Network-Based Analysis for the Quantification of Brain and Body Immune Axes with Total-Body PET Imaging

The brain has long been viewed as an isolated immune-privileged organ. However, growing evidence suggests a critical role of the interplay between central and peripheral inflammation in pathologic conditions. This highlights the urgent need for novel system-level analysis approaches to study the complex brain-body cross-talk during immune responses. This study aims to validate network analysis of total-body 18-kDa translocator protein (TSPO) PET imaging for studying brain and body immune axes. <b>Methods:</b> Two graph-based analysis frameworks were tested with total-body PET imaging and the third-generation TSPO radioligand [¹⁸F]LW223 in 2 mouse models of lipopolysaccharide-induced systemic infection (<i>n</i> = 31) and pharmacologic blocking (<i>n</i> = 19) with LW223. First, a perturbation covariance approach was adopted in the study of individualized deviation from the normative/reference interorgan immune covariance network; then, an interscan connectivity analysis was used to investigate intragroup and between-group similarities in whole-body TSPO expression patterns. <b>Results:</b> Application of the perturbation covariance approach showed increased deviations from the reference interorgan covariance network 2 h (<i>t</i>-statistic = 3.74; <i>P</i> = 8.88 × 10^-4) and 24 h (<i>t</i>-statistic = 4.02; <i>P</i> = 4.23 × 10^-4) after lipopolysaccharide challenge, with a 7-d recovery after infection (<i>t</i>-statistic = 0.03; <i>P</i> = 0.98), reflecting previous general evidence of a time-dependent immune response to lipopolysaccharide infection. Additionally, the perturbation approach revealed a widespread dose-specific increase in deviations after blocking agent administration, with a magnitude of deviations and several extreme deviations increasing with dose (<i>F</i>-statistic = 37.67; <i>P</i> = 2.33 × 10^-6). Interscan connectivity analysis confirmed strong alterations from the physiologic whole-body TSPO expression pattern 24 h after the lipopolysaccharide challenge and after administration of high-dose blocking agent. <b>Conclusion:</b> To our knowledge, this study represents the first application of network analysis to total-body TSPO PET data, supporting its adoption in the study of systemic immune responses for diagnosing immune-related conditions and evaluating immune therapies.