Plasma CHI3L1 as a marker of cognitive and structural brain changes in radiologically isolated syndrome

Radiologically isolated syndrome (RIS) is characterised by incidental MRI findings suggestive of multiple sclerosis (MS) in individuals without typical MS symptoms. People with RIS (pwRIS) may have subtle manifestations, including cognitive impairment. We aimed to examine whether plasma chitinase 3-like 1 (pCHI3L1) levels in pwRIS are associated with cognitive impairment and grey matter volumes in regions known to be vulnerable in MS.

We conducted a cross-sectional analysis of 45 individuals with pwRIS and 21 healthy controls. Cognitive performance was assessed with the Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS) battery, and global cognitive impairment was defined as failure on two or more MACFIMS subtests. Plasma CHI3L1 levels were measured using the Ella microfluidics system, and concentrations were natural log-transformed to reduce skewness.

Higher log-pCHI3L1 levels were inversely correlated with hippocampal volume (R² = 0.1360, p=0.01) and thalamic volume (R² = 0.1265, p=0.02). pwRIS with global cognitive impairment had higher log-pCHI3L1 levels (p=0.03). Associations were also observed between log-pCHI3L1 levels and design fluency switching (R² = 0.1365, p=0.01) as well as executive function (R² = 0.1636, p=0.01).

Log-pCHI3L1 levels were associated with cognitive impairment, hippocampal volume and thalamic volume in pwRIS. These results suggest that pCHI3L1 may represent a blood biomarker of cognitive dysfunction and neurodegeneration in RIS.