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Acta Neuropathologica

, Volume 131, Issue 1, pp 87–102 | Cite as

Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy

  • Gabor G. KovacsEmail author
  • Isidro Ferrer
  • Lea T. Grinberg
  • Irina Alafuzoff
  • Johannes Attems
  • Herbert Budka
  • Nigel J. Cairns
  • John F. Crary
  • Charles Duyckaerts
  • Bernardino Ghetti
  • Glenda M. Halliday
  • James W. Ironside
  • Seth Love
  • Ian R. Mackenzie
  • David G. Munoz
  • Melissa E. Murray
  • Peter T. Nelson
  • Hitoshi Takahashi
  • John Q. Trojanowski
  • Olaf Ansorge
  • Thomas Arzberger
  • Atik Baborie
  • Thomas G. Beach
  • Kevin F. Bieniek
  • Eileen H. Bigio
  • Istvan Bodi
  • Brittany N. Dugger
  • Mel Feany
  • Ellen Gelpi
  • Stephen M. Gentleman
  • Giorgio Giaccone
  • Kimmo J. Hatanpaa
  • Richard Heale
  • Patrick R. Hof
  • Monika Hofer
  • Tibor Hortobágyi
  • Kurt Jellinger
  • Gregory A. Jicha
  • Paul Ince
  • Julia Kofler
  • Enikö Kövari
  • Jillian J. Kril
  • David M. Mann
  • Radoslav Matej
  • Ann C. McKee
  • Catriona McLean
  • Ivan Milenkovic
  • Thomas J. Montine
  • Shigeo Murayama
  • Edward B. Lee
  • Jasmin Rahimi
  • Roberta D. Rodriguez
  • Annemieke Rozemüller
  • Julie A. Schneider
  • Christian Schultz
  • William Seeley
  • Danielle Seilhean
  • Colin Smith
  • Fabrizio Tagliavini
  • Masaki Takao
  • Dietmar Rudolf Thal
  • Jon B. Toledo
  • Markus Tolnay
  • Juan C. Troncoso
  • Harry V. Vinters
  • Serge Weis
  • Stephen B. Wharton
  • Charles L. WhiteIII
  • Thomas Wisniewski
  • John M. Woulfe
  • Masahito Yamada
  • Dennis W. DicksonEmail author
Consensus Paper

Abstract

Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or granular immunopositivity, typically in gray matter. Various forms of ARTAG may coexist in the same brain and might reflect different pathogenic processes. Based on morphology and anatomical distribution, ARTAG can be distinguished from primary tauopathies, but may be concurrent with primary tauopathies or other disorders. We recommend four steps for evaluation of ARTAG: (1) identification of five types based on the location of either morphologies of tau astrogliopathy: subpial, subependymal, perivascular, white matter, gray matter; (2) documentation of the regional involvement: medial temporal lobe, lobar (frontal, parietal, occipital, lateral temporal), subcortical, brainstem; (3) documentation of the severity of tau astrogliopathy; and (4) description of subregional involvement. Some types of ARTAG may underlie neurological symptoms; however, the clinical significance of ARTAG is currently uncertain and awaits further studies. The goal of this proposal is to raise awareness of astroglial tau pathology in the aged brain, facilitating communication among neuropathologists and researchers, and informing interpretation of clinical biomarkers and imaging studies that focus on tau-related indicators.

