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

Kasai, Takashi and Tokuda, Takahiko and Ishigami, Noriko and Sasayama, Hiroshi and Foulds, Penelope and Mitchell, Douglas J and Mann, David M A and Allsop, David and Nakagawa, Masanori (2009) Increased TDP-43 protein in cerebrospinal fluid of patients with amyotrophic lateral sclerosis. Acta Neuropathologica, 117 (1). pp. 55-62. ISSN 0001-6322

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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.

Item Type: Article
Journal or Publication Title: Acta Neuropathologica
Uncontrolled Keywords: Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis ; Biological Markers ; DNA-Binding Proteins ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Male ; Middle Aged ; Severity of Illness Index ; Time Factors
Subjects: UNSPECIFIED
Departments: Faculty of Health and Medicine > Biomedical & Life Sciences
Faculty of Health and Medicine
ID Code: 50809
Deposited By: ep_importer_pure
Deposited On: 07 Nov 2011 10:05
Refereed?: Yes
Published?: Published
Last Modified: 26 Jul 2012 19:43
Identification Number:
URI: http://eprints.lancs.ac.uk/id/eprint/50809

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