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Background and ObjectivesThe specificity of novel blood biomarkers for multiple sclerosis (MS)–related neurodegeneration is unclear because neurodegeneration also occurs during normal aging. To understand which aspects of neurodegeneration the serum biomarkers neurofilament light (sNfL), serum glial fibrillary acidic protein (sGFAP), and serum contactin-1 (sCNTN1) reflect, we here explore their cross-sectional association with disability outcome measures and MRI volumes in a unique cohort of people with MS (PwMS) of the same age.MethodssNfL, sGFAP (both singe-molecule array technology) and sCNTN1 (Luminex) were measured in serum samples of 288 PwMS and 125 healthy controls (HCs) of the Project Y cohort, a population-based cross-sectional study of PwMS born in the Netherlands in 1966 and age-matched HC.ResultssNfL (9.83 pg/mL [interquartile range {IQR}: 7.8–12.0]) and sGFAP (63.7 pg/mL [IQR: 48.5–84.5]) were higher in PwMS compared with HC (sNfL: 8.8 pg/mL [IQR: 7.0–10.5]; sGFAP: 51.7 pg/mL [IQR: 40.1–68.3]) (p< 0.001), whereas contactin-1 (7,461.3 pg/mL [IQR: 5,951.8–9,488.6]) did not significantly differ between PwMS compared with HC (7,891.2 pg/mL [IQR: 6,120.0–10,265.8]) (p= 0.068). sNfL and sGFAP levels were 1.2-fold higher in secondary progressive patients (SPMS) compared with relapsing remitting patients (p= 0.009 andp= 0.043). Stratified by MS subtype, no relations were seen for CNTN1, whereas sNfL and sGFAP correlated with the Expanded Disability Status Scale (ρ = 0.43 and ρ = 0.39), Nine-Hole Peg Test, Timed 25-Foot Walk Test, and Symbol Digit Modalities Test (average ρ = 0.38) only in patients with SPMS. Parallel to these clinical findings, correlations were only found for sNfL and sGFAP with MRI volumes. The strongest correlations were observed between sNfL and thalamic volume (ρ = −0.52) and between sGFAP with deep gray matter volume (ρ = − 0.56) in primary progressive patients.DiscussionIn our cohort of patients of the same age, we report consistent correlations of sNfL and sGFAP with a range of metrics, especially in progressive MS, whereas contactin-1 was not related to clinical or MRI measures. This demonstrates the potential of sNfL and sGFAP as complementary biomarkers of neurodegeneration, reflected by disability, in progressive MS.