{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T03:44:26Z","timestamp":1793763866281,"version":"4.6.1"},"reference-count":74,"publisher":"Springer Science and Business Media LLC","issue":"11","license":[{"start":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T00:00:00Z","timestamp":1660089600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T00:00:00Z","timestamp":1660089600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Psychiatry"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Astrocytes can adopt multiple molecular phenotypes in the brain of Alzheimer\u2019s disease (AD) patients. Here, we studied the associations of cerebrospinal fluid (CSF) glial fibrillary acidic protein (GFAP) and chitinase-3-like protein 1 (YKL-40) levels with brain amyloid-\u03b2 (A\u03b2) and tau pathologies. We assessed 121 individuals across the aging and AD clinical spectrum with positron emission tomography (PET) brain imaging for A\u03b2 ([\n                    <jats:sup>18<\/jats:sup>\n                    F]AZD4694) and tau ([\n                    <jats:sup>18<\/jats:sup>\n                    F]MK-6240), as well as CSF GFAP and YKL-40 measures. We observed that higher CSF GFAP levels were associated with elevated A\u03b2-PET but not tau-PET load. By contrast, higher CSF YKL-40 levels were associated with elevated tau-PET but not A\u03b2-PET burden. Structural equation modeling revealed that CSF GFAP and YKL-40 mediate the effects of A\u03b2 and tau, respectively, on hippocampal atrophy, which was further associated with cognitive impairment. Our results suggest the existence of distinct astrocyte biomarker signatures in response to brain A\u03b2 and tau accumulation, which may contribute to our understanding of the complex link between reactive astrogliosis heterogeneity and AD progression.\n                  <\/jats:p>","DOI":"10.1038\/s41380-022-01716-2","type":"journal-article","created":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T04:03:08Z","timestamp":1660104188000},"page":"4781-4789","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":136,"title":["Astrocyte biomarker signatures of amyloid-\u03b2 and tau pathologies in Alzheimer\u2019s disease"],"prefix":"10.1038","volume":"27","author":[{"given":"Jo\u00e3o Pedro","family":"Ferrari-Souza","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P\u00e2mela C. L.","family":"Ferreira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruna","family":"Bellaver","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2711-3833","authenticated-orcid":false,"given":"C\u00e9cile","family":"Tissot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Ting","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas T.","family":"Leffa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wagner S.","family":"Brum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9a L.","family":"Benedet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J.","family":"Ashton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3924-5278","authenticated-orcid":false,"given":"Marco Ant\u00f4nio","family":"De Bastiani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1567-3374","authenticated-orcid":false,"given":"Andr\u00e9ia","family":"Rocha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7826-4781","authenticated-orcid":false,"given":"Joseph","family":"Therriault","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6877-4825","authenticated-orcid":false,"given":"Firoza Z.","family":"Lussier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mira","family":"Chamoun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stijn","family":"Servaes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gleb","family":"Bezgin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min