Increased TDP-43 protein in cerebrospinal fluid of patients with amyotrophic lateral sclerosis

Abstract

There is mounting pathological, biochemical and genetic evidence that the metabolism and aggregation of the 43-kDa transactive response (TAR)-DNA-binding protein (TDP-43) play a crucial role in the pathogenesis of sporadic and some forms of familial amyotrophic lateral sclerosis (ALS). Recently, it was reported using an ELISA system that elevated levels of TDP-43 were detected in plasma samples from patients with Alzheimer's disease and frontotemporal dementia, compared to healthy controls. To determine whether quantification of TDP-43 in cerebrospinal fluid (CSF) is potentially informative in the diagnosis of ALS, we measured the concentration, by a similar ELISA method, of TDP-43 in CSF from 30 patients with ALS (diagnosed according to the revised El Escorial criteria) and 29 age-matched control patients without any neurodegenerative disease. We found that, as a group, the ALS patients had significantly higher levels of TDP-43 in their CSF than the age-matched controls (6.92 +/- 3.71 ng/ml in ALS versus 5.31 +/- 0.94 ng/ml in controls, p < 0.05), with levels of TDP-43 in CSF elevated beyond 95% upper confidence level for the control group in six (20%) of the patients with sporadic ALS. All the six patients with higher levels of CSF TDP-43 were examined within 10 months of the onset of illness. The patients examined within 10 months of onset showed significantly higher levels of CSF TDP-43 (8.24 +/- 4.72 ng/ml) than those examined after 11 months or more of onset (5.41 +/- 0.66 ng/ml, p < 0.05). These results suggest that the levels of TDP-43 in CSF may increase in the early stage of ALS. We also confirmed the existence of the TDP-43 protein in CSF from some patients with ALS, and a control subject, by western blotting of proteins immunocaptured from the CSF samples. Raised TDP-43 levels in the CSF may preempt the formation of TDP-43 pathology in the central nervous system, or correlate with early-stage TDP-43 pathology, and accordingly be a biomarker for the early stage of ALS.

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.…”

“…Overall, these studies identified increased levels of TDP-43 in CSF from patients with ALS compared with a variety of neurologically diseased and nondiseased controls. Additionally, increased TDP-43 levels were also observed among patients who were examined within 10 months of disease onset, suggesting that TDP-43 might be useful as a prognostic indicator for early stages of ALS [93]. However, the absolute levels of TDP-43 measured in CSF varies across the studies, suggesting that the TDP-43 immunoassays are inconsistent for measuring the protein within CSF or blood samples.…”

Recent biomarker approaches in the diagnosis of frontotemporal lobar degeneration/Neurochemische Ansätze in der Diagnose der Frontotemporalen Lobärdegeneration

“…Our studies focus on TDP-43 as a biological marker in CSF. As TDP-43 is mainly found in sporadic ALS cases and signifi cantly higher levels of TDP-43 are found in their CSF when compared with age-matched controls [44] , we decided to investigate these patients in a proof-of-principle type of manner, as here the neuropathology can be easier predicted compared with the other diagnosis of the FTLD spectrum, especially the bvFTD cases [37] . This included FTLD, FTLD + ALS and ALS cases.…”

Novel CSF biomarkers for frontotemporal lobar degenerations

“…Prior to the current study, only TDP-43 itself has been examined as a potential biomarker for nonfamilial cases of FTLD-TDP. 11,22 One study showed elevated plasma TDP-43 levels in 46% of clinical FTD cases and 22% of clinical AD cases, but the lack of pathologic confirmation in these groups limited confident interpretation of results.…”