Skip to main content

Advertisement

SpringerLink
Log in

4-Repeat tau seeds and templating subtypes as brain and CSF biomarkers of frontotemporal lobar degeneration

  • Original Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

A Correction to this article was published on 20 November 2019

This article has been updated

Abstract

To address the need for more meaningful biomarkers of tauopathies, we have developed an ultrasensitive tau seed amplification assay (4R RT-QuIC) for the 4-repeat (4R) tau aggregates of progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and other diseases with 4R tauopathy. The assay detected seeds in 106–109-fold dilutions of 4R tauopathy brain tissue but was orders of magnitude less responsive to brain with other types of tauopathy, such as from Alzheimer’s disease cases. The analytical sensitivity for synthetic 4R tau fibrils was ~ 50 fM or 2 fg/sample. A novel dimension of this tau RT-QuIC testing was the identification of three disease-associated classes of 4R tau seeds; these classes were revealed by conformational variations in the in vitro amplified tau fibrils as detected by thioflavin T fluorescence amplitudes and FTIR spectroscopy. Tau seeds were detected in postmortem cerebrospinal fluid (CSF) from all neuropathologically confirmed PSP and CBD cases but not in controls. CSF from living subjects had weaker seeding activities; however, mean assay responses for cases clinically diagnosed as PSP and CBD/corticobasal syndrome were significantly higher than those from control cases. Altogether, 4R RT-QuIC provides a practical cell-free method of detecting and subtyping pathologic 4R tau aggregates as biomarkers.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Change history

  • 20 November 2019

    The original version of this article unfortunately contained a mistake. The Panel A in the published figure 5 is incorrect. The corrected Figure 5 is placed in the following page.

References

  1. Alster P, Nieciecki M, Koziorowski DM, Cacko A, Charzynska I, Krolicki L et al (2019) Thalamic and cerebellar hypoperfusion in single photon emission computed tomography may differentiate multiple system atrophy and progressive supranuclear palsy. Medicine (Baltimore) 98:e16603. https://doi.org/10.1097/MD.0000000000016603

    Article  CAS  Google Scholar 

  2. Atarashi R, Satoh K, Sano K, Fuse T, Yamaguchi N, Ishibashi D et al (2011) Ultrasensitive human prion detection in cerebrospinal fluid by real-time quaking-induced conversion. Nat Med 17:175–178. https://doi.org/10.1038/nm.2294

    Article  CAS  PubMed  Google Scholar 

  3. Baron GS, Hughson AG, Raymond GJ, Offerdahl DK, Barton KA, Raymond LD et al (2011) Effect of glycans and the glycophosphatidylinositol anchor on strain dependent conformations of scrapie prion protein: improved purifications and infrared spectra. Biochemistry 50:4479–4490. https://doi.org/10.1021/bi2003907

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bessen RA, Kocisko DA, Raymond GJ, Nandan S, Lansbury PT Jr, Caughey B (1995) Nongenetic propagation of strain-specific phenotypes of scrapie prion protein. Nature 375:698–700

    Article  CAS  Google Scholar 

  5. Bongianni M, Orrù CD, Groveman BR, Sacchetto L, Fiorini M, Tonoli G et al (2017) Diagnosis of human prion disease using real-time quaking-induced conversion testing of olfactory mucosa and cerebrospinal fluid samples. JAMA Neurol 74:1–8. https://doi.org/10.1001/jamaneurol.2016.4614

    Article  Google Scholar 

  6. Caughey B, Raymond GJ, Bessen RA (1998) Strain-dependent differences in beta-sheet conformations of abnormal prion protein. JBiolChem 273:32230–32235

    CAS  Google Scholar 

  7. Chung DC, Carlomagno Y, Cook CN, Jansen-West K, Daughrity L, Lewis-Tuffin LJ et al (2019) Tau exhibits unique seeding properties in globular glial tauopathy. Acta Neuropathol Commun 7:36. https://doi.org/10.1186/s40478-019-0691-9

    Article  PubMed  PubMed Central  Google Scholar 

  8. Dinkel PD, Siddiqua A, Huynh H, Shah M, Margittai M (2011) Variations in filament conformation dictate seeding barrier between three- and four-repeat tau. Biochemistry 50:4330–4336. https://doi.org/10.1021/bi2004685

