This presentation details the first-in-human use of the novel PET tracer [11C]-CS1P1 to visualize sphingosine-1-phosphate receptor 1 (S1PR1) and its relationship with Alzheimer disease (AD) pathology. By combining CS1P1-PET, Aβ (PiB)-PET, MRI for white matter hyperintensities (WMH), and high-sensitivity plasma proteomics (NULISAseq CNS 120 v2), this cross-sectional study investigates the peripheral-central neuroimmune axis in 42 cognitively normal adults.

Key Findings:

• Aβ and Astrogliosis: Elevated cortical CS1P1 uptake is significantly associated with higher Aβ burden (Centiloid and plasma Aβ42/40) and plasma GFAP, linking S1PR1 activity to reactive astrogliosis and underlying pathology.

• Systemic Interplay: CS1P1 positively correlates with IL-6 and BMI; however, a significant IL-6×Centiloid interaction indicates that peripheral and central immune responses may decouple as Aβ burden increases.

• Neuroimmune Cascade: Structural Equation Modeling (SEM) reveals that the hypothesized S1PR1 pathway mediates 31.8% of the inflammatory drive from peripheral T-cell activation (CD40LG) to central CNS inflammation (GFAP).

This work establishes [11C]-CS1P1 as a promising in vivo imaging biomarker to evaluate the complex interplay between systemic inflammation, vascular injury, and AD pathology across the blood-brain barrier.