A peri-tumoral TREM2-high myeloid state, myeloid continuum polarization, and white matter disconnection in long-term cognitive survivorship after diffuse glioma: a neuroimmune-connectomic cohort study.

Background: Whether a TREM2-high myeloid state and myeloid continuum polarization are associated with long-term cognitive survivorship in diffuse glioma has not been integrated with white matter connectomics and systemic neuroinflammation in a longitudinal framework. Methods: In a single-center retrospective cohort of 214 adults with WHO grade 2-4 diffuse glioma (168 IDH-mutant and 46 IDH-wildtype; median follow-up, 5.2 years), a 6-plex tyramide-amplified multiplex immunofluorescence panel was applied to 186 tumors. FlowSOM meta-clustering of 2.41 × 10 Results: FlowSOM resolved six marker-defined meta-clusters (bootstrap Jaccard, 0.78-0.88). C4 was TREM2-high with all other panel markers intermediate (17.1% of myeloid cells), was enriched in peri-tumoral white matter relative to tumor core (21.0% vs. 13.8%, P < 0.001), and remained associated with arcuate fasciculus (AF) disconnection after adjustment for GAM-PCI (β = 0.21 per 10-percentage-point increase, P = 0.002). CD163+CD206+ cells showed greater spatial colocalization with myelin basic protein fragments in peri-tumoral white matter (Morisita-Horn index, 0.71 [0.58-0.82]) than at the infiltrative margin (0.42 [0.31-0.55]; P < 0.001), and their mean distance to the white matter boundary was 38 ± 14 µm versus a null median of 87 µm (P < 0.001). In 45 paired serum-tissue cases, T2 serum sTREM2 was associated with the peri-tumoral C4 proportion (Spearman ρ = 0.42, P = 0.004). Long-term cognitive decline occurred in 88 of 214 patients (41.1%), and AF disconnection independently predicted impairment (adjusted odds ratio, 1.52 per 10% increase; 95% CI, 1.25-1.88). In 162 complete tissue-connectomic cases, the model-based serial indirect association through MBP loss and AF disconnection was β = -0.19 (95% CI, -0.29 to -0.10; P < 0.001). In a separate 45-patient serum-path model, the estimated indirect association through T2 sTREM2/IL-6 was β = -0.06 (95% CI, -0.11 to -0.02; P = 0.004). The AF × IDH interaction was significant (P = 0.032), whereas a difference in C4 proportion by IDH status was not detected and equivalence was not established (TOST P = 0.078). Conclusion: In this observational cohort, marker-defined peri-tumoral myeloid states, white matter disconnection, and systemic neuroimmune abnormalities were associated with long-term cognitive outcome. The mediation analysis provide model-dependent structural decompositions under stated assumptions and do not establish causal direction, cellular origin, or treatment effects.