    Article  CAS  PubMed  Google Scholar 

  9. Drachman DA, Newell KL, Scully RE, Mark EJ, McNeely WF, Ebeling SH et al (1999) A 67-year-old man with three years of dementia—multisystem neurodegenerative disease (characterized by neurofibrillary changes and few plaques), findings consistent with dementia pugilistica. New Engl J Med 340:1269–1277. https://doi.org/10.1056/Nejm199904223401609

    Article  Google Scholar 

  10. Fairfoul G, McGuire LI, Pal S, Ironside JW, Neumann J, Christie S et al (2016) Alpha-synuclein RT-QuIC in the CSF of patients with alpha-synucleinopathies. Ann Clin Transl Neurol 3:812–818. https://doi.org/10.1002/acn3.338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Falcon B, Zhang W, Murzin AG, Murshudov G, Garringer HJ, Vidal R et al (2018) Structures of filaments from Pick’s disease reveal a novel tau protein fold. Nature 561:137–140. https://doi.org/10.1038/s41586-018-0454-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Falcon B, Zivanov J, Zhang W, Murzin AG, Garringer HJ, Vidal R et al (2019) Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules. Nature 568:420–423. https://doi.org/10.1038/s41586-019-1026-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Fitzpatrick AWP, Falcon B, He S, Murzin AG, Murshudov G, Garringer HJ et al (2017) Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature 547:185–190. https://doi.org/10.1038/nature23002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Foutz A, Appleby BS, Hamlin C, Liu X, Yang S, Cohen Y et al (2017) Diagnostic and prognostic value of human prion detection in cerebrospinal fluid. Ann Neurol 81:79–92. https://doi.org/10.1002/ana.24833

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Friedhoff P, Schneider A, Mandelkow EM, Mandelkow E (1998) Rapid assembly of Alzheimer-like paired helical filaments from microtubule-associated protein tau monitored by fluorescence in solution. Biochemistry 37:10223–10230. https://doi.org/10.1021/bi980537d

    Article  CAS  PubMed  Google Scholar 

  16. Friedhoff P, von Bergen M, Mandelkow EM, Davies P, Mandelkow E (1998) A nucleated assembly mechanism of Alzheimer paired helical filaments. Proc Natl Acad Sci USA 95:15712–15717

    Article  CAS  Google Scholar 

  17. Ghetti B, Oblak AL, Boeve BF, Johnson KA, Dickerson BC, Goedert M (2015) Invited review: frontotemporal dementia caused by microtubule-associated protein tau gene (MAPT) mutations: a chameleon for neuropathology and neuroimaging. Neuropathol Appl Neurobiol 41:24–46. https://doi.org/10.1111/nan.12213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gibbons GS, Lee VMY, Trojanowski JQ (2019) Mechanisms of cell-to-cell transmission of pathological tau: a review. JAMA Neurol 76:101–108. https://doi.org/10.1001/jamaneurol.2018.2505

    Article  PubMed  PubMed Central  Google Scholar 

  19. Goedert M, Eisenberg DS, Crowther RA (2017) Propagation of tau aggregates and neurodegeneration. Annu Rev Neurosci 40:189–210. https://doi.org/10.1146/annurev-neuro-072116-031153

    Article  CAS  PubMed  Google Scholar 

  20. Goedert M, Spillantini MG, Cairns NJ, Crowther RA (1992) Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 8:159–168

    Article  CAS  Google Scholar 

  21. Greene P (2019) Progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy. Continuum (Minneap Minn) 25:919–935. https://doi.org/10.1212/CON.0000000000000751

    Article  Google Scholar 

  22. Groveman BR, Dolan MA, Taubner LM, Kraus A, Wickner RB, Caughey B (2014) Parallel in-register intermolecular beta-sheet architectures for prion-seeded prion protein (PrP) amyloids. J Biol Chem 289:24129–24142. https://doi.org/10.1074/jbc.M114.578344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Groveman BR, Orru CD, Hughson AG, Raymond LD, Zanusso G, Ghetti B et al (2018) Rapid and ultra-sensitive quantitation of disease-associated alpha-synuclein seeds in brain and cerebrospinal fluid by alphaSyn RT-QuIC. Acta Neuropathol Commun 6:7. https://doi.org/10.1186/s40478-018-0508-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Guo JL, Lee VM (2011) Seeding of normal tau by pathological tau conformers drives pathogenesis of Alzheimer-like tangles. J Biol Chem 286:15317–15331. https://doi.org/10.1074/jbc.M110.209296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kaufman SK, Sanders DW, Thomas TL, Ruchinskas AJ, Vaquer-Alicea J, Sharma AM et al (2016) Tau prion strains dictate patterns of cell pathology, progression rate, and regional vulnerability in vivo. Neuron 92:796–812. https://doi.org/10.1016/j.neuron.2016.09.055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kraus A, Saijo E, Metrick MAI, Newell K, Sigurdson C, Zanusso G et al (2019) Seeding selectivity and ultrasensitive detection of tau aggregate conformers of Alzheimer disease. Acta Neuropathol 137:585–598. https://doi.org/10.1007/s00401-018-1947-3