Keywords

Aging ARTAG Tau astrogliopathy Tau 

Notes

Acknowledgments

We are extremely grateful to the patients, clinicians, and fellow researchers that made this effort possible. We also acknowledge the following funding sources: FP7 EU Project Develage No. 278486 (GGK); Grant “NIH P30 AG10133 (BG); NIA Grants P50 AG05681, P01 AG03991 (NJC), NIH R01 AG040311, institutional Grants NIH P01 AG019724-03 and P50 AG023501, and the tau consortium (LTG); the Nelson Family Foundation (MEM) and NIH Grants P50 AG016574 and P50 NS072187 (MEM, DWD); NIH Grant AG010124, AG017586 (JQT); NIH Grant P50 AG005138 (PRH); Alzheimer’s Research UK (ARUK), Alzheimer’s Society, National Institute for Health Research (NIHR), and UK Medical Research Council (MRC; G0400074) (JA); GMH is a National Health and Medical Research Council of Australia Senior Principal Research Fellow (#630434); Grant IGA NT12094-5 from Grant Agency of Ministry of Health of Czech Republic (RM); NIH Grant # AG028383 (PN); UK Medical Research Council (MRC; MR/L016400/1) (CS); NIA P50 AG005133 (JK); National Institute of Neurological Disorders and Stroke (1U01NS086659-01), Department of Veterans Affairs,), the National Institute of Aging Boston University Alzheimer’s Disease Center (P30AG13846; supplement 0572063345–5) (ACM); UK Medical Research Council (MC-PC-13044) (JWI and CS); National Brain Research Program, Hungary (KTIA_13_NAP-A-II/7) and Grant-in-Aid (KAKEN 26250017) (both for TH); NIH Grant P30AG12300 (KH, CLW); Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III—Fondos FEDER, a way to build Europe FIS Grants PI14/00757 and PI14/00328 (IF); DFG Grant (SFB 1134/A03) (CS); Johns Hopkins Alzheimer’s Disease Research Center NIH Grant #P50AG05146 (JCT); Alzheimer’s Disease Core Center Grant P30AG008051-26 (TW); Grant AG13854 (EHB); JSPS KAKENHI Grant Number 26430060 (MT); Italian Ministry of Health (GG and FT); National Institute of Health Grants P50 AG05136 and P50 NS062684 (TJM). The help of Brain Banks in collecting tissue is also highly acknowledged: Vienna KIN-Neurobiobank and VITA–study (GGK); GIE NeuroCEB (funded by the patients associations France Alzheimer, France Parkinson, Fondacion ARSEP and CSC) (CD); Sydney Brain Bank (funded by Neuroscience Research Australia and the University of New South Wales) (GMH); the Sheffield and Cambridge Brain Banks (CFAS) (PI, SW); Parkinson’s UK Tissue Bank at Imperial College, funded by Parkinson’s UK, a charity registered in England and Wales (948776) and Scotland (SC037554) (SG); The Edinburgh Brain Bank is supported by the UK Medical Research Council (MR/L016400/1) (CS, JWI).

