CSF sAPPβ, YKL-40, and NfL along the ALS-FTD spectrum

Objective To investigate the clinical utility of 3 CSF biomarkers along the clinical spectrum of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Methods We analyzed 3 CSF biomarkers: the soluble beta-fragment of amyloid precursor protein (sAPP beta), YKL-40, and neurofilament light (NfL) in FTD (n = 86), ALS (n = 38), and a group of age-matched cognitively normal controls (n = 49). Participants with FTD with a CSF profile of Alzheimer disease were excluded. We compared cross-sectional biomarker levels between groups, studied their correlation with cognitive and functional scales (global cognitive z score, frontotemporal lobar degeneration Clinical Dementia Rating, revised ALS Functional Rating Scale, and ALS progression rate), survival, and cortical thickness. Results We found increased levels of YKL-40 and decreased levels of sAPP beta in both FTD and ALS groups compared to controls. The lowest sAPP beta levels and sAPP beta/YKL-40 ratio were found in the FTD group. In FTD, sAPP beta and the sAPP beta/YKL-40 ratio correlated with the disease severity. In the whole ALS-FTD spectrum, NfL levels and the NfL: sAPP beta ratio correlated with global cognitive performance (r = -0.41, p < 0.001 and r = -0.44, p < 0.001, respectively). In the ALS group, YKL-40 correlated with disease progression rate (r = 0.51, p = 0.001) and was independently associated with shorter survival. In both FTD and ALS groups, the sAPP beta/YKL-40 ratio showed a positive correlation with cortical thickness in frontotemporal regions. Conclusions sAPP beta, YKL-40, and NfL could represent valuable tools for the staging and prognosis of patients within the ALS-FTD clinical spectrum. Classification of evidence This study provides Class III evidence that CSF levels of sAPP beta, YKL-40, and NfL are useful to assess frontotemporal neurodegeneration and the progression rate in the ALS-FTD continuum.