    Article  PubMed  Google Scholar 

  27. Litvan I, Hauw JJ, Bartko JJ, Lantos PL, Daniel SE, Horoupian DS et al (1996) Validity and reliability of the preliminary NINDS neuropathologic criteria for progressive supranuclear palsy and related disorders. J Neuropathol Exp Neurol 55:97–105. https://doi.org/10.1097/00005072-199601000-00010

    Article  CAS  PubMed  Google Scholar 

  28. McGuire LI, Peden AH, Orru CD, Wilham JM, Appleford NE, Mallinson G et al (2012) RT-QuIC analysis of cerebrospinal fluid in sporadic Creutzfeldt-Jakob disease. Ann Neurol 72:278–285

    Article  Google Scholar 

  29. Mirbaha H, Chen D, Morazova OA, Ruff KM, Sharma AM, Liu X et al (2018) Inert and seed-competent tau monomers suggest structural origins of aggregation. Elife. https://doi.org/10.7554/eLife.36584

    Article  PubMed  PubMed Central  Google Scholar 

  30. Moda F, Gambetti P, Notari S, Concha-Marambio L, Catania M, Park KW et al (2014) Prions in the urine of patients with variant Creutzfeldt-Jakob disease. N Engl J Med 371:530–539. https://doi.org/10.1056/NEJMoa1404401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Narasimhan S, Guo JL, Changolkar L, Stieber A, McBride JD, Silva LV et al (2017) Pathological tau strains from human brains recapitulate the diversity of tauopathies in nontransgenic mouse brain. J Neurosci 37:11406–11423. https://doi.org/10.1523/JNEUROSCI.1230-17.2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Orru CD, Bongianni M, Tonoli G, Ferrari S, Hughson AG, Groveman BR et al (2014) A test for Creutzfeldt-Jakob disease using nasal brushings. New Engl J Med 371:519–529

    Article  CAS  Google Scholar 

  33. Orru CD, Groveman BR, Hughson AG, Zanusso G, Coulthart MB, Caughey B (2015) Rapid and sensitive RT-QuIC detection of human Creutzfeldt-Jakob disease using cerebrospinal fluid. MBio. https://doi.org/10.1128/mBio.02451-14

    Article  PubMed  PubMed Central  Google Scholar 

  34. Orru CD, Soldau K, Cordano C, Llibre-Guerra J, Green AJ, Sanchez H et al (2018) Prion seeds distribute throughout the eyes of sporadic Creutzfeldt-Jakob disease patients. MBio. https://doi.org/10.1128/mBio.02095-18

    Article  PubMed  PubMed Central  Google Scholar 

  35. Orru CD, Yuan J, Appleby BS, Li B, Li Y, Winner D et al (2017) Prion seeding activity and infectivity in skin samples from patients with sporadic Creutzfeldt-Jakob disease. Sci Transl Med. https://doi.org/10.1126/scitranslmed.aam7785

    Article  PubMed  PubMed Central  Google Scholar 

  36. Redaelli V, Bistaffa E, Zanusso G, Salzano G, Sacchetto L, Rossi M et al (2017) Detection of prion seeding activity in the olfactory mucosa of patients with fatal familial insomnia. Sci Rep 7:46269. https://doi.org/10.1038/srep46269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Saijo E, Ghetti B, Zanusso G, Oblak A, Furman JL, Diamond MI et al (2017) Ultrasensitive and selective detection of three-repeat tau seeding activity in Pick disease brain and cerebrospinal fluid. Acta Neuropathol 133:751–765. https://doi.org/10.1007/s00401-017-1692-z