Su","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenna","family":"Stevenson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nesrine","family":"Rahmouni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Pallen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina Margherita","family":"Poltronetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William E.","family":"Klunk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana L.","family":"Tudorascu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann D.","family":"Cohen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor L.","family":"Villemagne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serge","family":"Gauthier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1890-4193","authenticated-orcid":false,"given":"Kaj","family":"Blennow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3930-4354","authenticated-orcid":false,"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diogo O.","family":"Souza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1422-4358","authenticated-orcid":false,"given":"Thomas K.","family":"Karikari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo R.","family":"Zimmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9116-1376","authenticated-orcid":false,"given":"Pedro","family":"Rosa-Neto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9057-8014","authenticated-orcid":false,"given":"Tharick A.","family":"Pascoal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,8,10]]},"reference":[{"key":"1716_CR1","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1016\/j.ajpath.2011.05.047","volume":"179","author":"A Serrano-Pozo","year":"2011","unstructured":"Serrano-Pozo A, Mielke ML, Gomez-Isla T, Betensky RA, Growdon JH, Frosch MP, et al. Reactive glia not only associates with plaques but also parallels tangles in Alzheimer\u2019s disease. Am J Pathol. 2011;179:1373\u201384.","journal-title":"Am J Pathol"},{"key":"1716_CR2","doi-asserted-by":"crossref","DOI":"10.1186\/1742-2094-10-90","volume":"10","author":"A Marutle","year":"2013","unstructured":"Marutle A, Gillberg PG, Bergfors A, Yu W, Ni R, Nennesmo I, et al. (3)H-deprenyl and (3)H-PIB autoradiography show different laminar distributions of astroglia and fibrillar beta-amyloid in Alzheimer brain. J Neuroinflammation. 2013;10:90.","journal-title":"J Neuroinflammation"},{"key":"1716_CR3","volume":"7","author":"L Lemoine","year":"2017","unstructured":"Lemoine L, Saint-Aubert L, Nennesmo I, Gillberg PG, Nordberg A. Cortical laminar tau deposits and activated astrocytes in Alzheimer\u2019s disease visualised by (3)H-THK5117 and (3)H-deprenyl autoradiography. Sci Rep. 2017;7:45496.","journal-title":"Sci Rep"},{"key":"1716_CR4","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/nature21029","volume":"541","author":"SA Liddelow","year":"2017","unstructured":"Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541:481\u20137.","journal-title":"Nature."},{"key":"1716_CR5","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/s41593-020-0624-8","volume":"23","author":"N Habib","year":"2020","unstructured":"Habib N, McCabe C, Medina S, Varshavsky M, Kitsberg D, Dvir-Szternfeld R, et al. Disease-associated astrocytes in Alzheimer\u2019s disease and aging. Nat Neurosci. 2020;23:701\u20136.","journal-title":"Nat Neurosci"},{"key":"1716_CR6","doi-asserted-by":"crossref","first-page":"114","DOI":"10.3389\/fnagi.2018.00114","volume":"10","author":"BG Perez-Nievas","year":"2018","unstructured":"Perez-Nievas BG, Serrano-Pozo A. Deciphering the astrocyte reaction in Alzheimer\u2019s disease. Front Aging Neurosci. 