Cerebrospinal fluid biomarkers predict frontotemporal dementia trajectory

Objective: The prognostic value of cerebrospinal fluid neurofilament light chain, total tau, phosphorylated tau₁₈₁, and amyloid beta_1-42 was examined in frontotemporal dementia subtypes. Methods: We compared baseline biomarkers between 49 controls, 40 patients with behavioral variant frontotemporal dementia, 24 with semantic variant primary progressive aphasia, and 26 with nonfluent variant primary progressive aphasia. Linear mixed effect models were used to assess the value of baseline biomarkers in predicting clinical and radiographic change in patient cohorts over multiple yearly follow up visits. Results: Neurofilament light chain concentrations were lowest in controls. Elevated baseline neurofilament light chain predicted faster worsening in clinical severity, frontotemporal volume and frontotemporal fractional anisotropy in patients with behavioral variant frontotemporal dementia and nonfluent variant primary progressive aphasia. High total tau similarly predicted faster progression in nonfluent variant primary progressive aphasia. In behavioral variant frontotemporal dementia, higher phosphorylated tau₁₈₁ predicted faster clinical progression whereas lower amyloid beta_1-42 predicted faster volumetric and fractional anisotropy reduction. Neurofilament light chain and phosphorylated tau₁₈₁ were of greater predictive value in patients with tau pathology as compared to TDP-43 pathology. Baseline neurofilament light chain correlated with baseline clinical severity and frontotemporal volume in behavioral variant frontotemporal dementia. Baseline total tau correlated with baseline clinical severity in semantic variant primary progressive aphasia. Interpretation: High cerebrospinal fluid neurofilament light chain predicts more aggressive disease in behavioral variant frontotemporal dementia and nonfluent variant primary progressive aphasia. Total tau, phosphorylated tau₁₈₁, and amyloid beta_1-42 also predict some measures of disease aggressiveness in frontotemporal dementia.