    Article  CAS  PubMed  Google Scholar 

  38. Saijo E, Groveman BR, Kraus A, Metrick M, Orru CD, Hughson AG et al (2019) Ultrasensitive RT-QuIC seed amplification assays for disease-associated tau, alpha-synuclein, and prion aggregates. Methods Mol Biol 1873:19–37. https://doi.org/10.1007/978-1-4939-8820-4_2

    Article  CAS  PubMed  Google Scholar 

  39. Salvadores N, Shahnawaz M, Scarpini E, Tagliavini F, Soto C (2014) Detection of misfolded Abeta oligomers for sensitive biochemical diagnosis of Alzheimer’s disease. Cell Rep 7:261–268. https://doi.org/10.1016/j.celrep.2014.02.031

    Article  CAS  PubMed  Google Scholar 

  40. Sanders DW, Kaufman SK, DeVos SL, Sharma AM, Mirbaha H, Li A et al (2014) Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 82:1271–1288. https://doi.org/10.1016/j.neuron.2014.04.047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Shahnawaz M, Tokuda T, Waragai M, Mendez N, Ishii R, Trenkwalder C et al (2017) Development of a biochemical diagnosis of parkinson disease by detection of alpha-synuclein misfolded aggregates in cerebrospinal fluid. JAMA Neurol 74:163–172. https://doi.org/10.1001/jamaneurol.2016.4547

    Article  PubMed  Google Scholar 

  42. Sharma AM, Thomas TL, Woodard DR, Kashmer OM, Diamond MI (2018) Tau monomer encodes strains. Elife. https://doi.org/10.7554/eLife.37813

    Article  PubMed  PubMed Central  Google Scholar 

  43. Spillantini MG, Goedert M, Crowther RA, Murrell JR, Farlow MR, Ghetti B (1997) Familial multiple system tauopathy with presenile dementia: a disease with abundant neuronal and glial tau filaments. Proc Natl Acad Sci USA 94:4113–4118

    Article  CAS  Google Scholar 

  44. Takeda S, Commins C, DeVos SL, Nobuhara CK, Wegmann S, Roe AD et al (2016) Seed-competent HMW tau species accumulates in the cerebrospinal fluid of Alzheimer’s disease mouse model and human patients. Ann Neurol. https://doi.org/10.1002/ana.24716

    Article  PubMed  PubMed Central  Google Scholar 

  45. Telling GC, Parchi P, DeArmond SJ, Cortelli P, Montagna P, Gabizon R et al (1996) Evidence for the conformation of the pathologic isoform of the prion protein enciphering and propagating prion diversity. Science 274:2079–2082

    Article  CAS  Google Scholar 

  46. Tucker KL, Meyer M, Barde YA (2001) Neurotrophins are required for nerve growth during development. Nat Neurosci 4:29–37. https://doi.org/10.1038/82868

    Article  CAS  PubMed  Google Scholar 

  47. von Bergen M, Barghorn S, Li L, Marx A, Biernat J, Mandelkow EM et al (2001) Mutations of tau protein in frontotemporal dementia promote aggregation of paired helical filaments by enhancing local beta-structure. J Biol Chem. https://doi.org/10.1074/jbc.M105196200

    Article  Google Scholar 

  48. Wickner RB, Edskes HK, Gorkovskiy A, Bezsonov EE, Stroobant EE (2016) Yeast and fungal prions: amyloid-handling systems, amyloid structure, and prion biology. Adv Genet 93:191–236. https://doi.org/10.1016/bs.adgen.2015.12.003

    Article  CAS  PubMed  Google Scholar 

  49. Wilham JM, Orrú CD, Bessen RA, Atarashi R, Sano K, Race B et al (2010) Rapid end-point quantitation of prion seeding activity with sensitivity comparable to bioassays. PLoS Path 6:e1001217. https://doi.org/10.1371/journal.ppat.1001217

    Article  CAS  Google Scholar 

  50. Woerman AL, Aoyagi A, Patel S, Kazmi SA, Lobach I, Grinberg LT et al (2016) Tau prions from Alzheimer’s disease and chronic traumatic encephalopathy patients propagate in cultured cells. Proc Natl Acad Sci USA 113:E8187–E8196. https://doi.org/10.1073/pnas.1616344113

