{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T06:56:05Z","timestamp":1790751365247,"version":"4.1.0"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100012542","name":"Sichuan Provincial Science and Technology Support Program","doi-asserted-by":"publisher","award":["2023JDKP0072"],"award-info":[{"award-number":["2023JDKP0072"]}],"id":[{"id":"10.13039\/100012542","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In a single-center retrospective cohort of 214 adults with WHO grade 2\u20134 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 \u00d7 10\n                      <jats:sup>6<\/jats:sup>\n                      myeloid cells across the tumor core, peri-tumoral white matter, and infiltrative margin generated a patient-level Glioma-Associated Myeloid Polarization Continuum Index (GAM-PCI). Connectome-based lesion-symptom mapping, longitudinal serum biomarker profiling, and observational mediation models were integrated. The tissue-connectomic mediation model included 162 complete cases, and the serum-path model included 45 patients with complete paired serum and tissue data.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>FlowSOM resolved six marker-defined meta-clusters (bootstrap Jaccard, 0.78\u20130.88). 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 &amp;lt; 0.001), and remained associated with arcuate fasciculus (AF) disconnection after adjustment for GAM-PCI (\u03b2 = 0.21 per 10-percentage-point increase, P\u00a0=\u00a00.002). CD163+CD206+ cells showed greater spatial colocalization with myelin basic protein fragments in peri-tumoral white matter (Morisita\u2013Horn index, 0.71 [0.58\u20130.82]) than at the infiltrative margin (0.42 [0.31\u20130.55]; P &amp;lt; 0.001), and their mean distance to the white matter boundary was 38 \u00b1 14 \u00b5m versus a null median of 87 \u00b5m (P &amp;lt; 0.001). In 45 paired serum\u2013tissue cases, T2 serum sTREM2 was associated with the peri-tumoral C4 proportion (Spearman \u03c1 = 0.42, P\u00a0=\u00a00.004). 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\u20131.88). In 162 complete tissue-connectomic cases, the model-based serial indirect association through MBP loss and AF disconnection was \u03b2 = \u22120.19 (95% CI, \u22120.29 to \u22120.10; P &amp;lt; 0.001). In a separate 45-patient serum-path model, the estimated indirect association through T2 sTREM2\/IL-6 was \u03b2 = \u22120.06 (95% CI, \u22120.11 to \u22120.02; P\u00a0=\u00a00.004). The AF \u00d7 IDH interaction was significant (P\u00a0=\u00a00.032), whereas a difference in C4 proportion by IDH status was not detected and equivalence was not established (TOST P\u00a0=\u00a00.078).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1861684","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T06:05:27Z","timestamp":1790748327000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["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"],"prefix":"10.3389","volume":"17","author":[{"given":"Zheng","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Neurology, The Third People\u2019s Hospital of Chengdu","place":["Chengdu, Sichuan, 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