Extended Data Fig. 12. NPH is characterized by convergent inflammatory-fibrotic CSF signatures.

(a) CSF injury–homeostatic axis score across atlas diagnoses, ranked low to high; NPH position along the spectrum is indicated. (b) Sample-level axis-score distributions for atlas controls, two pediatric hydrocephalus cohorts (pHC1, Kim 2024; pHC2, Bruschi 2021), and two adult NPH cohorts (Mikolajewicz 2022, n = 20; de Geus 2025, n = 44). Points, individual samples; violins and box plots, group distributions; diamonds, means; dashed line, axis zero. (c) Axis and meta-program (MP) activity in the two adult NPH cohorts. Bars show z-scores relative to controls; red, enrichment; blue, depletion. BH-adjusted Wilcoxon p values, *FDR<0.05, **FDR<0.01, ***FDR<0.001. (d) Proposed NPH model: inflammatory activation drives fibrotic remodeling, impairing CSF absorption and producing communicating hydrocephalus. (e) Cross-cohort comparison of NPH-associated protein log fold changes (Mikolajewicz 2022 vs. de Geus 2025) among 917 shared proteins. Dashed lines, |logFC| = 0.30; dark points, proteins with concordant significance (FDR ≤ 0.05; n = 28); grey points, all other proteins. (f, g) Receiver operating characteristic (f) and precision–recall (g) curves from stratified five-fold cross-validated weighted logistic regression distinguishing pooled adult NPH from all other atlas diagnoses. MASP1 alone: AUROC = 0.85, AUPRC = 0.21. Five-marker panel (MASP1, LTBP2, RNASE4, ENO2, L1CAM): AUROC = 0.94, AUPRC = 0.41