2018;10:114.","journal-title":"Front Aging Neurosci"},{"key":"1716_CR7","doi-asserted-by":"crossref","unstructured":"Galea E, Weinstock LD, Larramona-Arcas R, Pybus AF, Gim\u00e9nez-Llort L, Escartin C, et al. Multi-transcriptomic analysis points to early organelle dysfunction in human astrocytes in Alzheimer\u2019s disease. 2021. https:\/\/www.medrxiv.org\/content\/10.1101\/2021.02.25.21252422.","DOI":"10.1101\/2021.02.25.21252422"},{"key":"1716_CR8","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1038\/s41593-020-00783-4","volume":"24","author":"C Escartin","year":"2021","unstructured":"Escartin C, Galea E, Lakatos A, O\u2019Callaghan JP, Petzold GC, Serrano-Pozo A, et al. Reactive astrocyte nomenclature, definitions, and future directions. Nat Neurosci. 2021;24:312\u201325.","journal-title":"Nat Neurosci"},{"key":"1716_CR9","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-021-27702-w","volume":"13","author":"Z Jiwaji","year":"2022","unstructured":"Jiwaji Z, Tiwari SS, Aviles-Reyes RX, Hooley M, Hampton D, Torvell M, et al. Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Ass pathology. Nat Commun. 2022;13:135.","journal-title":"Nat Commun"},{"key":"1716_CR10","doi-asserted-by":"crossref","unstructured":"De Bastiani MA, Bellaver B, Brum WS, Souza DG, Lukasewicz Ferreira PC, Rocha AS, et al. Hippocampal GFAP-positive astrocyte responses to amyloid and tau pathologies. 2022. https:\/\/www.biorxiv.org\/content\/10.1101\/2022.02.25.481812.","DOI":"10.1101\/2022.02.25.481812"},{"key":"1716_CR11","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.molmed.2018.11.006","volume":"25","author":"SF Carter","year":"2019","unstructured":"Carter SF, Herholz K, Rosa-Neto P, Pellerin L, Nordberg A, Zimmer ER. Astrocyte biomarkers in Alzheimer\u2019s disease. Trends Mol Med. 2019;25:77\u201395.","journal-title":"Trends Mol Med"},{"key":"1716_CR12","doi-asserted-by":"crossref","unstructured":"Bellaver B, Ferrari-Souza JP, Uglione da Ros L, Carter SF, Rodriguez-Vieitez E, Nordberg A, et al. Astrocyte biomarkers in Alzheimer disease: a systematic review and meta-analysis. Neurology. 2021;96:e2944\u201355.","DOI":"10.1212\/WNL.0000000000012109"},{"key":"1716_CR13","doi-asserted-by":"crossref","first-page":"102870","DOI":"10.1016\/j.msard.2021.102870","volume":"51","author":"M Sun","year":"2021","unstructured":"Sun M, Liu N, Xie Q, Li X, Sun J, Wang H, et al. A candidate biomarker of glial fibrillary acidic protein in CSF and blood in differentiating multiple sclerosis and its subtypes: a systematic review and meta-analysis. Mult Scler Relat Disord. 2021;51:102870.","journal-title":"Mult Scler Relat Disord"},{"key":"1716_CR14","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.jneuroim.2016.01.013","volume":"292","author":"J Burman","year":"2016","unstructured":"Burman J, Raininko R, Blennow K, Zetterberg H, Axelsson M, Malmestrom C. YKL-40 is a CSF biomarker of intrathecal inflammation in secondary progressive multiple sclerosis. J Neuroimmunol. 2016;292:52\u20137.","journal-title":"J Neuroimmunol"},{"key":"1716_CR15","doi-asserted-by":"crossref","unstructured":"Pereira JB, Janelidze S, Smith R, Mattsson-Carlgren N, Palmqvist S, Teunissen CE, et al. Plasma GFAP is an early marker of amyloid-beta but not tau pathology in Alzheimer\u2019s disease. Brain. 2021;144:3505\u201316.","DOI":"10.1093\/brain\/awab223"},{"key":"1716_CR16","doi-asserted-by":"crossref","unstructured":"Benedet AL, Mila-Aloma M, Vrillon A, Ashton NJ, Pascoal TA, Lussier F, et al. Differences between plasma and cerebrospinal fluid glial fibrillary acidic protein levels across the Alzheimer disease continuum. JAMA Neurol. 2021;78:1471\u201383.","DOI":"10.1001\/jamaneurol.2021.3671"},{"key":"1716_CR17","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1002\/alz.12131","volume":"16","author":"M Mila-Aloma","year":"2020","unstructured":"Mila-Aloma M, Salvado G, Gispert JD, Vilor-Tejedor N, Grau-Rivera O, Sala-Vila A, et al. Amyloid beta, tau, synaptic, neurodegeneration, and glial biomarkers in the preclinical stage of the Alzheimer\u2019s continuum. Alzheimers Dement. 