Purpose <p>Microglia-mediated neuroinflammation is implicated in Parkinson’s disease (PD), but its relationship with clinical severity remains controversial. Using [¹⁸F]FEPPA translocator protein (TSPO) PET with plasma biomarkers, we examined associations among neuroinflammation, glial activation, neuronal injury, and motor and cognitive impairment.</p> Methods <p>Ninety participants (71 patients with PD and 19 age-matched controls) underwent TSPO PET and plasma measurements of soluble triggering receptor expression on myeloid cells-2 (sTREM2), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Binding potential relative to the non-displaceable compartment (BP_ND) was quantified across cortical and subcortical regions. Motor severity was assessed with Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III and Hoehn–Yahr stage in the off state. Cognitive performance was evaluated using the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). PD dementia (PDD) was diagnosed according to MDS Task Force criteria.</p> Results <p>Patients with PD had higher TSPO BP_ND in the basal ganglia than controls (<i>p</i> = 0.01), most prominent in advanced motor stage (Hoehn–Yahr ≥ 3) and PDD, particularly in the pallidum (<i>p</i> &lt; 0.01). Higher MDS-UPDRS part III scores correlated with increased BP_ND in the bilateral putamen and frontal and parietal cortices. Patients with PDD had significantly higher pallidal BP_ND than those without cognitive impairment and controls (both <i>p</i> &lt; 0.001). Higher pallidal BP_ND was associated with worse global cognitive performance (MMSE, MoCA) and correlated with plasma NfL, GFAP, and sTREM2 levels, especially in patients with advanced disease.</p> Conclusion <p>TSPO PET with plasma biomarkers revealed region-specific neuroinflammation associated with motor and cognitive severity in Parkinson’s disease progression.</p>