Striatal Dopaminergic Reserve Shapes the Longitudinal Impact of Peripheral Immune Activation on Motor Progression in Parkinson's Disease

Abstract Background Peripheral immune dysregulation has been implicated in Parkinson's disease (PD) progression, but whether motor deterioration reflects accelerated nigrostriatal degeneration or residual dopaminergic reserve remains unclear. Objectives To examine whether baseline and time‐varying neutrophil‐to‐lymphocyte ratio (NLR) relate to motor progression and striatal dopamine transporter (DAT) decline, and whether baseline DAT modifies the NLR–motor relationship. Methods We analyzed 7 years of Parkinson's Progression Markers Initiative (PPMI) data from 335 drug‐naive patients with PD and 305 healthy controls. Linear mixed‐effects models assessed NLR trajectories, longitudinal Unified Parkinson's Disease Rating Scale‐Part III (UPDRS‐III) and DAT associations, and moderation by baseline DAT; follow‐up motor assessments were ON‐medication. Results NLR remained higher in PD than controls ( P < 0.001). A 1 SD higher baseline NLR was associated with an additional 0.350 UPDRS ‐ III points/year ( P < 0.001), while higher‐than‐usual visit‐wise NLR was associated with higher concurrent motor severity ( β = 0.352, P = 0.041). Neither baseline nor time‐varying NLR was consistently associated with DAT decline. Higher baseline DAT binding moderated NLR ‐related motor progression in the left caudate ( β = 0.326, P < 0.001), right caudate ( β = 0.183, P = 0.036), and left putamen ( β = 0.168, P = 0.023); within the DAT ‐imaging interval, moderation persisted in the left caudate ( β = 0.314, P = 0.044) and left putamen ( β = 0.223, P = 0.047). Conclusions Higher baseline NLR predicted faster treated‐state motor worsening, while visit‐wise NLR tracked concurrent severity. These associations were not accompanied by clear evidence of accelerated DAT decline, supporting a reserve‐dependent relationship between peripheral inflammation and motor progression. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.