Limited role of free TDP-43 as a diagnostic tool in neurodegenerative diseases

Abstract

TAR DNA-binding protein 43 (TDP-43) is one of the neuropathological hallmarks in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). It is present in patients' blood and cerebrospinal fluid (CSF); however, the source and clinical relevance of TDP-43 measurements in body fluids is uncertain. We investigated paired CSF and serum samples, blood lymphocytes, brain urea fractions and purified exosomes from CSF for TDP-43 by one-(1D), and two-dimensional (2D) Western immunoblotting (WB) and quantitative mass spectrometry (MRM) in patients with ALS, FTLD and non-neurodegenerative diseases. By means of 2D-WB we were able to demonstrate a similar isoform pattern of TDP-43 in lymphocytes, serum and CSF in contrast to that of brain urea fractions with TDP-43 pathology. We found that the TDP-43 CSF to blood concentration ratio is about 1:200. As a possible brain specific fraction we found TDP-43 in exosome preparations from CSF by immunoblot and MRM. We conclude that TDP-43 in CSF originates mainly from blood. Measurements of TDP-43 in CSF and blood are of minor importance as a diagnostic tool, but may be important for monitoring therapy effects of TDP-43 modifying drugs.