Neuropathology of iatrogenic Creutzfeldt–Jakob disease and immunoassay of French cadaver-sourced growth hormone batches suggest possible transmission of tauopathy and long incubation periods for the transmission of Abeta pathology
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Abeta deposits and tau pathology were investigated in 24 French patients that died from iatrogenic Creutzfeldt–Jakob disease after exposure to cadaver-derived human growth hormone (c-hGH) in the 1980s. Abeta deposits were found only in one case that had experienced one of the longest incubation periods. Three cases had also intracellular tau accumulation. The analysis of 24 batches of c-hGH, produced between 1974 and 1988, demonstrated for the first time the presence of Abeta and tau contaminants in c-hGH (in 17 and 6 batches, respectively). The incubation of prion disease was shorter in the French patients than the incubation times reported in two previously published British series. We interpreted the low incidence of Abeta in this French series as a consequence of the shorter incubation period observed in France, as compared to that observed in the United Kingdom. This concept suggested that a mean incubation period for the development of detectable Abeta deposits would be longer than 18 years after the first exposure. Moreover, we hypothesized that tau pathology might also be transmissible in humans.
KeywordsCreutzfeldt–Jakob disease Abeta pathology Tau pathology Alzheimer’s disease Transmission Prions Growth hormone
This work was supported by Santé Publique France (CNR-ATNC) and by the program “Investissements d’avenir” (ANR-10-IAIHU-06).
C.D., V.S., D.S., and S.H. performed neuropathological and biochemical diagnoses and analyzed the data. L.P., J.P. Bra., and S.H. diagnosed and recruited the patients and contributed to the clinical analyses. K.A., Z.Y., and J.P. Bri. performed Gallyas staining, double staining with Gallyas and tau and Western blot analyses of tau. N.P., V.S., C.D., and S.H. performed tau, PrP and Abeta immunohistochemistry and analyzed results. E.A. performed PRNP and ApoE genotyping. E.C., A.M., and S.L. performed the hormone batch study. C.D. and S.H. oversaw the study, analyzed data, and drafted the manuscript with contributions from all authors.
- 3.Audouard E, Houben S, Masaracchia C, Yilmaz Z, Suain V, Authelet M, Dedecker R, Buée L, Boom A, Leroy K, Ando K, Brion J (2016) High molecular weight PHF from Alzheimer brain induce seeding of wild-type mouse tau into an argyrophilic 4R tau pathology in vivo. Am J Pathol 186:2709–2722CrossRefPubMedGoogle Scholar
- 9.de Silva R, Lashley T, Gibb G, Hanger D, Hope A, Reid A, Bandopadhyay R, Utton M, Strand C, Jowett T, Khan N, Anderton B, Wood N, Holton J, Revesz T, Lees A (2003) Pathological inclusion bodies in tauopathies contain distinct complements of tau with three or four microtubule-binding repeat domains as demonstrated by new specific monoclonal antibodies. Neuropathol Appl Neurobiol 29:288–302CrossRefPubMedGoogle Scholar
- 10.Eisele YS, Obermuller U, Heilbronner G, Baumann F, Kaeser SA, Wolburg H, Walker LC, Staufenbiel M, Heikenwalder M, Jucker M (2010) Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis. Science 330:980–982. https://doi.org/10.1126/science.1194516 CrossRefPubMedPubMedCentralGoogle Scholar
- 11.Fritschi SK, Langer F, Kaeser SA, Maia LF, Portelius E, Pinotsi D, Kaminski CF, Winkler DT, Maetzler W, Keyvani K, Spitzer P, Wiltfang J, Kaminski Schierle GS, Zetterberg H, Staufenbiel M, Jucker M (2014) Highly potent soluble amyloid-beta seeds in human Alzheimer brain but not cerebrospinal fluid. Brain 137:2909–2915. https://doi.org/10.1093/brain/awu255 CrossRefPubMedPubMedCentralGoogle Scholar
- 12.Gabelle A, Dumurgier J, Vercruysse O, Paquet C, Bombois S, Laplanche JL, Peoc’h K, Schraen S, Buee L, Pasquier F, Hugon J, Touchon J, Lehmann S (2013) Impact of the 2008–2012 French Alzheimer Plan on the use of cerebrospinal fluid biomarkers in research memory center: the PLM Study. J Alzheimers Dis 34:297–305. https://doi.org/10.3233/JAD-121549 PubMedGoogle Scholar
