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Evidence of corticofugal tau spreading in patients with frontotemporal dementia

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Abstract

Common neurodegenerative diseases feature progressive accumulation of disease-specific protein aggregates in selectively vulnerable brain regions. Increasing experimental evidence suggests that misfolded disease proteins exhibit prion-like properties, including the ability to seed corruptive templating and self-propagation along axons. Direct evidence for transneuronal spread in patients, however, remains limited. To test predictions made by the transneuronal spread hypothesis in human tissues, we asked whether tau deposition within axons of the corticospinal and corticopontine pathways can be predicted based on clinical syndromes and cortical atrophy patterns seen in frontotemporal lobar degeneration (FTLD). Sixteen patients with Pick’s disease, 21 with corticobasal degeneration, and 3 with FTLD-MAPT were included, spanning a range of clinical syndromes across the frontotemporal dementia (FTD) spectrum. Cortical involvement was measured using a neurodegeneration score, a tau score, and a composite score based on semiquantitative ratings and complemented by an MRI-based cortical atrophy W-map based on antemortem imaging. Midbrain cerebral peduncle and pontine base descending fibers were divided into three subregions, representing prefrontopontine, corticospinal, and parieto-temporo-occipital fiber pathways. Tau area fraction was calculated in each subregion and related to clinical syndrome and cortical measures. Within each clinical syndrome, there were predicted relationships between cortical atrophy patterns and axonal tau deposition in midbrain cerebral peduncle and pontine base. Between syndromes, contrasting and predictable patterns of brainstem axonal tau deposition emerged, with, for example, greater tau in prefrontopontine fibers in behavioral variant FTD and in corticospinal fibers in corticobasal syndrome. Finally, semiquantitative and quantitative cortical degeneration scores predicted brainstem axonal tau deposition based on anatomical principles. Taken together, these findings provide important human evidence in support of axonal tau spreading in patients with specific forms of tau-related neurodegeneration.

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References

  1. Aguzzi A (2009) Cell biology: beyond the prion principle. Nature 459:924–925

    Article  CAS  PubMed  Google Scholar 

  2. Amador-Ortiz C, Lin WL, Ahmed Z, Personett D, Davies P, Duara R et al (2007) TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease. Ann Neurol 61:435–445

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Boluda S, Iba M, Zhang B, Raible KM, Lee VM, Trojanowski JQ (2015) Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer's disease or corticobasal degeneration brains. Acta Neuropathol 129:221–237

    Article  CAS  PubMed  Google Scholar 

  4. Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259

    Article  CAS  PubMed  Google Scholar 

  5. Braak H, Del Tredici K, Rüb U, de Vos R, Jansen Steur E, Braak E (2003) Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 24:197–211

    Article  PubMed  Google Scholar 

  6. Braak H, Thal DR, Ghebremedhin E, Del Tredici K (2011) Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol 70:960–969

    Article  CAS  PubMed  Google Scholar 

  7. Brettschneider J, Del Tredici K, Lee VM, Trojanowski JQ (2015) Spreading of pathology in neurodegenerative diseases: a focus on human studies. Nat Rev Neurosci 16:109–120

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Brodal P (1978) The corticopontine projection in the rhesus monkey. Origin and principles of organization Brain 101:251–283

    CAS  PubMed  Google Scholar 

  9. Carpenter MB (1991) Core text of neuroanatomy. Williams & Wilkins, Baltimore

    Google Scholar 

  10. Caso F, Gesierich B, Henry M, Sidhu M, LaMarre A, Babiak M et al (2013) Nonfluent/agrammatic PPA with in-vivo cortical amyloidosis and Pick's disease pathology. Behav Neurol 26:95–106

    Article  PubMed Central  PubMed  Google Scholar 

  11. Cearley CN, Wolfe JH (2007) A single injection of an adeno-associated virus vector into nuclei with divergent connections results in widespread vector distribution in the brain and global correction of a neurogenetic disease. J Neurosci 27:9928–9940

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Clavaguera F, Akatsu H, Fraser G, Crowther RA, Frank S, Hench J et al (2013) Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc Natl Acad Sci USA 110:9535–9540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A et al (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 11:909–913

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. de Calignon A, Polydoro M, Suarez-Calvet M, William C, Adamowicz DH, Kopeikina KJ et al (2012) Propagation of tau pathology in a model of early Alzheimer's disease. Neuron 73:685–697

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. DeArmond SJ, Fusco MM, Dewey MM (1989) Structure of the human brain, a photographic atlas. Oxford University Press, Oxford

