Clinical Accuracy of Serum Neurofilament Light to Differentiate Frontotemporal Dementia from Primary Psychiatric Disorders is Age-Dependent

•What is the primary question addressed by this study?Can serum neurofilament light (sNfL) be used as an accurate biomarker to differentiate the behavioral variant of Frontotemporal dementia (bvFTD), a form of early-onset dementia, from Primary Psychiatric Disorders (PPD)?•What is the main finding of this study?sNfL values are slightly higher in patients with psychiatric disorders compared to healthy participants, while bvFTD patients had much higher sNfL values. sNfL has good accuracy as a biomarker to accurately differentiate PPD from bvFTD in patients aged 60 and below.•What is the meaning of the finding?There are positive clinical implications for clinicians, as sNfL is increasingly available in practice; by improving early diagnostic recognition for bvFTD, patients will be able to receive appropriate treatments as well as have opportunities to enroll in clinical trials, ultimately improving patient outcomes. Clinicians will have to factor in the impact of age in their clinical interpretation. Symptoms of behavioral variant frontotemporal dementia (bvFTD) overlap with primary psychiatric disorders (PPD) making diagnosis challenging. Serum neurofilament light (sNfL) is a candidate biomarker to distinguish bvFTD from PPD, but large-scale studies in PPD are lacking. Determine factors that influence sNfL from a large database of PPD patients, and test its diagnostic accuracy. Clinical data of people aged 40–81 were obtained from healthy subjects (n = 69), and patients with PPD (n = 848) or bvFTD (n = 82). sNfL was measured using Simoa technology on an HD-X instrument. Data were analyzed using general linear models, and Receiver Operating Characteristic (ROC) curve analyses to determine global and age-specific sNfL cutoffs to distinguish bvFTD from PPD, using the Youden Index. sNfL increased with age, while sex, BMI and diabetes status were modestly associated with sNfL. sNfL was slightly higher in PPD than healthy subjects (14.1 versus 11.7 pg/mL), when controlling for covariates. sNfL was markedly lower in PPD than bvFTD (14.1 versus 44.1 pg/mL). sNfL could differentiate PPD from bvFTD with an AUC = 0.868, but the effect was driven by the younger subjects between age 40–60 years at a cutoff of 16.0 pg/mL. No valid cutoff was detected over age 60, however, values of sNfL above 38.5 pg/mL, or below 13.9 pg/mL, provided 90% diagnostic certainty of bvFTD or PPD, respectively. PPD have mildly elevated sNfL compared to healthy subjects but much lower than bvFTD