- 13.Giaccone G, Mangieri M, Capobianco R, Limido L, Hauw JJ, Haik S, Fociani P, Bugiani O, Tagliavini F (2008) Tauopathy in human and experimental variant Creutzfeldt–Jakob disease. Neurobiol Aging 29:1864–1873. https://doi.org/10.1016/j.neurobiolaging.2007.04.026 CrossRefPubMedGoogle Scholar
- 14.Hashizume M, Takagi J, Kanehira T, Otake K, Mimuro M, Yoshida M, Hashizume Y (2011) Histologic study of age-related change in the posterior pituitary gland focusing on abnormal deposition of tau protein. Pathol Int 61:13–18. https://doi.org/10.1111/j.1440-1827.2010.02610.x CrossRefPubMedGoogle Scholar
- 16.Irwin DJ, Abrams JY, Schonberger LB, Leschek EW, Mills JL, Lee VM, Trojanowski JQ (2013) Evaluation of potential infectivity of Alzheimer and Parkinson disease proteins in recipients of cadaver-derived human growth hormone. JAMA Neurol 70:462–468. https://doi.org/10.1001/jamaneurol.2013.1933 CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Levavasseur E, Laffont-Proust I, Morain E, Faucheux BA, Privat N, Peoc’h K, Sazdovitch V, Brandel JP, Hauw JJ, Haik S (2008) Regulating factors of PrP glycosylation in Creutzfeldt–Jakob disease—implications for the dissemination and the diagnosis of human prion strains. PLoS ONE 3:e2786CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Malia TJ, Teplyakov A, Ernst R, Wu SJ, Lacy ER, Liu X, Vandermeeren M, Mercken M, Luo J, Sweet RW, Gilliland GL (2016) Epitope mapping and structural basis for the recognition of phosphorylated tau by the anti-tau antibody AT8. Proteins 84:427–434. https://doi.org/10.1002/prot.24988 CrossRefPubMedPubMedCentralGoogle Scholar
- 20.Meyer-Luehmann M, Coomaraswamy J, Bolmont T, Kaeser S, Schaefer C, Kilger E, Neuenschwander A, Abramowski D, Frey P, Jaton AL, Vigouret JM, Paganetti P, Walsh DM, Mathews PM, Ghiso J, Staufenbiel M, Walker LC, Jucker M (2006) Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science 313:1781–1784CrossRefPubMedGoogle Scholar
- 22.Parchi P, de Boni L, Saverioni D, Cohen ML, Ferrer I, Gambetti P, Gelpi E, Giaccone G, Hauw JJ, Hoftberger R, Ironside JW, Jansen C, Kovacs GG, Rozemuller A, Seilhean D, Tagliavini F, Giese A, Kretzschmar HA (2012) Consensus classification of human prion disease histotypes allows reliable identification of molecular subtypes: an inter-rater study among surveillance centres in Europe and USA. Acta Neuropathol 124:517–529. https://doi.org/10.1007/s00401-012-1002-8 CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Peoc’h K, Levavasseur E, Delmont E, De Simone A, Laffont-Proust I, Privat N, Chebaro Y, Chapuis C, Bedoucha P, Brandel JP, Laquerriere A, Kemeny JL, Hauw JJ, Borg M, Rezaei H, Derreumaux P, Laplanche JL, Haik S (2012) Substitutions at residue 211 in the prion protein drive a switch between CJD and GSS syndrome, a new mechanism governing inherited neurodegenerative disorders. Hum Mol Genet 21:5417–5428CrossRefPubMedGoogle Scholar
- 24.Pletnikova O, Rudow GL, Hyde TM, Kleinman JE, Ali SZ, Bharadwaj R, Gangadeen S, Crain BJ, Fowler DR, Rubio AI, Troncoso JC (2015) Alzheimer lesions in the autopsied brains of people 30 to 50 years of age. Cogn Behav Neurol 28:144–152. https://doi.org/10.1097/WNN.0000000000000071 CrossRefPubMedPubMedCentralGoogle Scholar
- 27.Rissin DM, Kan CW, Campbell TG, Howes SC, Fournier DR, Song L, Piech T, Patel PP, Chang L, Rivnak AJ, Ferrell EP, Randall JD, Provuncher GK, Walt DR, Duffy DC (2010) Single-molecule enzyme-linked immunosorbent assay detects serum proteins at subfemtomolar concentrations. Nat Biotechnol 28:595–599. https://doi.org/10.1038/nbt.1641 CrossRefPubMedPubMedCentralGoogle Scholar
- 28.Ritchie DL, Adlard P, Peden AH, Lowrie S, Le Grice M, Burns K, Jackson RJ, Yull H, Keogh MJ, Wei W, Chinnery PF, Head MW, Ironside JW (2017) Amyloid-beta accumulation in the CNS in human growth hormone recipients in the UK. Acta Neuropathol 134:221–240. https://doi.org/10.1007/s00401-017-1703-0 CrossRefPubMedPubMedCentralGoogle Scholar
- 30.Rudge P, Jaunmuktane Z, Adlard P, Bjurstrom N, Caine D, Lowe J, Norsworthy P, Hummerich H, Druyeh R, Wadsworth JD, Brandner S, Hyare H, Mead S, Collinge J (2015) Iatrogenic CJD due to pituitary-derived growth hormone with genetically determined incubation times of up to 40 years. Brain 138:3386–3399. https://doi.org/10.1093/brain/awv235 CrossRefPubMedPubMedCentralGoogle Scholar