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.

The Role of TDP-43 in Alzheimer’s Disease

“…When detected with phospho-independent antibody, plasma TDP-43 level is not significantly different between FTLD and AD, with or without TDP-43 pathology; when detected with phospho-dependent antibody, plasma TDP-43 level is higher in patients with TDP-43 pathology than in those without TDP-43 pathology in FTLD, but this phenomenon is not found in AD patients [44]. Recent study finds that the concentration ratio of TDP-43 CSF to blood is about 1:200, suggesting that CSF TDP-43 may originate from blood [45].…”

“…Because of the low concentration of TDP-43 in CSF compared to blood, no such relation between CSF TDP-43 and clinical phenotype has been reported [45]. A study indicated that CSF levels of many analytes including Fas, neuropeptides, and chemokines are different between FTLD-TDP and FTLD-tau, and the classification analysis in the autopsy cohort shows high sensitivity for FTLD-TDP (86 %) and modest specificity (78 %) [46].…”

Cerebrospinal Fluid TAR DNA-Binding Protein 43 Combined with Tau Proteins as a Candidate Biomarker for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Spectrum Disorders

“…Although initially thought to exist as an intracellular/intranuclear protein, studies by ELISA and Western blotting have shown that it is detectable in the extracellular fluids, such as CSF and human plasma [32]. In CSF it may originate from blood [33] or from neural cells [18]. Compatible with the latter hypothesis, no disruption of the blood-brain barrier could be detected in our cohort, as assessed by normal albumin index in both patients and controls.…”

Extracellular vesicles and intercellular communication within the nervous system

“…CSF EVs from patients with AD have abnormally high levels of phosphorylated tau (79), while those from patients with MS have high levels of isolectin B4 (IB4), which is associated with neuroinflammation (80). CSF EVs from patients with ALS have elevated TDP-43 (81). Increased levels of the PD-associated proteins deglycase DJ-1 and leucine-rich repeat kinase 2 (LRRK2) have been found in bloodderived EVs in patients with PD (82,83).…”