{
  "abstract": "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.\n\nMethods: 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 ⁶ 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\nResults: 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).\n\nConclusion: 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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Neurology, The Third People’s Hospital of Chengdu , , ,",
    "Department of Oncology, The Third People’s Hospital of Chengdu , , ,"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 2,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Zheng Zhang"
    },
    {
      "affs": [
        1
      ],
      "name": "Yanyu Qi"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/60jpwtws4cjjk.bib",
  "cited_by": 0,
  "doi": "10.3389/fimmu.2026.1861684",
  "fulltext_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13662105/?tool=EBI",
  "id": "60jpwtws4cjjk",
  "issns": [
    "1664-3224"
  ],
  "landing_url": "https://europepmc.org/article/PMC/PMC13662105",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2716|Glioma Diagnosis and Treatment"
    ]
  ],
  "openalex": "W7214929944",
  "pdf_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13662105/pdf/?tool=EBI",
  "pmcid": "PMC13662105",
  "pmid": null,
  "published": "2026-09-30",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/60jpwtws4cjjk.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:20Z",
      "native_id": "PMC:PMC13662105",
      "source": "europepmc",
      "url": "https://europepmc.org/article/PMC/PMC13662105"
    },
    {
      "first_seen": "2026-10-30T12:19:15Z",
      "native_id": "10.3389/fimmu.2026.1861684",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1861684/full"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2716|Glioma Diagnosis and Treatment",
      "subfield": "human-genetics"
    }
  ],
  "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",
  "title_text": "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",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:15Z",
  "url": "https://research.draconitic.com/paper/60jpwtws4cjjk",
  "venue": "Frontiers in immunology",
  "versions": []
}