2020;16:1358\u201371.","journal-title":"Alzheimers Dement"},{"key":"1716_CR18","doi-asserted-by":"crossref","first-page":"157","DOI":"10.3233\/JAD-140240","volume":"42","author":"D Alcolea","year":"2014","unstructured":"Alcolea D, Carmona-Iragui M, Suarez-Calvet M, Sanchez-Saudinos MB, Sala I, Anton-Aguirre S, et al. Relationship between beta-Secretase, inflammation and core cerebrospinal fluid biomarkers for Alzheimer\u2019s disease. J Alzheimers Dis. 2014;42:157\u201367.","journal-title":"J Alzheimers Dis"},{"key":"1716_CR19","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1212\/WNL.0000000000001859","volume":"85","author":"D Alcolea","year":"2015","unstructured":"Alcolea D, Martinez-Lage P, Sanchez-Juan P, Olazaran J, Antunez C, Izagirre A, et al. Amyloid precursor protein metabolism and inflammation markers in preclinical Alzheimer disease. Neurology. 2015;85:626\u201333.","journal-title":"Neurology."},{"key":"1716_CR20","doi-asserted-by":"crossref","first-page":"901","DOI":"10.3233\/JAD-140624","volume":"42","author":"A Antonell","year":"2014","unstructured":"Antonell A, Mansilla A, Rami L, Llado A, Iranzo A, Olives J, et al. Cerebrospinal fluid level of YKL-40 protein in preclinical and prodromal Alzheimer\u2019s disease. J Alzheimers Dis. 2014;42:901\u20138.","journal-title":"J Alzheimers Dis"},{"key":"1716_CR21","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/s41380-020-00923-z","volume":"26","author":"TK Karikari","year":"2021","unstructured":"Karikari TK, Benedet AL, Ashton NJ, Lantero Rodriguez J, Snellman A, Suarez-Calvet M, et al. Diagnostic performance and prediction of clinical progression of plasma phospho-tau181 in the Alzheimer\u2019s disease neuroimaging initiative. Mol Psychiatry. 2021;26:429\u201342.","journal-title":"Mol Psychiatry"},{"key":"1716_CR22","doi-asserted-by":"crossref","first-page":"3234","DOI":"10.1093\/brain\/awaa286","volume":"143","author":"N Mattsson-Carlgren","year":"2020","unstructured":"Mattsson-Carlgren N, Janelidze S, Palmqvist S, Cullen N, Svenningsson AL, Strandberg O, et al. Longitudinal plasma p-tau217 is increased in early stages of Alzheimer\u2019s disease. Brain. 2020;143:3234\u201341.","journal-title":"Brain."},{"key":"1716_CR23","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1111\/j.1365-2796.2004.01388.x","volume":"256","author":"RC Petersen","year":"2004","unstructured":"Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med. 2004;256:183\u201394.","journal-title":"J Intern Med"},{"key":"1716_CR24","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.jalz.2011.03.005","volume":"7","author":"GM McKhann","year":"2011","unstructured":"McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr., Kawas CH, et al. The diagnosis of dementia due to Alzheimer\u2019s disease: recommendations from the National Institute on Aging-Alzheimer\u2019s Association workgroups on diagnostic guidelines for Alzheimer\u2019s disease. Alzheimers Dement. 2011;7:263\u20139.","journal-title":"Alzheimers Dement"},{"key":"1716_CR25","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.jalz.2018.02.018","volume":"14","author":"CR Jack Jr.","year":"2018","unstructured":"Jack CR Jr., Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer\u2019s disease. Alzheimers Dement. 2018;14:535\u201362.","journal-title":"Alzheimers Dement"},{"key":"1716_CR26","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1001\/jama.2018.12917","volume":"320","author":"R Ossenkoppele","year":"2018","unstructured":"Ossenkoppele R, Rabinovici GD, Smith R, Cho H, Scholl M, Strandberg O, et al. Discriminative accuracy of [18F]flortaucipir positron emission tomography for Alzheimer disease vs other neurodegenerative disorders. JAMA. 2018;320:1151\u201362.","journal-title":"JAMA."