    Article  CAS  PubMed  Google Scholar 

  51. Zhukareva V, Mann D, Pickering-Brown S, Uryu K, Shuck T, Shah K et al (2002) Sporadic Pick’s disease: a tauopathy characterized by a spectrum of pathological tau isoforms in gray and white matter. Ann Neurol 51:730–739. https://doi.org/10.1002/ana.10222

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank David Dorward and Cindi Schwartz of the NIAID Research Technology Branch for help with electron microscopy. We thank Drs. Suzette Priola, Ankit Srivastava, and Bradley Groveman for helpful internal review of the initial manuscript. This work was supported in part by the Intramural Research Program of the NIAID. MM is supported by the NIH/Cambridge Scholars program. B. G. was supported by a grant of the US National Institutes of Health (P30AG010133) and the Department of Pathology and Laboratory Medicine, Indiana University School of Medicine. D. G. is supported by NIH grant AGO5131 and the Shiley-Marcos Alzheimer’s Disease Research Center at UCSD. S. K. was supported by a research grant from the CBD Solutions. Some of the tissue specimens were obtained with support of the Massachusetts Alzheimer’s Disease Research Center (P50 AG005134). We also acknowledge the Department of Pathology and Laboratory Medicine, University of Kansas School of Medicine. Human tissue was obtained from the NIH NeuroBioBank. The UCSF Neurodegenerative Disease Brain Bank is supported by NIH Grants AG023501 and AG019724, the Tau Consortium, and the Bluefield Project to Cure FTD. LTG is funded by NIH K24053435. This study is also supported by Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Grant No. ZIA AI001086-08). SS is funded by NIH K08 AG052648.

Author information

Authors and Affiliations

  1. LPVD, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, MT, USA

    Eri Saijo, Michael A. Metrick II, Allison Kraus & Byron Caughey

  2. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA

    Shunsuke Koga & Dennis W. Dickson

  3. IRCCS Istituto delle Scienze Neurologiche di Bologna, 40139, Bologna, Italy

    Piero Parchi & Marcello Rossi

  4. Department of Experimental Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138, Bologna, Italy

    Piero Parchi

  5. Department of Neurosciences, Parkinson and Other Movement Disorders Center, University of California, San Diego, CA, USA

    Irene Litvan

  6. Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA

    Salvatore Spina, Adam Boxer, Julio C. Rojas, Lea T. Grinberg & William W. Seeley

  7. Department of Neurosciences, University of California, San Diego, CA, USA

    Douglas Galasko

  8. Indiana University School of Medicine, Indianapolis, IN, USA

    Kathy Newell & Bernardino Ghetti

  9. University of Verona, Verona, Italy

    Gianluigi Zanusso

  10. Department of Pathology, LIM-22, University of Sao Paulo, Sao Paulo, Brazil

    Lea T. Grinberg

Authors
  1. Eri Saijo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael A. Metrick II
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shunsuke Koga
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Piero Parchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Irene Litvan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Salvatore Spina
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Adam Boxer
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Julio C. Rojas
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Douglas Galasko
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Allison Kraus
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Marcello Rossi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Kathy Newell
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Gianluigi Zanusso
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Lea T. Grinberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. William W. Seeley
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Bernardino Ghetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Dennis W. Dickson
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Byron Caughey
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ES and BC conceived the overall project. ES and MAM designed, performed, and interpreted the primary experiments. ES developed the 4R RT-QuIC assays for brain and CSF. MAM helped to optimize the assay for brain tissue. MAM developed and performed the ATR-FTIR-based tau conformer subtyping. SK, PP, IL, SS, AB, MR, KN, GZ, LTG, WWS, BG, DG, and DWD provided tissue and/or fluid specimens and key clinical and neuropathological information, insights, and interpretations. AK, ES, MAM, and BC performed and/or interpreted electron microscopy analyses. ES, MAM, and BC prepared the manuscript. All authors helped to interpret the results and edit the manuscript.

Corresponding author

Correspondence to Byron Caughey.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Eri Saijo and Michael A. Metrick II are co-first authors.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 2921 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Saijo, E., Metrick, M.A., Koga, S. et al. 4-Repeat tau seeds and templating subtypes as brain and CSF biomarkers of frontotemporal lobar degeneration. Acta Neuropathol 139, 63–77 (2020). https://doi.org/10.1007/s00401-019-02080-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-019-02080-2

Keywords

Search

Navigation