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

doi:10.1007/s00401-015-1509-x

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 AnsorgeThomas 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

^*Corresponding author for this work

Pathology

Research output: Contribution to journal › Article › peer-review

380 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 language	English (US)
Pages (from-to)	87-102
Number of pages	16
Journal	Acta Neuropathologica
Volume	131
Issue number	1
DOIs	https://doi.org/10.1007/s00401-015-1509-x
State	Published - Jan 1 2016

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).

Keywords

ARTAG
Aging
Tau
Tau astrogliopathy

ASJC Scopus subject areas

Clinical Neurology
Cellular and Molecular Neuroscience
Pathology and Forensic Medicine

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10.1007/s00401-015-1509-x

Cite this

Kovacs, G. G., Ferrer, I., Grinberg, L. T., Alafuzoff, I., Attems, J., Budka, H., Cairns, N. J., Crary, J. F., Duyckaerts, C., Ghetti, B., Halliday, G. M., Ironside, J. W., Love, S., Mackenzie, I. R., Munoz, D. G., Murray, M. E., Nelson, P. T., Takahashi, H., Trojanowski, J. Q., ... Dickson, D. W. (2016). Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy. Acta Neuropathologica, 131(1), 87-102. https://doi.org/10.1007/s00401-015-1509-x

@article{0eaa42d6bd9a43cd9ea19d44a9791b7d,

title = "Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy",

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 = "ARTAG, Aging, Tau, Tau astrogliopathy",

author = "Kovacs, {Gabor G.} and Isidro Ferrer and Grinberg, {Lea T.} and Irina Alafuzoff and Johannes Attems and Herbert Budka and Cairns, {Nigel J.} and Crary, {John F.} and Charles Duyckaerts and Bernardino Ghetti and Halliday, {Glenda M.} and Ironside, {James W.} and Seth Love and Mackenzie, {Ian R.} and Munoz, {David G.} and Murray, {Melissa E.} and Nelson, {Peter T.} and Hitoshi Takahashi and Trojanowski, {John Q.} and Olaf Ansorge and Thomas Arzberger and Atik Baborie and Beach, {Thomas G.} and Bieniek, {Kevin F.} and Bigio, {Eileen H.} and Istvan Bodi and Dugger, {Brittany N.} and Mel Feany and Ellen Gelpi and Gentleman, {Stephen M.} and Giorgio Giaccone and Hatanpaa, {Kimmo J.} and Richard Heale and Hof, {Patrick R.} and Monika Hofer and Tibor Hortob{\'a}gyi and Kurt Jellinger and Jicha, {Gregory A.} and Paul Ince and Julia Kofler and Enik{\"o} K{\"o}vari and Kril, {Jillian J.} and Mann, {David M.} and Radoslav Matej and McKee, {Ann C.} and Catriona McLean and Ivan Milenkovic and Montine, {Thomas J.} and Shigeo Murayama and Lee, {Edward B.} and Jasmin Rahimi and Rodriguez, {Roberta D.} and Annemieke Rozem{\"u}ller and Schneider, {Julie A.} and Christian Schultz and William Seeley and Danielle Seilhean and Colin Smith and Fabrizio Tagliavini and Masaki Takao and Thal, {Dietmar Rudolf} and Toledo, {Jon B.} and Markus Tolnay and Troncoso, {Juan C.} and Vinters, {Harry V.} and Serge Weis and Wharton, {Stephen B.} and White, {Charles L.} and Thomas Wisniewski and Woulfe, {John M.} and Masahito Yamada and Dickson, {Dennis W.}",

note = "Publisher Copyright: {\textcopyright} 2015, Springer-Verlag Berlin Heidelberg.",