},{"key":"1716_CR27","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1001\/jama.2020.12134","volume":"324","author":"S Palmqvist","year":"2020","unstructured":"Palmqvist S, Janelidze S, Quiroz YT, Zetterberg H, Lopera F, Stomrud E, et al. Discriminative accuracy of plasma phospho-tau217 for Alzheimer disease vs other neurodegenerative disorders. JAMA. 2020;324:772\u201381.","journal-title":"JAMA."},{"key":"1716_CR28","doi-asserted-by":"crossref","first-page":"1592","DOI":"10.1038\/s41591-021-01456-w","volume":"27","author":"TA Pascoal","year":"2021","unstructured":"Pascoal TA, Benedet AL, Ashton NJ, Kang MS, Therriault J, Chamoun M, et al. Microglial activation and tau propagate jointly across Braak stages. Nat Med. 2021;27:1592\u20139.","journal-title":"Nat Med"},{"key":"1716_CR29","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1186\/s13195-018-0402-y","volume":"10","author":"TA Pascoal","year":"2018","unstructured":"Pascoal TA, Shin M, Kang MS, Chamoun M, Chartrand D, Mathotaarachchi S, et al. In vivo quantification of neurofibrillary tangles with [(18)F]MK-6240. Alzheimers Res Ther. 2018;10:74.","journal-title":"Alzheimers Res Ther"},{"key":"1716_CR30","doi-asserted-by":"crossref","first-page":"415","DOI":"10.2967\/jnumed.111.094029","volume":"53","author":"Z Cselenyi","year":"2012","unstructured":"Cselenyi Z, Jonhagen ME, Forsberg A, Halldin C, Julin P, Schou M, et al. Clinical validation of 18F-AZD4694, an amyloid-beta-specific PET radioligand. J Nucl Med. 2012;53:415\u201324.","journal-title":"J Nucl Med"},{"key":"1716_CR31","doi-asserted-by":"crossref","first-page":"171","DOI":"10.3389\/fnins.2012.00171","volume":"6","author":"A Klein","year":"2012","unstructured":"Klein A, Tourville J. 101 labeled brain images and a consistent human cortical labeling protocol. Front Neurosci. 2012;6:171.","journal-title":"Front Neurosci"},{"key":"1716_CR32","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.jalz.2016.08.005","volume":"13","author":"CR Jack Jr.","year":"2017","unstructured":"Jack CR Jr., Wiste HJ, Weigand SD, Therneau TM, Lowe VJ, Knopman DS, et al. Defining imaging biomarker cut points for brain aging and Alzheimer\u2019s disease. Alzheimers Dement. 2017;13:205\u201316.","journal-title":"Alzheimers Dement"},{"key":"1716_CR33","doi-asserted-by":"crossref","first-page":"247","DOI":"10.2967\/jnumed.120.245209","volume":"62","author":"J Therriault","year":"2021","unstructured":"Therriault J, Benedet AL, Pascoal TA, Savard M, Ashton NJ, Chamoun M, et al. Determining amyloid-beta positivity using (18)F-AZD4694 PET imaging. J Nucl Med. 2021;62:247\u201352.","journal-title":"J Nucl Med"},{"key":"1716_CR34","doi-asserted-by":"crossref","first-page":"1-15 e1","DOI":"10.1016\/j.jalz.2014.07.003","volume":"11","author":"WE Klunk","year":"2015","unstructured":"Klunk WE, Koeppe RA, Price JC, Benzinger TL, Devous MD Sr., Jagust WJ, et al. The Centiloid Project: standardizing quantitative amyloid plaque estimation by PET. Alzheimers Dement. 2015;11:1-15 e1\u20134.","journal-title":"Alzheimers Dement"},{"key":"1716_CR35","doi-asserted-by":"crossref","first-page":"103836","DOI":"10.1016\/j.ebiom.2022.103836","volume":"76","author":"NJ Ashton","year":"2022","unstructured":"Ashton NJ, Benedet AL, Pascoal TA, Karikari TK, Lantero-Rodriguez J, Brum WS, et al. Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer\u2019s disease. EBioMedicine. 2022;76:103836.","journal-title":"EBioMedicine."},{"key":"1716_CR36","doi-asserted-by":"crossref","first-page":"e975","DOI":"10.1212\/WNL.0000000000011081","volume":"96","author":"J Therriault","year":"2021","unstructured":"Therriault J, Pascoal TA, Benedet AL, Tissot C, Savard M, Chamoun M, et al. Frequency of biologically defined Alzheimer disease in relation to age, sex, APOE epsilon4, and cognitive impairment. Neurology. 