In PD, these associations were attenuated and became dependent on immune status. These findings indicate that thyroid regulation in PD is context-dependent, characterized by preserved central axis activity but immune-linked modulation of peripheral hormone conversion. This dissociation provides a framework for understanding heterogeneous thyroid findings in PD.