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[Preprint]. 2026 Aug 11:rs.3.rs-10480838. [Version 1] doi: 10.21203/rs.3.rs-10480838/v1

Figure 1. Construction of a cross-cohort CSF proteomic meta-atlas and derivation of an injury–homeostasis axis.

Figure 1.

(a) Atlas construction workflow. Proteomic profiles from 35 CSF cohorts were preprocessed within study, and shared matrices were harmonized for atlas-wide analyses. Coverage-aware meta-analysis of protein detection across 21 discovery mass-spectrometry studies stratified 12,606 proteins into five evidence tiers: A, 337; B, 410; C, 497; D, 1,518; and E, 9,844. Tiers A and B define the 747-protein core mass-spectrometry-accessible CSF proteome. Detection modelling and latent-class analysis characterized the determinants and biological organization of recurrently detected proteins. (b) Composition of the quality-controlled atlas comprising 10,560 samples. Cohorts are ordered by sample size on a logarithmic scale (left); stacked bars show cohort- and sample-level distributions by diagnostic theme, proteomic profiling method and CSF sampling site (right). (c) Recurrent CSF proteomic meta-programs. Independent within-cohort decomposition by non-negative matrix factorization (NMF), independent component analysis (ICA) and scale-free shared-nearest-neighbour network analysis (SSN) yielded 13 consensus meta-programs spanning neuronal–synaptic, metabolic, extracellular-matrix, barrier–epithelial, immune–inflammatory and plasma–complement biology. (d) Clinical organization and translation of the dominant axis. The first principal component of meta-program activity defines a continuous injury–homeostasis gradient, extending from neuronal–synaptic homeostasis (negative, blue) to complement-, plasma- and inflammation-associated injury (positive, red). Axis activity tracked adverse clinical features in neuro-oncological cohorts, distinguished progressive from relapsing–remitting multiple sclerosis and was enriched across four neurodegenerative diagnoses. Complement component 5 (C5) and neuronal cell adhesion molecule (NRCAM) mark the opposing poles and provide a candidate two-protein approximation of the axis. CNSL, central nervous system lymphoma; LMD, leptomeningeal disease; MS, multiple sclerosis; AD, Alzheimer’s disease; DLB, dementia with Lewy bodies; FTD, frontotemporal dementia; PD, Parkinson’s disease.