    Google Scholar 

  16. Dickson DW, Ahmed Z, Algom AA, Tsuboi Y, Josephs KA (2010) Neuropathology of variants of progressive supranuclear palsy. Curr Opin Neurol 23:394–400

    Article  PubMed  Google Scholar 

  17. Dickson DW, Kouri N, Murray ME, Josephs KA (2011) Neuropathology of frontotemporal lobar degeneration-tau (FTLD-tau). J Mol Neurosci 45:384–389

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Eisele YS, Obermüller U, Heilbronner G, Baumann F, Kaeser SA, Wolburg H et al (2010) Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis. Science 330:980–982

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Fan L, Li H, Zhuo J, Zhang Y, Wang J, Chen L et al (2016) The human brainnetome atlas: a new brain atlas based on connectional architecture. Cereb Cortex 26:3508–3526

    Article  PubMed Central  PubMed  Google Scholar 

  21. Gardner RC, Boxer AL, Trujillo A, Mirsky JB, Guo CC, Gennatas ED et al (2013) Intrinsic connectivity network disruption in progressive supranuclear palsy. Ann Neurol 73:603–616

    Article  PubMed Central  PubMed  Google Scholar 

  22. Goedert M (2015) Neurodegeneration. Alzheimer's and Parkinson's diseases: the prion concept in relation to assembled Aβ, tau, and α-synuclein. Science 349:1255555

    Article  CAS  PubMed  Google Scholar 

  23. Gorno-Tempini ML, Hillis AE, Weintraub S, Kertesz A, Mendez M, Cappa SF et al (2011) Classification of primary progressive aphasia and its variants. Neurology 76:1006–1014

    Article  PubMed Central  PubMed  Google Scholar 

  24. Guo JL, Lee VM (2013) Neurofibrillary tangle-like tau pathology induced by synthetic tau fibrils in primary neurons over-expressing mutant tau. FEBS Lett 587:717–723

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Habas C, Cabanis EA (2007) Anatomical parcellation of the brainstem and cerebellar white matter: a preliminary probabilistic tractography study at 3 T. Neuroradiology 49:849–863

    Article  PubMed  Google Scholar 

  26. Hof PR, Bouras C, Perl DP, Morrison JH (1994) Quantitative neuropathologic analysis of Pick's disease cases: cortical distribution of Pick bodies and coexistence with Alzheimer's disease. Acta Neuropathol 87:115–124

    Article  CAS  PubMed  Google Scholar 

  27. Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC et al (2012) National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease. Alzheimers Dement 8:1–13

    Article  PubMed Central  PubMed  Google Scholar 

  28. Iba M, Guo JL, McBride JD, Zhang B, Trojanowski JQ, Lee VM (2013) Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer's-like tauopathy. J Neurosci 33:1024–1037

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Jackson SJ, Kerridge C, Cooper J, Cavallini A, Falcon B, Cella CV et al (2016) Short fibrils constitute the major species of seed-competent tau in the brains of mice transgenic for human P301S tau. J Neurosci 36:762–772

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Kim E-J, Vatsavayai S, Seeley WW (2017) Neuropathology of dementia. Cambridge university press, Cambridge

  32. Kim EJ, Brown JA, Deng J, Hwang JL, Spina S, Miller ZA et al (2018) Mixed TDP-43 proteinopathy and tauopathy in frontotemporal lobar degeneration: nine case series. J Neurol 265:2960–2971

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Lee SE, Rabinovici GD, Mayo MC, Wilson SM, Seeley WW, DeArmond SJ et al (2011) Clinicopathological correlations in corticobasal degeneration. Ann Neurol 70:327–340

    Article  PubMed Central  PubMed  Google Scholar 

  34. Ling H, Kovacs GG, Vonsattel JP, Davey K, Mok KY, Hardy J et al (2016) Astrogliopathy predominates the earliest stage of corticobasal degeneration pathology. Brain 139:3237–3252

    Article  PubMed  Google Scholar 

  35. Litvan I, Agid Y, Calne D, Campbell G, Dubois B, Duvoisin RC et al (1996) Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology 47:1–9

    Article  CAS  PubMed  Google Scholar 

  36. Liu L, Drouet V, Wu JW, Witter MP, Small SA, Clelland C et al (2012) Trans-synaptic spread of tau pathology in vivo. PLoS ONE 7:e31302

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Mackenzie I, Neumann M, Bigio E, Cairns N, Alafuzoff I, Kril J et al (2010) Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol 119:1–4

