Genetic spectrum features and diagnostic accuracy of four plasma biomarkers in 248 Chinese patients with frontotemporal dementia

Abstract INTRODUCTION Frontotemporal dementia (FTD) is characterized by phenotypic and genetic heterogeneities. However, reports on the large Chinese FTD cohort are lacking. METHODS Two hundred forty‐eight patients with FTD were enrolled. All patients and 2010 healthy controls underwent next generation sequencing. Plasma samples were analyzed for glial fibrillary acidic protein (GFAP), α‐synuclein (α‐syn), neurofilament light chain (NfL), and phosphorylated tau protein 181 (p‐tau181). RESULTS Gene sequencing identified 48 pathogenic or likely pathogenic mutations in a total of 19.4% of patients with FTD (48/248). The most common mutation was the C9orf72 dynamic mutation (5.2%, 13/248). Significantly increased levels of GFAP, α‐syn, NfL, and p‐tau181 were detected in patients compared to controls (all p < 0.05). GFAP and α‐syn presented better performance for diagnosing FTD. DISCUSSION We investigated the characteristics of phenotypic and genetic spectrum in a large Chinese FTD cohort, and highlighted the utility of plasma biomarkers for diagnosing FTD. Highlights This study used a frontotemporal dementia (FTD) cohort with a large sample size in Asia to update and reveal the clinical and genetic spectrum, and explore the relationship between multiple plasma biomarkers and FTD phenotypes as well as genotypes. We found for the first time that the C9orf72 dynamic mutation frequency ranks first among all mutations, which broke the previous impression that it was rare in Asian patients. Notably, it was the first time the C9orf72 G4C2 repeat expansion had been identified via whole‐genome sequencing data, and this was verified using triplet repeat primed polymerase chain reaction (TP‐PCR). We analyzed the diagnostic accuracy of four plasma biomarkers (glial fibrillary acidic protein [GFAP], α‐synuclein [α‐syn], neurofilament light chain [NfL], and phosphorylated tau protein 181 [p‐tau181]) at the same time, especially for α‐syn being included in the FTD cohort for the first time, and found GFAP and α‐syn had the highest diagnostic accuracy for FTD and its varied subtypes.