Cerebrospinal Fluid TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis Patients with and without the C9ORF72 Hexanucleotide Expansion

Abstract

Background: TDP-43 is the main protein component of ubiquitinated inclusions in a subgroup of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) patients. The C9ORF72 hexanucleotide expansion is one of the main mutations associated with TDP-43 pathology in FTLD and ALS. Our aim was to analyze cerebrospinal fluid (CSF) TDP-43 levels and Alzheimer's disease biomarkers in FTLD and ALS patients and to test whether the C9ORF72 expansion carrier status affects these variables. Methods: The patient cohort consisted of 90 clinically well-characterized FTLD (n = 69) and ALS (n = 21) patients. There were 30 patients with the C9ORF72 expansion and 60 patients without the expansion. CSF TDP-43, Aβ_1-42, t-tau, and phospho-tau levels were measured using commercial ELISA kits. Results: There was no difference in CSF TDP-43 levels between the C9ORF72 expansion carriers and the noncarriers. CSF TDP-43 levels were higher in ALS patients than in FTLD patients, and this finding was independent of the C9ORF72 expansion carrier status. Males had significantly higher TDP-43 levels than females (p = 0.008 in the total cohort). Conclusion: CSF TDP-43 does not seem to distinguish the C9ORF72 expansion carriers from noncarriers. However, higher CSF TDP-43 levels were detected in ALS than in FTLD, which might be an indicator of a more rapid progression of TDP-43 pathology in ALS.

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

“…No significant effect of age and disease severity on CSF TDP-43 levels were observed in any of the studied groups, with the exception of males tending to present with higher TDP-43 levels than females. A similar increase in CSF TDP-43 levels in males has been previously reported in a mixed group of ALS and FTD patients [20]. Of note, the present study is the first where a healthy control group was included, whereas in previous studies the control group comprised (either as a whole or in part) patients suffering from other neurological diseases [17,18,19].…”

“…Two previous studies on CSF have also reported increased TDP-43 levels in ALS patients compared to neurological controls [18,19], while others found no difference using a different method (immunoblot) [17]. Junttila et al [20] also reported higher TDP-43 levels in ALS versus FTD in both sporadic and genetic (C9ORF72) cases.…”

“…Thus, a biomarker or a combination thereof is highly required [16]. Attempts to quantify TDP-43 in biological fluids of ALS and FTD patients have been infrequent and the results are contradictory [17,18,19,20], probably due to different methodologies used, sample source and collection, and set of patients versus controls.…”

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

“…In postmortem studies, TDP-43 inclusions are detected in approximately 97% of patients with ALS. Based on these findings, investigators have pursued TDP-43 as a biofluid biomarker for ALS [92][93][94][95]. If changes can be reliably detected in blood or CSF, TDP-43 could be a valuable biomarker for the majority of patients with ALS.…”

The emerging TDP-43 proteinopathy

“…Recently, however, CSF TDP-43 (either alone or in combination with other markers such as tau) has emerged as a candidate biomarker of ALS and FTLD and its levels are increased in both conditions [11,12] . Extensive investigation in order to determine and optimize its diagnostic potential is currently under way.…”