    Article  PubMed  Google Scholar 

  38. McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H et al (2005) Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65:1863–1872

    Article  CAS  PubMed  Google Scholar 

  39. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan E (1984) Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 34:939–944

    Article  CAS  PubMed  Google Scholar 

  40. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Kawas CH et al (2011) The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 7:263–269

    Article  PubMed Central  PubMed  Google Scholar 

  41. Meyer-Luehmann M, Coomaraswamy J, Bolmont T, Kaeser S, Schaefer C, Kilger E et al (2006) Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science 313:1781–1784

    Article  CAS  PubMed  Google Scholar 

  42. Miki Y, Mori F, Tanji K, Kurotaki H, Kakita A, Takahashi H et al (2014) An autopsy case of incipient Pick's disease: immunohistochemical profile of early-stage Pick body formation. Neuropathology 34:386–391

    Article  CAS  PubMed  Google Scholar 

  43. Montine TJ, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Dickson DW et al (2012) National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease: a practical approach. Acta Neuropathol 123:1–11

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Naidich TP, Duvernoy HM, Delman BN, Sorensen AG, Kollias SS, Haacke EM (2009) Duvernoy's Atlas of the human brain stem and cerebellum. Springer, Vienna, NewYork

    Book  Google Scholar 

  45. Narasimhan S, Lee VMY (2017) The use of mouse models to study cell-to-cell transmission of pathological tau. Methods Cell Biol 141:287–305

    Article  PubMed Central  PubMed  Google Scholar 

  46. Neary D, Snowden J, Gustafson L, Passant U, Stuss D, Black S et al (1998) Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 51:1546–1554

    Article  CAS  PubMed  Google Scholar 

  47. Porta S, Xu Y, Restrepo CR, Kwong LK, Zhang B, Brown HJ et al (2018) Patient-derived frontotemporal lobar degeneration brain extracts induce formation and spreading of TDP-43 pathology in vivo. Nat Commun 9:4220

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Prusiner SB (1982) Novel proteinaceous infectious particles cause scrapie. Science 216:136–144

    Article  CAS  PubMed  Google Scholar 

  49. Rahimi J, Milenkovic I, Kovacs GG (2015) Patterns of tau and α-synuclein pathology in the visual system. J Parkinsons Dis 5:333–340

    Article  CAS  PubMed  Google Scholar 

  50. Raj A, Kuceyeski A, Weiner M (2012) A network diffusion model of disease progression in dementia. Neuron 73:1204–1215

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Raman MR, Kantarci K, Murray ME, Jack CR, Vemuri P (2016) Imaging markers of cerebrovascular pathologies: pathophysiology, clinical presentation, and risk factors. Alzheimers Dement (Amst) 5:5–14

    Google Scholar 

  52. Rascovsky K, Hodges JR, Knopman D, Mendez MF, Kramer JH, Neuhaus J et al (2011) Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 134:2456–2477

    Article  PubMed Central  PubMed  Google Scholar 

  53. Rebeiz JJ, Kolodny EH, Richardson EP Jr (1968) Corticodentatonigral degeneration with neuronal achromasia. Arch Neurol 18:20–33

    Article  CAS  PubMed  Google Scholar 

  54. Rorden C, Brett M (2000) Stereotaxic display of brain lesions. Behav Neurol 12:191–200

    Article  PubMed  Google Scholar 

  55. 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Santos-Santos MA, Mandelli ML, Binney RJ, Ogar J, Wilson SM, Henry ML et al (2016) Features of patients with nonfluent/agrammatic primary progressive aphasia with underlying progressive supranuclear palsy pathology or corticobasal degeneration. JAMA Neurol 73:733–742

    Article  PubMed Central  PubMed  Google Scholar 

  57. Schmahmann JD, Ko R, MacMore J (2004) The human basis pontis: motor syndromes and topographic organization. Brain 127:1269–1291

    Article  PubMed  Google Scholar 

  58. Schmahmann JD, Pandya DN (1997) Anatomic organization of the basilar pontine projections from prefrontal cortices in rhesus monkey. J Neurosci 17:438–458

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Schmahmann JD, Pandya DN (1989) Anatomical investigation of projections to the basis pontis from posterior parietal association cortices in rhesus monkey. J Comp Neurol 289:53–73

    Article  CAS  PubMed  Google Scholar 

  60. Schmahmann JD, Pandya DN (1995) Prefrontal cortex projections to the basilar pons in rhesus monkey: implications for the cerebellar contribution to higher function. Neurosci Lett 199:175–178