2021;96:e975\u2013e85.","journal-title":"Neurology."},{"key":"1716_CR37","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1148\/radiology.172.2.2748838","volume":"172","author":"CR Jack Jr.","year":"1989","unstructured":"Jack CR Jr., Twomey CK, Zinsmeister AR, Sharbrough FW, Petersen RC, Cascino GD. Anterior temporal lobes and hippocampal formations: normative volumetric measurements from MR images in young adults. Radiology. 1989;172:549\u201354.","journal-title":"Radiology."},{"key":"1716_CR38","doi-asserted-by":"crossref","first-page":"264","DOI":"10.3389\/fnagi.2014.00264","volume":"6","author":"O Voevodskaya","year":"2014","unstructured":"Voevodskaya O, Simmons A, Nordenskjold R, Kullberg J, Ahlstrom H, Lind L, et al. The effects of intracranial volume adjustment approaches on multiple regional MRI volumes in healthy aging and Alzheimer\u2019s disease. Front Aging Neurosci. 2014;6:264.","journal-title":"Front Aging Neurosci"},{"key":"1716_CR39","doi-asserted-by":"crossref","unstructured":"Therriault J, Pascoal TA, Lussier FZ, Tissot C, Chamoun M, Bezgin G, et al. Biomarker modeling of Alzheimer\u2019s disease using PET-based Braak staging. Nat Aging. 2022;2:526\u201335.","DOI":"10.1038\/s43587-022-00204-0"},{"key":"1716_CR40","doi-asserted-by":"crossref","first-page":"20","DOI":"10.3389\/fninf.2016.00020","volume":"10","author":"S Mathotaarachchi","year":"2016","unstructured":"Mathotaarachchi S, Wang S, Shin M, Pascoal TA, Benedet AL, Kang MS, et al. VoxelStats: a MATLAB package for multi-modal voxel-wise brain image analysis. Front Neuroinform. 2016;10:20.","journal-title":"Front Neuroinform"},{"key":"1716_CR41","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1080\/00401706.1972.10488966","volume":"14","author":"WA Larsen","year":"1972","unstructured":"Larsen WA, McCleary SJ. The use of partial residual plots in regression analysis. Technometrics. 1972;14:781\u201390.","journal-title":"Technometrics."},{"key":"1716_CR42","doi-asserted-by":"crossref","unstructured":"Ryan TP. Modern regression methods. John Wiley & Sons, Inc: Hoboken, 2008.","DOI":"10.1002\/9780470382806"},{"key":"1716_CR43","doi-asserted-by":"crossref","first-page":"S189","DOI":"10.1016\/j.neuroimage.2004.07.026","volume":"23","author":"KJ Worsley","year":"2004","unstructured":"Worsley KJ, Taylor JE, Tomaiuolo F, Lerch J. Unified univariate and multivariate random field theory. Neuroimage. 2004;23:S189\u201395.","journal-title":"Neuroimage."},{"key":"1716_CR44","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v048.i02","volume":"48","author":"Y Rosseel","year":"2012","unstructured":"Rosseel Y. lavaan: an R package for structural equation modeling. J Stat Softw. 2012;48:1\u201336.","journal-title":"J Stat Softw"},{"key":"1716_CR45","doi-asserted-by":"crossref","unstructured":"Mueller RO, Hancock GR. Best practices in structural equation modeling. In: Osborne J, editor. Best practices in quantitative methods. SAGE: Thousand Oaks, 2008, pp 488\u2013508.","DOI":"10.4135\/9781412995627.d38"},{"key":"1716_CR46","first-page":"23","volume":"8","author":"K Schermelleh-Engel","year":"2003","unstructured":"Schermelleh-Engel K, Moosbrugger H, M\u00fcller H. Evaluating the fit of structural equation models: tests of significance and descriptive goodness-of-fit measures. Methods Psychol Res. 2003;8:23\u201374.","journal-title":"Methods Psychol Res"},{"key":"1716_CR47","doi-asserted-by":"crossref","first-page":"D607","DOI":"10.1093\/nar\/gky1131","volume":"47","author":"D Szklarczyk","year":"2019","unstructured":"Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47:D607\u2013D13.","journal-title":"Nucleic