Serum Neurofilament Light Chain and Glial Fibrillary Acidic Protein as Biomarkers in Hereditary Transthyretin Amyloidosis Polyneuropathy

BACKGROUND AND AIMS: In individuals with hereditary transthyretin amyloidosis (ATTRv) polyneuropathy, monitoring of disease progression and treatment response is crucial. The objective is to determine if serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) are reliable biomarkers of ATTRv polyneuropathy. METHODS: We included 48 ATTRv individuals (38 symptomatic, 10 asymptomatic). Yearly assessments (over 4 years) included a full clinical examination with disease severity and functional scores, electrochemical skin conductance, nerve conduction studies, and measurement of sNfL and sGFAP levels. Using a reference database, sNfL and sGFAP were converted to Z-scores (zNfL and zGFAP). RESULTS: Median zNfL was -0.50 in asymptomatic, 1.44 in converters, and 2.46 in symptomatic subjects. zNfL > 1.42 discriminated symptomatic from asymptomatic subjects (AUC 0.936), not zGFAP (AUC 0.588). zNfL, not zGFAP, correlated with most clinical and electrophysiological neuropathy severity scales. Two asymptomatic carriers became symptomatic during follow-up. In one of them, a significant rise in zNfL occurred 1 year before symptomatic transition. INTERPRETATION: In ATTRv, zNfL correlates with neuropathy severity and symptomatic transition. A zNfL > 1.42 may discriminate symptomatic from asymptomatic subjects. zGFAP is not a reliable biomarker of polyneuropathy in ATTRv. Routine use of NfL should be based on deviation measure such as Z-score.