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Background Chronic hydrocephalus (CH) is a heterogeneous neurological disorder characterized by persistent ventricular enlargement and neurovascular dysfunction in the aging brain. Despite its clinical relevance, genetically anchored RNA biomarkers reflecting CH-associated metabolic and stress-related pathology remain poorly defined. Methods We performed bulk RNA sequencing of postmortem caudate nucleus tissue from individuals with CH and age-matched neurologically normal controls. Disease-associated transcriptional programs were identified using principal component analysis (PCA), unsupervised hierarchical clustering, and gene set enrichment analysis (GSEA). Key candidate transcripts were validated by RT-PCR. Comparative genomic analyses across mouse, rat, pig, and human genomes examined transcript length, chromosomal positioning, and nucleotide composition. Results PCA of the top 1,000 most variable transcripts demonstrated robust separation between CH and controls. Analysis of transcripts ranked 1,001–2,000 independently reproduced disease segregation, indicating distinct transcriptional programs. GSEA revealed significant enrichment of xenobiotic metabolism and oxidative stress pathways, with pyruvate dehydrogenase kinase 4 ( PDK4 ) emerging as the top-ranked gene among ∼40,000 transcripts. RT-PCR confirmed robust PDK4 upregulation. Comparative genomics showed conserved transcript length but increased telomeric proximity and A+T content in humans. Conclusion PDK4: is identified as a prominent RNA marker of chronic hydrocephalus in the elderly, providing a neurogenomic foundation for future fluid-based RNA biomarker development.
Clarke et al. (2026) studied this question.