Cerebrospinal fluid neurofilament light chain differentiates behavioural variant frontotemporal dementia progressors from ‘phenocopy’ non‐progressors

Background Distinguishing behavioural variant frontotemporal dementia (bvFTD) from non‐neurodegenerative ‘non‐progressor’, ‘phenocopy’ mimics of frontal lobe dysfunction, can be one of the most challenging clinical dilemmas. A biomarker of neuronal injury, neurofilament light chain (NfL), could reduce misdiagnosis and delay. Method Cerebrospinal fluid (CSF) NfL, amyloid beta 1‐42 (AB42), total and phosphorylated tau (T‐tau, P‐tau) levels were examined in patients with an initial diagnosis of bvFTD. Based on follow up information, patients were categorised as Progressors. Non‐Progressors were subtyped in to Phenocopy Non‐Progressors (non‐neurological/neurodegenerative final diagnosis), and Static Non‐Progressors (static deficits, not fully explained by non‐neurological/neurodegenerative causes). Result Forty‐three patients were included: 20 Progressors, 23 Non‐Progressors (15 Phenocopy, 8 Static), 20 controls. NfL concentrations were lower in Non‐Progressors (Non‐Progressors Mean, M=554pg/mL, 95%CI:[461, 675], Phenocopy Non‐Progressors M=459pg/mL, 95%CI:[385, 539], Static Non‐Progressors M=730pg/mL, 95%CI:[516, 940]), compared to bvFTD Progressors (M=2397pg/mL, 95%CI:[1607, 3332]). NfL distinguished Progressors from Non‐Progressors with the highest accuracy (area under the curve 0.92, 90%/87% sensitivity/specificity, 86%/91% positive/negative predictive value, 88% accuracy). Static Non‐Progressors tended to have higher T‐tau and P‐tau levels compared to Phenocopy Non‐Progressors. Conclusion This study demonstrated strong diagnostic utility of CSF NfL in distinguishing bvFTD from phenocopy non‐progressor variants, at baseline, with high accuracy, in a real‐world clinical setting. This has important clinical implications to improve outcomes for patients and clinicians facing this challenging clinical dilemma, as well as for healthcare services, and clinical trials. Further research is required to investigate heterogeneity within the non‐progressor group and potential diagnostic algorithms, and prospective studies are underway assessing plasma NfL.