Plasma phosphorylated-TDP-43 protein levels correlate with brain pathology in frontotemporal lobar degeneration
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.
KeywordsFrontotemporal lobar degeneration Alzheimer's disease TDP-43 ELISA Plasma
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.
- 2.Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, Mann D, Tsuchiya K, Yoshida M, Hashizume Y, Oda T (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351:602–611CrossRefPubMedGoogle Scholar
- 4.Baker M, Mackenzie IRA, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, Snowden J, Adamson J, Sadovnick AD, Rollinson S, Cannon A, Dwosh E, Neary D, Melquist S, Richardson A, Dickson D, Eriksen J, Robinson T, Zehr C, Dickey CA, Crook R, McGowan E, Mann D, Boeve B, Feldman H, Hutton M (2006) Mutations in Progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442:916–919CrossRefPubMedGoogle Scholar
- 5.Boeve BF, Baker M, Dickson DW, Parisi JE, Giannini C, Jsephs KA, Hutton M, Pickering-Brown SM, Rademakers R, Tang-Wai D, Jack CR, Kantarci K, Shiung MM, Golde T, Smith GE, Geda YE, Knopman DS, Petersen RC (2006) Frontotemporal dementia and parkinsonism associated with the IVS1 + 1G → A mutation in progranulin: a clinicopathologic study. Brain 129:3103–3114CrossRefPubMedGoogle Scholar
- 6.Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D, Rademakers R, Vandenberghe R, Dermaut B, Martin J-J, van Duijn C, Peeters K, Sciot R, Santens P, De Pooter T, Mattheijssens M, Van den Broeck M, Cujit I, Vennekens K, De Deyn PP, Kumar-Singh S, Van Broeckhoven C (2006) Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442:920–924CrossRefPubMedGoogle Scholar
- 18.Mackenzie IRA, Neumann M, Bigio EH, Cairns NJ, Alafuzoff I, Kril J, Kovacs GG, Ghetti B, Halliday G, Holm IE, Ince PG, Kamphorst W, Revesz T, Rozemuller AJM, Kumar-Singh S, Akiyama H, Baborie A, Spina S, Dickson DW, Trojanowski JQ, Mann DMA (2009) Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations. Acta Neuropathol 117:15–18CrossRefPubMedGoogle Scholar
- 21.Nakashima-Yasuda H, Uryu K, Robinson J, Xie SX, Hurtig H, Duda JE, Arnold SE, Siderowf A, Grossman M, Leverenz JB, Woltjer R, Lopez OL, Hamilton R, Tsuang DW, Galasko D, Masliah E, Kaye J, Clark CM, Montine JB, Lee VM-Y, Trojanowski JQ (2007) Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. Acta Neuropathol 114:221–229CrossRefPubMedGoogle Scholar
- 24.Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuk T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar H, Trojanowski JQ, M-Y LeeV (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133CrossRefPubMedGoogle Scholar
- 25.Neumann M, Kwong LK, Lee EB, Kremmer E, Flatley A, Xu Y, Forman MS, Troost D, Kretzschmar HA, Trojanowski JQ, Lee VM (2009) Phosphorylation of S409/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathies. Acta Neuropathol 117(2):137–149CrossRefPubMedGoogle Scholar
- 29.Steinacker P, Hendrich C, Sperfeld AD, Jesse S, von Arnim CAR, Lehnert S, Pabst A, Uttner I, M-Y LeeV, Trojanowski JQ, Kretzschmar HA, Ludolph A, Neumann M, Otto M (2008) TDP-43 in cerebrospinal fluid of patients with frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Arch Neurol 65:1481–1487CrossRefPubMedGoogle Scholar
- 31.Uryu K, Nakashima-Yasuda H, Forman MS, Kwong LK, Clark CM, Grossman M, Miller BL, Kretzschmar HA, Lee VM-Y, Trojanowski JQ, Neumann M (2008) Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies. J Neuropathol Exp Neurol 67:555–564CrossRefPubMedGoogle Scholar