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Plasma phosphorylated-TDP-43 protein levels correlate with brain pathology in frontotemporal lobar degeneration

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Abstract

In the present study, we have correlated plasma TDP-43 levels, as measured by ELISA, with the presence of TDP-43 pathological changes in the brains of 28 patients with frontotemporal lobar degeneration (FTLD) (14 with FTLD-TDP and 14 with FTLD-tau) and 24 patients with pathologically confirmed AD (8 with, and 16 without, TDP-43 pathological changes). Western blotting revealed full-length TDP-43, including a phosphorylated form, and a phosphorylated C-terminal fragment, in all samples examined. Both ELISA and immunohistochemistry were performed using phospho-dependent and phospho-independent TDP-43 antibodies for detection of phosphorylated and total TDP-43, respectively. Over all 52 cases, plasma levels of TDP-43, and scores of brain TDP-43 pathology, determined using TDP-43 phospho-dependent antibody correlated with the equivalent measure determined using the TDP phospho-independent antibody. In FTLD, but not AD, TDP-43 plasma levels correlated significantly with the pathology score when using the TDP-43 phospho-dependent antibody, but a similar correlation was not seen in either FTLD or AD using the TDP-43 phospho-independent antibody. With the TDP-43 phospho-independent antibody, there were no significant differences in median plasma TDP-43 levels between FTLD, or AD, patients with or without TDP-43 pathology. Using TDP-43 phospho-dependent antibody, median plasma TDP-43 levels were greater in patients with, than in those without, TDP-43 pathology for FTLD patients, though not significantly so, but not for AD patients. Present assays for TDP-43 do not differentiate between FTLD, or AD, patients with or without TDP-43 pathological changes in their brains. However, the levels of phosphorylated TDP-43 in plasma do correlate with the extent of TDP-43 brain pathology in FTLD, and therefore might be a useful surrogate marker for tracking changes in TDP-43 brain pathology during the course of this disease.

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Acknowledgments

We acknowledge support (to PGF, DA and DMAM) from The Medical Research Council through grant G0601364. EHB, MM, NJ and SW are all supported by NIH grant AG13854. KMH was supported by The George Barton Trust and MT by the Alzheimer’s Research Trust.

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Authors and Affiliations

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

    Penelope G. Foulds, David J. Hobson, Kirsty M. Humphreys, Mark Taylor, Fiona E. Benson & David Allsop

  2. Clinical Neurosciences Research Group, University of Manchester, Hope Hospital, Stott Lane, Salford, M6 8HD, UK

    Yvonne Davidson & David M. A. Mann

  3. Northwestern CNADC Neuropathology Core, Northwestern University Feinberg School of Medicine, 710N Fairbanks Ct, Olson 2-459, Chicago, IL, 60611, USA

    Manjari Mishra, Nancy Johnson, Sandra Weintraub & Eileen H. Bigio

  4. Departments of Psychogeriatrics, Tokyo Institute of Psychiatry, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo, 156-8585, Japan

    Haruhiko Akiyama & Tetsuaki Arai

  5. Department of Molecular Neuropathology, Tokyo Institute of Psychiatry, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo, 156-8585, Japan

    Masato Hasegawa

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  1. Penelope G. Foulds
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Correspondence to David M. A. Mann.

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Foulds, P.G., Davidson, Y., Mishra, M. et al. Plasma phosphorylated-TDP-43 protein levels correlate with brain pathology in frontotemporal lobar degeneration. Acta Neuropathol 118, 647–658 (2009). https://doi.org/10.1007/s00401-009-0594-0

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  • DOI: https://doi.org/10.1007/s00401-009-0594-0

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