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

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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.

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Acknowledgments

This work was supported by Grant-in-Aid from the Research Committee of CNS Degenerative Disease, the Ministry of Health, Labor, and Welfare of Japan (to M.N.) and by Grant-in-Aid for Scientific Research (C) (20591007), the Ministry of Education, Culture, Sports, Science and Technology and Japan Society for the Promotion of Science (to T.T.). P·F. is supported by a grant from The Medical Research Council, UK.

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Authors and Affiliations

  1. Department of Neurology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-0841, Japan

    Takashi Kasai, Takahiko Tokuda, Noriko Ishigami, Hiroshi Sasayama & Masanori Nakagawa

  2. Division of Biomedical and Life Sciences, School of Health and Medicine, Lancaster University, Lancaster, LA1 4YQ, UK

    Penelope Foulds & David Allsop

  3. MND Care and Research Centre, Royal Preston Hospital, Sharoe Green Lane, Preston, PR2 9HT, UK

    Douglas J. Mitchell

  4. Clinical Neurosciences Research Group, School of Translational Medicine, Faculty of Medical and Human Sciences, University of Manchester, Greater Manchester Neurosciences Centre, Hope Hospital, Salford, M6 8HD, UK

    David M. A. Mann

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  1. Takashi Kasai
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Correspondence to Takahiko Tokuda.

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Kasai, T., Tokuda, T., Ishigami, N. et al. Increased TDP-43 protein in cerebrospinal fluid of patients with amyotrophic lateral sclerosis. Acta Neuropathol 117, 55–62 (2009). https://doi.org/10.1007/s00401-008-0456-1

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  • DOI: https://doi.org/10.1007/s00401-008-0456-1

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