    Article  CAS  PubMed  Google Scholar 

  61. Schmahmann JD, Pandya DN (1993) Prelunate, occipitotemporal, and parahippocampal projections to the basis pontis in rhesus monkey. J Comp Neurol 337:94–112

    Article  CAS  PubMed  Google Scholar 

  62. Schmahmann JD, Rosene DL, Pandya DN (2004) Motor projections to the basis pontis in rhesus monkey. J Comp Neurol 478:248–268

    Article  PubMed  Google Scholar 

  63. Seeley W, Crawford R, Zhou J, Miller B, Greicius M (2009) Neurodegenerative diseases target large-scale human brain networks. Neuron 62:42–52

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. Seeley WW (2017) Map** neurodegenerative disease onset and progression. Cold Spring Harb Perspect Biol 9

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Stieltjes B, Kaufmann WE, van Zijl PC, Fredericksen K, Pearlson GD, Solaiyappan M et al (2001) Diffusion tensor imaging and axonal tracking in the human brainstem. Neuroimage 14:723–735

    Article  CAS  PubMed  Google Scholar 

  66. Tartaglia M, Sidhu M, Laluz V, Racine C, Rabinovici G, Creighton K et al (2010) Sporadic corticobasal syndrome due to FTLD-TDP. Acta Neuropathol 119:365–374

    Article  PubMed  Google Scholar 

  67. Tredici G, Barajon I, Pizzini G, Sanguineti I (1990) The organization of corticopontine fibres in man. Acta Anat (Basel) 137:320–323

    Article  CAS  Google Scholar 

  68. Tsuboi Y, Josephs KA, Boeve BF, Litvan I, Caselli RJ, Caviness JN et al (2005) Increased tau burden in the cortices of progressive supranuclear palsy presenting with corticobasal syndrome. Mov Disord 20:982–988

    Article  PubMed  Google Scholar 

  69. Whitwell JL, Boeve BF, Weigand SD, Senjem ML, Gunter JL, Baker MC et al (2015) Brain atrophy over time in genetic and sporadic frontotemporal dementia: a study of 198 serial magnetic resonance images. Eur J Neurol 22:745–752

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  70. Witelson SF (1989) Hand and sex differences in the isthmus and genu of the human corpus callosum. A postmortem morphological study. Brain 112(Pt 3):799–835

    Article  PubMed  Google Scholar 

  71. Wu JW, Herman M, Liu L, Simoes S, Acker CM, Figueroa H et al (2013) Small misfolded Tau species are internalized via bulk endocytosis and anterogradely and retrogradely transported in neurons. J Biol Chem 288:1856–1870

    Article  CAS  PubMed  Google Scholar 

  72. Zhou J, Gennatas ED, Kramer JH, Miller BL, Seeley WW (2012) Predicting regional neurodegeneration from the healthy brain functional connectome. Neuron 73:1216–1227

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgements

We thank our patients and their families for participating in neurodegeneration research. We thank Norbert Lee and Anna Karydas for technical assistance.

Funding

Funding was provided by Financial Supporting Project of Long-term Overseas Dispatch of PNU's Tenure-track Faculty (2015) to Eun-Joo Kim, National Institute on Aging (AG023501, AG019724), Tau Consortium, and Bluefield Project to Cure FTD to William W. Seeley and Bruce L. Miller.

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  1. Department of Neurology, Memory and Aging Center, University of California, 675 Nelson Rising Lane, San Francisco, CA, 94158, USA

    Eun-Joo Kim, Ji-Hye L. Hwang, Stephanie E. Gaus, Alissa L. Nana, Jersey Deng, Jesse A. Brown, Salvatore Spina, Lea T. Grinberg, Joel H. Kramer, Adam L. Boxer, Maria Luisa Gorno-Tempini, Howard J. Rosen, Bruce L. Miller & William W. Seeley

  2. Department of Neurology, Pusan National University Hospital, Pusan National University School of Medicine and Medical Research Institute, Busan, Republic of Korea

    Eun-Joo Kim & Myung Jun Lee

  3. Department of Pathology, University of California, San Francisco, USA

    Lea T. Grinberg & William W. Seeley

  4. Department of Psychiatry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA

    Eliana Marisa Ramos

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Kim, EJ., Hwang, JH.L., Gaus, S.E. et al. Evidence of corticofugal tau spreading in patients with frontotemporal dementia. Acta Neuropathol 139, 27–43 (2020). https://doi.org/10.1007/s00401-019-02075-z

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