year = "2016",

month = jan,

day = "1",

doi = "10.1007/s00401-015-1509-x",

language = "English (US)",

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pages = "87--102",

journal = "Acta Neuropathologica",

issn = "0001-6322",

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Kovacs, GG, Ferrer, I, Grinberg, LT, Alafuzoff, I, Attems, J, Budka, H, Cairns, NJ, Crary, JF, Duyckaerts, C, Ghetti, B, Halliday, GM, Ironside, JW, Love, S, Mackenzie, IR, Munoz, DG, Murray, ME, Nelson, PT, Takahashi, H, Trojanowski, JQ, Ansorge, O, Arzberger, T, Baborie, A, Beach, TG, Bieniek, KF, Bigio, EH, Bodi, I, Dugger, BN, Feany, M, Gelpi, E, Gentleman, SM, Giaccone, G, Hatanpaa, KJ, Heale, R, Hof, PR, Hofer, M, Hortobágyi, T, Jellinger, K, Jicha, GA, Ince, P, Kofler, J, Kövari, E, Kril, JJ, Mann, DM, Matej, R, McKee, AC, McLean, C, Milenkovic, I, Montine, TJ, Murayama, S, Lee, EB, Rahimi, J, Rodriguez, RD, Rozemüller, A, Schneider, JA, Schultz, C, Seeley, W, Seilhean, D, Smith, C, Tagliavini, F, Takao, M, Thal, DR, Toledo, JB, Tolnay, M, Troncoso, JC, Vinters, HV, Weis, S, Wharton, SB, White, CL, Wisniewski, T, Woulfe, JM, Yamada, M & Dickson, DW 2016, 'Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy', Acta Neuropathologica, vol. 131, no. 1, pp. 87-102. https://doi.org/10.1007/s00401-015-1509-x

TY - JOUR

T1 - Aging-related tau astrogliopathy (ARTAG)

T2 - harmonized evaluation strategy

AU - Kovacs, Gabor G.

AU - Ferrer, Isidro

AU - Grinberg, Lea T.

AU - Alafuzoff, Irina

AU - Attems, Johannes

AU - Budka, Herbert

AU - Cairns, Nigel J.

AU - Crary, John F.

AU - Duyckaerts, Charles

AU - Ghetti, Bernardino

AU - Halliday, Glenda M.

AU - Ironside, James W.

AU - Love, Seth

AU - Mackenzie, Ian R.

AU - Munoz, David G.

AU - Murray, Melissa E.

AU - Nelson, Peter T.

AU - Takahashi, Hitoshi

AU - Trojanowski, John Q.

AU - Ansorge, Olaf

AU - Arzberger, Thomas

AU - Baborie, Atik

AU - Beach, Thomas G.

AU - Bieniek, Kevin F.

AU - Bigio, Eileen H.

AU - Bodi, Istvan

AU - Dugger, Brittany N.

AU - Feany, Mel

AU - Gelpi, Ellen

AU - Gentleman, Stephen M.

AU - Giaccone, Giorgio

AU - Hatanpaa, Kimmo J.

AU - Heale, Richard

AU - Hof, Patrick R.

AU - Hofer, Monika

AU - Hortobágyi, Tibor

AU - Jellinger, Kurt

AU - Jicha, Gregory A.

AU - Ince, Paul

AU - Kofler, Julia

AU - Kövari, Enikö

AU - Kril, Jillian J.

AU - Mann, David M.

AU - Matej, Radoslav

AU - McKee, Ann C.

AU - McLean, Catriona

AU - Milenkovic, Ivan

AU - Montine, Thomas J.

AU - Murayama, Shigeo

AU - Lee, Edward B.

AU - Rahimi, Jasmin

AU - Rodriguez, Roberta D.

AU - Rozemüller, Annemieke

AU - Schneider, Julie A.

AU - Schultz, Christian

AU - Seeley, William

AU - Seilhean, Danielle

AU - Smith, Colin

AU - Tagliavini, Fabrizio

AU - Takao, Masaki

AU - Thal, Dietmar Rudolf

AU - Toledo, Jon B.

AU - Tolnay, Markus

AU - Troncoso, Juan C.

AU - Vinters, Harry V.

AU - Weis, Serge

AU - Wharton, Stephen B.

AU - White, Charles L.

AU - Wisniewski, Thomas

AU - Woulfe, John M.

AU - Yamada, Masahito

AU - Dickson, Dennis W.

PY - 2016/1/1

Y1 - 2016/1/1

N2 - 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.

AB - 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.

KW - ARTAG

KW - Aging

KW - Tau

KW - Tau astrogliopathy

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UR - http://www.scopus.com/inward/citedby.url?scp=84952984309&partnerID=8YFLogxK

U2 - 10.1007/s00401-015-1509-x

DO - 10.1007/s00401-015-1509-x

M3 - Article

C2 - 26659578

AN - SCOPUS:84952984309

SN - 0001-6322

VL - 131

SP - 87

EP - 102

JO - Acta Neuropathologica

JF - Acta Neuropathologica

IS - 1

ER -

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

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