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Gabor G. Kovacs
    • 1
    Email author
  • Isidro Ferrer
    • 2
  • Lea T. Grinberg
    • 3
    • 4
  • Irina Alafuzoff
    • 5
  • Johannes Attems
    • 6
  • Herbert Budka
    • 7
  • Nigel J. Cairns
    • 8
  • John F. Crary
    • 9
    • 33
  • Charles Duyckaerts
    • 10
  • Bernardino Ghetti
    • 11
  • Glenda M. Halliday
    • 12
  • James W. Ironside
    • 13
  • Seth Love
    • 14
  • Ian R. Mackenzie
    • 15
  • David G. Munoz
    • 16
  • Melissa E. Murray
    • 17
  • Peter T. Nelson
    • 18
  • Hitoshi Takahashi
    • 19
  • John Q. Trojanowski
    • 20
  • Olaf Ansorge
    • 21
  • Thomas Arzberger
    • 22
  • Atik Baborie
    • 23
  • Thomas G. Beach
    • 24
  • Kevin F. Bieniek
    • 17
  • Eileen H. Bigio
    • 25
  • Istvan Bodi
    • 26
  • Brittany N. Dugger
    • 24
    • 27
  • Mel Feany
    • 28
  • Ellen Gelpi
    • 29
  • Stephen M. Gentleman
    • 30
  • Giorgio Giaccone
    • 31
  • Kimmo J. Hatanpaa
    • 32
  • Richard Heale
    • 6
  • Patrick R. Hof
    • 33
  • Monika Hofer
    • 21
  • Tibor Hortobágyi
    • 34
  • Kurt Jellinger
    • 35
  • Gregory A. Jicha
    • 36
  • Paul Ince
    • 37
  • Julia Kofler
    • 38
  • Enikö Kövari
    • 39
  • Jillian J. Kril
    • 40
  • David M. Mann
    • 41
  • Radoslav Matej
    • 42
  • Ann C. McKee
    • 43
  • Catriona McLean
    • 44
  • Ivan Milenkovic
    • 1
    • 45
  • Thomas J. Montine
    • 46
  • Shigeo Murayama
    • 47
  • Edward B. Lee
    • 20
  • Jasmin Rahimi
    • 1
  • Roberta D. Rodriguez
    • 48
  • Annemieke Rozemüller
    • 49
  • Julie A. Schneider
    • 50
    • 51
  • Christian Schultz
    • 52
  • William Seeley
    • 3
  • Danielle Seilhean
    • 10
  • Colin Smith
    • 13
  • Fabrizio Tagliavini
    • 31
  • Masaki Takao
    • 53
  • Dietmar Rudolf Thal
    • 54
    • 55
  • Jon B. Toledo
    • 20
  • Markus Tolnay
    • 56
  • Juan C. Troncoso
    • 57
  • Harry V. Vinters
    • 58
    • 59
  • Serge Weis
    • 60
  • Stephen B. Wharton
    • 37
  • Charles L. WhiteIII
    • 32
  • Thomas Wisniewski
    • 61
    • 62
    • 63
  • John M. Woulfe
    • 64
  • Masahito Yamada
    • 65
  • Dennis W. Dickson
    • 17
    Email author
  1. 1.Institute of Neurology, Medical University of ViennaViennaAustria
  2. 2.Institute of Neuropathology, Bellvitge University HospitalUniversity of Barcelona, Hospitalet de LlobregatBarcelonaSpain
  3. 3.Department of Neurology, Memory and Aging CenterUniversity of CaliforniaSan FranciscoUSA
  4. 4.Department of Pathology, LIM-22University of Sao Paulo Medical SchoolSao PauloBrazil
  5. 5.Department of Immunology, Genetics and PathologyUppsala UniversityUppsalaSweden
  6. 6.Institute of NeuroscienceNewcastle UniversityNewcastle upon TyneUK
  7. 7.Institute of NeuropathologyUniversity Hospital ZürichZurichSwitzerland
  8. 8.Department of Pathology and ImmunologyWashington University School of MedicineSt. LouisUSA
  9. 9.Department of Pathology, Friedman Brain Institute, and the Ronald M. Loeb Center for Alzheimer’s DiseaseIcahn School of Medicine at Mount SinaiNew YorkUSA
  10. 10.Neuropathology Department, Hopital de La Salpetrière, AP-HPUPMC-Sorbonne-UniversityParisFrance
  11. 11.Department of Pathology and Laboratory MedicineIndiana University School of MedicineIndianapolisUSA
  12. 12.GMH-Neuroscience Research Australia and the University of New South WalesSydneyAustralia
  13. 13.Centre for Clinical Brain SciencesUniversity of EdinburghEdinburghUK
  14. 14.Institute of Clinical NeurosciencesUniversity of Bristol, Learning and Research Level 2, Southmead HospitalBristolUK
  15. 15.Department of Pathology and Laboratory MedicineUniversity of British ColumbiaVancouverCanada
  16. 16.Division of PathologySt. Michael’s HospitalTorontoCanada
  17. 17.Department of NeuroscienceMayo ClinicJacksonvilleUSA
  18. 18.Department of Pathology and Sanders-Brown Center on AgingUniversity of KentuckyLexingtonUSA
  19. 19.Department of Pathology, Brain Research InstituteNiigata UniversityNiigataJapan
  20. 20.Department of Pathology and Laboratory Medicine of the Perelman School of Medicine, Center for Neurodegenerative Disease Research, Institute On AgingUniversity of PennsylvaniaPhiladelphiaUSA
  21. 21.Department of NeuropathologyJohn Radcliffe HospitalOxfordUK
  22. 22.Department of Psychiatry and Psychotherapy, Centre for Neuropathology and Prion ResearchLudwig-Maximilians-University MunichMunichGermany
  23. 23.Department of NeuropathologyWalton CentreLiverpoolUK
  24. 24.Civin Laboratory for NeuropathologyBanner Sun Health Research InstituteSun CityUSA