Acids Res"},{"key":"1716_CR48","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/0006-8993(88)90410-6","volume":"463","author":"TG Beach","year":"1988","unstructured":"Beach TG, McGeer EG. Lamina-specific arrangement of astrocytic gliosis and senile plaques in Alzheimer\u2019s disease visual cortex. Brain Res. 1988;463:357\u201361.","journal-title":"Brain Res"},{"key":"1716_CR49","doi-asserted-by":"crossref","first-page":"481","DOI":"10.3233\/JAD-180325","volume":"67","author":"P Oeckl","year":"2019","unstructured":"Oeckl P, Halbgebauer S, Anderl-Straub S, Steinacker P, Huss AM, Neugebauer H, et al. Glial fibrillary acidic protein in serum is increased in Alzheimer\u2019s disease and correlates with cognitive impairment. J Alzheimers Dis. 2019;67:481\u20138.","journal-title":"J Alzheimers Dis"},{"key":"1716_CR50","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1002\/alz.12283","volume":"17","author":"J Simren","year":"2021","unstructured":"Simren J, Leuzy A, Karikari TK, Hye A, Benedet AL, Lantero-Rodriguez J, et al. The diagnostic and prognostic capabilities of plasma biomarkers in Alzheimer\u2019s disease. Alzheimers Dement. 2021;17:1145\u201356.","journal-title":"Alzheimers Dement"},{"key":"1716_CR51","doi-asserted-by":"crossref","unstructured":"Schulz I, Kruse N, Gera RG, Kremer T, Cedarbaum J, Barbour R, et al. Systematic assessment of 10 biomarker candidates focusing on alpha-synuclein-related disorders. Mov Disord. 2021;36:2874\u201387.","DOI":"10.1002\/mds.28738"},{"key":"1716_CR52","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1177\/1352458514561906","volume":"21","author":"G Hinsinger","year":"2015","unstructured":"Hinsinger G, Galeotti N, Nabholz N, Urbach S, Rigau V, Demattei C, et al. Chitinase 3-like proteins as diagnostic and prognostic biomarkers of multiple sclerosis. Mult Scler. 2015;21:1251\u201361.","journal-title":"Mult Scler"},{"key":"1716_CR53","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1093\/brain\/awv017","volume":"138","author":"E Canto","year":"2015","unstructured":"Canto E, Tintore M, Villar LM, Costa C, Nurtdinov R, Alvarez-Cermeno JC, et al. Chitinase 3-like 1: prognostic biomarker in clinically isolated syndromes. Brain. 2015;138:918\u201331.","journal-title":"Brain."},{"key":"1716_CR54","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1515\/revneuro-2019-0100","volume":"31","author":"V Dichev","year":"2020","unstructured":"Dichev V, Kazakova M, Sarafian V. YKL-40 and neuron-specific enolase in neurodegeneration and neuroinflammation. Rev Neurosci. 2020;31:539\u201353.","journal-title":"Rev Neurosci"},{"key":"1716_CR55","doi-asserted-by":"crossref","DOI":"10.1186\/s12974-017-0893-7","volume":"14","author":"M Querol-Vilaseca","year":"2017","unstructured":"Querol-Vilaseca M, Colom-Cadena M, Pegueroles J, San Martin-Paniello C, Clarimon J, Belbin O, et al. YKL-40 (Chitinase 3-like I) is expressed in a subset of astrocytes in Alzheimer\u2019s disease and other tauopathies. J Neuroinflammation. 2017;14:118.","journal-title":"J Neuroinflammation"},{"key":"1716_CR56","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1016\/j.biopsych.2010.08.025","volume":"68","author":"R Craig-Schapiro","year":"2010","unstructured":"Craig-Schapiro R, Perrin RJ, Roe CM, Xiong C, Carter D, Cairns NJ, et al. YKL-40: a novel prognostic fluid biomarker for preclinical Alzheimer\u2019s disease. Biol Psychiatry. 2010;68:903\u201312.","journal-title":"Biol Psychiatry"},{"key":"1716_CR57","first-page":"86","volume":"2","author":"CE Teunissen","year":"2016","unstructured":"Teunissen CE, Elias N, Koel-Simmelink MJ, Durieux-Lu S, Malekzadeh A, Pham TV, et al. Novel diagnostic cerebrospinal fluid biomarkers for pathologic subtypes of frontotemporal dementia identified by proteomics. Alzheimers Dement. 