Lifespan Modeling of Choroid Plexus Volume in Multiple Sclerosis and Its Dynamic Associations With Clinical, MRI, and HLA Susceptibility

Background and objectives: The choroid plexus (ChP) regulates CSF production and CNS homeostasis. In multiple sclerosis (MS), ChP enlargement occurs early in the disease course, yet its normative lifespan trajectory and relationship with MS-specific features remain poorly defined. We aimed to define the normative ChP volume model, to characterize its trajectory across the healthy lifespan, and to assess ChP enlargement in MS using z-scores, evaluating associations with demographic, clinical, MRI, and genetic variables, including human leukocyte antigen (HLA) and non-HLA polygenic risk scores (PRSs). Methods: This monocentric retrospective cross-sectional study included 461 healthy controls (HCs) and 727 patients with MS (age 18-70 years) who underwent 3T brain MRI and neurologic assessment. ChP volumes were quantified using ASCHOPLEX, normalized for head size, and modeled in HCs. We derived age-related normalized ChP volume (NChPV) trajectory across adulthood. Z-scores for patients with MS were computed. PRSs were calculated from established MS susceptibility loci, encompassing both HLA and non-HLA regions. Results: In HCs, normalized brain volume, lateral ventricle volume, and its squared term were independently associated with NChPV (R2 = 0.54). Model-derived NChPV trajectory remained stable until age 35 and then increased nonlinearly (p-FDR<0.002), with annualized growth rates rising from 0.24% at age 35 to over 0.7% in later decades. Patients with MS had significantly higher NChPV z-scores than controls (estimated mean [EM] z-score = 0.452, p-FDR<0.001), consistently across phenotypes (p = 0.744) and ages, with no evidence of age-dependent variation (β = 0.02 × 10-2, p = 0.957). In cross-sectional analyses, NChPV z-scores, already elevated 1 year after disease onset (EM z-scores = 0.252, p-FDR<0.001), increased further up to 5 years after disease onset (EM z-scores = 0.463, p-FDR<0.001), before plateauing. Higher z-scores were associated with greater T2-hyperintense white matter lesion volume (β = 0.012 × 10-2, p < 0.001) and HLA genetic burden (standardized β = 0.097, p = 0.038), but not non-HLA PRSs (p ≥ 0.177). Discussion: We provided a normative ChP volume model, characterized its trajectory across the healthy lifespan, and showed early, consistently higher ChP volume in patients with MS across ages and disease durations in cross-sectional analyses, linked to inflammatory lesion burden and HLA-mediated genetic risk. The ChP may represent a noninvasive biomarker of neuroinflammation and HLA-related immunogenetic background in MS.