Choroid Plexus Enlargement in Multiple Sclerosis: Normative Trajectories, Clinical Correlates, and Genetic Associations
Paolo Preziosa1, Gianluca Corazzolla1, Alessandro Meani3, Monica Margoni4, Loredana Storelli3, Elisabetta Pagani3, Martina Rubin1, Ferdinando Clarelli5, Elisabetta Mascia5, Melissa Sorosina5, Federica Esposito6, Maria Rocca1, Massimo Filippi2
1Neuroimaging Research Unit, Division of Neuroscience, and Neurology Unit, 2Neuroimaging Research Unit, Division of Neuroscience, Neurology Unit, Neurorehabilitation Unit, and Neurophysiology Service, IRCCS San Raffaele Scientific Institute; and Vita-salute San Raffaele University, 3Neuroimaging Research Unit, Division of Neuroscience, 4Neuroimaging Research Unit, Division of Neuroscience, Neurology Unit, and Neurorehabilitation Unit, 5Laboratory of Human Genetics of Neurological Disorders, 6Neurology Unit, and Laboratory of Human Genetics of Neurological Disorders, IRCCS San Raffaele Scientific Institute
Objective:
To define normative choroid plexus (ChP) volume trajectories across the healthy lifespan and compute z-scores in multiple sclerosis (MS) patients, evaluating associations with demographic, clinical, MRI, and genetic variables, including Human Leukocyte Antigen (HLA) and non-HLA polygenic risk scores (PRS).
Background:
The ChP regulates cerebrospinal fluid production and CNS homeostasis. In MS, ChP enlargement has been reported early in the disease course, but its normative trajectory and associations with MS-related features remain unclear.
Design/Methods:
This multicenter retrospective study included 461 healthy controls (HC) and 727 MS patients (age 18-70 years) who underwent 3T brain MRI and neurological assessment. ChP volumes were quantified using ASCHOPLEX, normalized for head size, modeled in HC to compute z-scores for MS patients, and correlated with demographic, clinical, MRI, and genetic data. PRSs were calculated based on established MS-associated susceptibility loci.
Results:
In HC, normalized ChP volume (NChPV) was predicted by normalized brain volume, lateral ventricle volume, and its squared term (R²=0.54), remaining stable until age 35, then increasing nonlinearly (p-FDR<0.002). MS patients had significantly higher NChPV z-scores than HC (p-FDR<0.001), independent of age or phenotype (p-FDR≥0.484). NChPV z-scores rose during the first five years after onset (p-FDR=0.012–0.015) before plateauing. Higher z-scores were associated with higher T2-hyperintense white matter lesion volume (β=0.012, p<0.001), higher Expanded Disability Status Scale (EDSS) score only in patients with EDSS score<3.0 (β=0.303, p=0.001), and higher HLA genetic burden (β=0.103, p=0.027). No significant association with other brain volumetric measures or non-HLA PRSs was found (p≥0.177).
Conclusions:
We provided normative ChP trajectories and found early, sustained NChPV enlargement in MS, associated with inflammatory lesion burden, HLA genetic risk, disease duration and disability in the earliest phases of the disease. The ChP may contribute to MS pathophysiology and its volumetric assessment may represent a non-invasive biomarker of MS susceptibility and neuroinflammation.
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