Longitudinal Repeatome Remodeling in Peripheral Blood Following Parkinson's Disease Diagnosis.
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BACKGROUND/OBJECTIVES: Parkinson's disease (PD) is associated with systemic molecular alterations that extend beyond the central nervous system, including changes in peripheral blood transcriptomic profiles. While prior studies have focused predominantly on coding-gene expression, the longitudinal behavior of the peripheral blood repeatome following clinical diagnosis remains poorly characterized. Here, we investigated temporal remodeling of repetitive-element transcription over 36 months post-diagnosis by integrating repeat subfamily- and locus-specific analyses. METHODS: Repeatome expression was quantified using SalmonTE and DESeq2 in peripheral blood RNA-seq data from 1560 PD and control individuals at diagnostic baseline (BL) and four follow-up visits (6, 12, 24, and 36 months). Differential expression was assessed at the subfamily level, with additional locus-specific validation in a representative subset. RESULTS: A total of 259 repeat subfamilies were differentially expressed (padj < 0.05), of which 224 (86.5%) were already detected at baseline. Enrichment of differential expression was significantly higher at baseline than at later visits (odds ratio = 30.9, p < 2.2 × 10-16), with limited additional divergence over time. Longitudinal analyses revealed non-linear trajectories in selected repeat families, including Alu and SVA subfamilies. Locus-specific analysis identified 237 significantly regulated elements, demonstrating heterogeneous, site-specific transcriptional changes, including clusters of differentially expressed loci and instances within PD-relevant genomic regions (e.g., SNCA and IKZF2). CONCLUSIONS: Peripheral blood repeatome expression differs between PD and control groups, with the dominant signal established at clinical diagnosis and modest longitudinal modulation thereafter. Integration of locus-level analysis indicates that subfamily level patterns arise from discrete genomic events rather than uniform regulation. These findings support a model of systemic, immune-associated transcriptomic remodeling in circulating blood cells and position the peripheral repeatome as a dynamic framework for biomarker discovery and future mechanistic investigation.