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

  • Gabor G. Kovacs
  • , 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. White, Thomas Wisniewski, John M. Woulfe, Masahito Yamada, Dennis W. Dickson

Research output: Contribution to journalArticlepeer-review

462 Scopus citations

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.

Original languageEnglish
Pages (from-to)87-102
Number of pages16
JournalActa Neuropathologica
Volume131
Issue number1
DOIs
StatePublished - Jan 1 2016

Bibliographical note

Publisher Copyright:
© 2015, Springer-Verlag Berlin Heidelberg.

Funding

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).

FundersFunder number
Alzheimer’s Research United Kingdom
Alzheimer's Society
Ministerio de Ciencia, Innovación y Universidades
Instituto de Salud Carlos III
National Institute for Health Research
Sydney Brain Bank
Sheffield and Cambridge Brain Banks
European Commission
Neuroscience Research Australia
Ministero della Salute
China Scholarship Council
CFAS
Virginia Information Technologies Agency
U.S. Department of Veterans Affairs
FP7 CFUND
Parkinson’s UK Tissue Bank at Imperial College
University of New South Wales
Fondation pour l'Aide à la Recherche sur la Sclérose en Plaques
UK Industrial Decarbonization Research and Innovation Centre
Nelson Family FoundationP50 AG005138, AG010124, P50 AG016574, P50 NS072187, AG017586
National Institute of Aging Boston University Alzheimer’s Disease CenterP30AG13846, 0572063345–5, MC-PC-13044
National Key Basic Research and Development Program of ChinaKAKEN 26250017, KTIA_13_NAP-A-II/7, P30AG12300
UK Medical Research Council, Engineering and Physical Sciences Research CouncilG0900580, G0900582, G0600953, G1100540, G0400074, G0901945, P50 AG005133, MR/L016400/1, MR/L016451/1, G0502157, G0900652
Johns Hopkins Alzheimer’s Disease Research Center NIH50AG05146
Japan Society for the Promotion of Science26430060
NIH Alzheimer’s Disease Core CenterP30AG008051-26
Seventh Framework Programme278486
Ministerstvo Zdravotnictví Ceské RepublikyAG028383
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke CouncilU01NS086659, R01NS094003, P50NS072187, P50NS062684
National Institutes of Health (NIH)R18CA016400, R10CA016451, K04CA000540
Deutsche ForschungsgemeinschaftSFB 1134/A03
Australian National Health and Medical Research Council630434, IGA NT12094-5
Parkinson's Disease Foundation/National Parkinson's Disease joint program948776, SC037554
National Institute on Alcohol Abuse and AlcoholismR28AA012725
European Regional Development FundPI14/00757, PI14/00328
National Institute on AgingP50AG005133, P50AG005146, R01AG040311, P01AG017586, P50AG005681, P01AG019724, P30AG013854, P30AG010124, P50AG016574, P30AG012300, P30AG028383, P30AG010133, P30AG013846, P01AG003991, P30AG008051, P50AG005136, P50AG023501, P50AG005138

    Keywords

    • ARTAG
    • Aging
    • Tau
    • Tau astrogliopathy

    ASJC Scopus subject areas

    • Pathology and Forensic Medicine
    • Clinical Neurology
    • Cellular and Molecular Neuroscience

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