  25. 25.Northwestern ADC Neuropathology CoreNorthwestern University Feinberg School of MedicineChicagoUSA
  26. 26.Clinical Neuropathology, King’s College Hospital, London Neurodegenerative Brain BankLondonUK
  27. 27.Institute for Neurodegenerative Diseases, University of California San FranciscoSan FranciscoUSA
  28. 28.Department of PathologyBrigham and Women’s Hospital, Harvard Medical SchoolBostonUSA
  29. 29.Neurological Tissue Bank of the Biobank-Hospital Clinic-IDIBAPS, Institut d’Investigacions Biomediques August Pi i SunyerBarcelonaSpain
  30. 30.Department of MedicineImperial College LondonLondonUK
  31. 31.IRCCS Foundation “Carlo Besta” Neurological InstituteMilanItaly
  32. 32.Department of PathologyUniversity of Texas Southwestern Medical CenterDallasUSA
  33. 33.Fishberg Department of Neuroscience, Friedman Brain Institute, and Ronald M. Loeb Center for Alzheimer’s DiseaseIcahn School of Medicine at Mount SinaiNew YorkUSA
  34. 34.Department of Neuropathology, Faculty of Medicine, Institute of PathologyUniversity of DebrecenDebrecenHungary
  35. 35.Institute of Clinical NeurobiologyViennaAustria
  36. 36.Department of Neurology and Sanders-Brown Center on AgingUniversity of KentuckyLexingtonUSA
  37. 37.Sheffield Institute for Translational NeuroscienceUniversity of SheffieldSheffieldUK
  38. 38.Department of PathologyUniversity of PittsburghPittsburghUSA
  39. 39.Department of Mental Health and PsychiatryUniversity Hospitals and University of Geneva School of MedicineGenevaSwitzerland
  40. 40.Discipline of Pathology, Sydney Medical SchoolThe University of SydneySydneyAustralia
  41. 41.Institute of Brain, Behaviour and Mental HealthManchester University Faculty of Medical and Health SciencesManchesterUK
  42. 42.Department of Pathology and Molecular MedicineThomayer HospitalPrague 4Czech Republic
  43. 43.Department of Neurology and PathologyBoston University School of Medicine and VA Healthcare SystemBostonUSA
  44. 44.Department of Anatomical PathologyAlfred HospitalPrahranAustralia
  45. 45.Department of NeurologyMedical University of ViennaViennaAustria
  46. 46.Department of PathologyUniversity of WashingtonSeattleUSA
  47. 47.Department of Neuropathology (The Brain Bank for Aging Research)Tokyo Metropolitan Geriatric Hospital and Institute of GerontologyTokyoJapan
  48. 48.Physiopathology in Aging Lab/Brazilian Aging Brain Study Group-LIM22University of Sao Paulo Medical SchoolSao PauloBrazil
  49. 49.Netherlands Brainbank and Department of PathologyVU University Medical CenterAmsterdamThe Netherlands
  50. 50.Department of PathologyRush University Medical CenterChicagoUSA
  51. 51.Department of Neurological SciencesRush University Medical CenterChicagoUSA
  52. 52.Institute of Neuroanatomy, Centre for Biomedicine and Medical Technology Mannheim, Medical Faculty MannheimHeidelberg UniversityHeidelbergGermany
  53. 53.Department of NeurologySaitama Medical University International Medical CenterSaitamaJapan
  54. 54.Laboratory of Neuropathology, Institute of PathologyUniversity of UlmUlmGermany
  55. 55.Department of NeuroscienceKU-LeuvenLouvainBelgium
  56. 56.Institute of PathologyUniversity Hospital BaselBaselSwitzerland
  57. 57.Division of Neuropathology, Department of PathologyJohns Hopkins University School of MedicineBaltimoreUSA
  58. 58.Section of Neuropathology, Department of Pathology and Laboratory Medicine, Brain Research InstituteUniversity of California, Los Angeles (UCLA) Medical Center and David Geffen School of MedicineLos AngelesUSA
  59. 59.Department of Neurology, Brain Research InstituteUniversity of California, Los Angeles (UCLA) Medical Center and David Geffen School of MedicineLos AngelesUSA
  60. 60.Department of Pathology and Neuropathology, Laboratory of Neuropathology, Neuromed Campus, Kepler University Hospital, Medical SchoolJohannes Kepler UniversityLinzAustria
  61. 61.Department of Neurology, Center for Cognitive NeurologyNew York University School of Medicine, ERSPNew YorkUSA
  62. 62.Department of Pathology, Center for Cognitive NeurologyNew York University School of Medicine, ERSPNew YorkUSA
  63. 63.Department of Psychiatry, Center for Cognitive NeurologyNew York University School of Medicine, ERSPNew YorkUSA
  64. 64.Department of Pathology and Laboratory Medicine, Centre for Cancer Therapeutics, Ottawa Hospital Research InstituteUniversity of OttawaOttawaCanada
  65. 65.Department of Neurology and Neurobiology of AgingKanazawa University Graduate School of Medical SciencesKanazawaJapan

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