CSF Osteopontin as a Predictor of Early Cortical Damage and Disability in Multiple Sclerosis

Multiple sclerosis (MS) is a prevalent immune-mediated disorder affecting the central nervous system (CNS). The disease often initiates with a relapsing-remitting phase (RRMS), characterized by episodic neurologic symptoms and subsequent disability. Over time, many patients transition to secondary progressive MS (SPMS), marked by progressive disability independent of relapses. This study, published in Neurology: Neuroimmunology & Neuroinflammation, explores the association between cerebrospinal fluid (CSF) levels of osteopontin (OPN) and cortical atrophy, alongside disability in early MS.

MS pathology is characterized by damage to both white matter (WM) and gray matter (GM). Early GM damage is a negative prognostic factor for MS-related disability and is linked to persistent meningeal and perivascular inflammation. Understanding the inflammatory markers associated with early severe MS could facilitate personalized therapeutic strategies and shed light on the mechanisms behind GM damage accumulation.

Osteopontin (OPN) has emerged as a significant inflammatory marker, involved in lymphocyte recruitment and activation in the CNS. This study aims to evaluate OPN and other inflammatory molecules' association with early GM damage, cortical lesions (CLs), and atrophy in a cohort of patients with RRMS at diagnosis, predicting MRI and clinical outcomes.

The study included 107 treatment-naive RRMS patients enrolled from January 2018 at the MS Center of Verona University Hospital. These patients, aged 35.7 years on average, were followed for at least two years, with 39 patients completing a four-year follow-up. They underwent regular neurologic evaluation and brain MRI scans at specific intervals, and CSF samples were collected for analysis.

CSF levels of 67 inflammatory markers were assessed using immune-assay multiplex techniques. The protein levels were normalized to the total protein concentration of each CSF sample. The levels of neurofilament protein light chain (Nf-L) were measured using ELISA.

Statistical methods included Mann-Whitney and chi-square/Fisher exact tests, Spearman rank test, random forest (RF) approach, and multivariable linear and logistic regression models to analyze the data.

Study Cohort
After two years, 48% of the patients remained free from disease activity. Patients with disease activity showed higher baseline EDSS scores and increased CL load.

Osteopontin and CXCL13
OPN and CXCL13 levels were associated with increased cortical thinning. Random forest analysis identified OPN, CXCL13, and other markers as significantly related to changes in CTh. OPN was notably linked to accumulating atrophy, both at the two-year and four-year marks. Multivariate models confirmed OPN, CXCL13, and sTNFR1 as predictors of cortical thinning.

Predicting Disease Activity and Disability Accumulation
OPN levels were significantly associated with confirmed disability worsening (CDW). Patients with high OPN levels had higher atrophy rates, correlating with disability progression. CXCL13 was linked to relapses and radiologic activity, underscoring its role in focal cortical damage.

This study confirms the prognostic value of CSF inflammatory profiles in predicting early MS progression. OPN, alongside CXCL13, plays a crucial role in GM atrophy and disease activity. OPN's association with lymphocyte recruitment and chronic inflammation highlights its potential as a biomarker for MS. These findings suggest that early CSF assessment could aid in identifying patients at risk for severe disease progression and tailoring personalized therapeutic strategies.

References
Marastoni, D., Turano, E., Tamanti, A., Colato, E., Pisani, A. I., Scartezzini, A., Carotenuto, S., Mazziotti, V., Camera, V., Anni, D., Ziccardi, S., Guandalini, M., Pizzini, F. B., Virla, F., Mariotti, R., Magliozzi, R., Bonetti, B., Steinman, L., & Calabrese, M. (2024). Association of Levels of CSF Osteopontin With Cortical Atrophy and Disability in Early Multiple Sclerosis. Neurology(R) neuroimmunology & neuroinflammation, 11(5), e200265.