Serum Neurofilament light correlates with CADASIL disease severity and survival.

Objective: To validate whether serum Neurofilament Light-chain (NfL) levels correlate with disease severity in CADASIL, and to determine whether serum NfL predicts disease progression and survival.

Methods: Fourty-one (pre-) manifest individuals with CADASIL causing NOTCH3 mutations and 22 healthy controls were recruited from CADASIL families. At baseline, MRI-lesion load and clinical severity was determined and serum was stored. Disease progression was measured in 30/41 patients at 7-year follow-up, and survival of all individuals was determined at 17-year follow-up. Serum NfL levels were quantified using an ultra-sensitive molecule array. Generalized estimated equation regression (GEE) was used to analyze association between serum NfL, MRI-lesion load, disease severity, and disease progression. With GEE-based Cox regression, survival was analyzed.

Results: At baseline, serum NfL levels correlated with MRI-lesion load [lacune count ( s  =   0.64, P  = 0.002), brain atrophy ( r  =   -0.50, P  = 0.001), and microbleed count ( s  =   0.48, P  = 0.044)], cognition [CAMCOG ( s  =   -0.45, P  = 0.010), MMSE ( r  =   -0.61, P  = 0.003), GIT ( r  =   -0.61, P  < 0.001), TMT-A ( r  =   0.70, P  < 0.001)) and disability (mRS ( r  =   0.70, P  = 0.002)]. Baseline serum NfL predicted 7-year changes in disability ( B  = 0.34, P  < 0.001) and cognition (CAMCOG B  = -4.94, P  = 0.032), as well as 17-year survival. Higher NfL levels were associated with increased mortality (HR=1.8 per twofold increase in NfL levels, P  = 0.006).

Interpretation: Serum NfL levels correlate with disease severity, disease progression and 17-year survival in CADASIL patients. Serum NfL is a promising biomarker to monitor and predict disease course in CADASIL, as well as potentially assessing therapeutic response in future clinical trials.