2016;2:86\u201394.","journal-title":"Alzheimers Dement"},{"key":"1716_CR58","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1212\/WNL.0000000000004088","volume":"89","author":"D Alcolea","year":"2017","unstructured":"Alcolea D, Vilaplana E, Suarez-Calvet M, Illan-Gala I, Blesa R, Clarimon J, et al. CSF sAPPbeta, YKL-40, and neurofilament light in frontotemporal lobar degeneration. Neurology. 2017;89:178\u201388.","journal-title":"Neurology."},{"key":"1716_CR59","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1016\/j.immuni.2017.06.006","volume":"46","author":"SA Liddelow","year":"2017","unstructured":"Liddelow SA, Barres BA. Reactive astrocytes: production, function, and therapeutic potential. Immunity 2017;46:957\u201367.","journal-title":"Immunity"},{"key":"1716_CR60","doi-asserted-by":"crossref","first-page":"107776","DOI":"10.1016\/j.celrep.2020.107776","volume":"31","author":"KA Guttenplan","year":"2020","unstructured":"Guttenplan KA, Stafford BK, El-Danaf RN, Adler DI, Munch AE, Weigel MK, et al. Neurotoxic reactive astrocytes drive neuronal death after retinal injury. Cell Rep. 2020;31:107776.","journal-title":"Cell Rep"},{"key":"1716_CR61","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-020-17514-9","volume":"11","author":"KA Guttenplan","year":"2020","unstructured":"Guttenplan KA, Weigel MK, Adler DI, Couthouis J, Liddelow SA, Gitler AD, et al. Knockout of reactive astrocyte activating factors slows disease progression in an ALS mouse model. Nat Commun. 2020;11:3753.","journal-title":"Nat Commun"},{"key":"1716_CR62","doi-asserted-by":"crossref","unstructured":"Guttenplan KA, Weigel MK, Prakash P, Wijewardhane PR, Hasel P, Rufen-Blanchette U, et al. Neurotoxic reactive astrocytes induce cell death via saturated lipids. Nature. 2021;599:102\u20137.","DOI":"10.1038\/s41586-021-03960-y"},{"key":"1716_CR63","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/s13024-017-0200-1","volume":"12","author":"M Bolos","year":"2017","unstructured":"Bolos M, Llorens-Martin M, Perea JR, Jurado-Arjona J, Rabano A, Hernandez F, et al. Absence of CX3CR1 impairs the internalization of Tau by microglia. Mol Neurodegener. 2017;12:59.","journal-title":"Mol Neurodegener"},{"key":"1716_CR64","doi-asserted-by":"crossref","first-page":"711","DOI":"10.3233\/JAD-143186","volume":"48","author":"FH Duits","year":"2015","unstructured":"Duits FH, Hernandez-Guillamon M, Montaner J, Goos JD, Montanola A, Wattjes MP, et al. Matrix metalloproteinases in Alzheimer\u2019s disease and concurrent cerebral microbleeds. J Alzheimers Dis. 2015;48:711\u201320.","journal-title":"J Alzheimers Dis"},{"key":"1716_CR65","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1093\/brain\/awu318","volume":"138","author":"G Cantarella","year":"2015","unstructured":"Cantarella G, Di Benedetto G, Puzzo D, Privitera L, Loreto C, Saccone S, et al. Neutralization of TNFSF10 ameliorates functional outcome in a murine model of Alzheimer\u2019s disease. Brain. 2015;138:203\u201316.","journal-title":"Brain."},{"key":"1716_CR66","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/S0006-8993(97)00958-X","volume":"779","author":"H Fenton","year":"1998","unstructured":"Fenton H, Finch PW, Rubin JS, Rosenberg JM, Taylor WG, Kuo-Leblanc V, et al. Hepatocyte growth factor (HGF\/SF) in Alzheimer\u2019s disease. Brain Res. 1998;779:262\u201370.","journal-title":"Brain Res"},{"key":"1716_CR67","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/S0002-9440(10)64603-2","volume":"157","author":"GM Murphy Jr.","year":"2000","unstructured":"Murphy GM Jr., Zhao F, Yang L, Cordell B. Expression of macrophage colony-stimulating factor receptor is increased in the AbetaPP(V717F) transgenic mouse model of Alzheimer\u2019s disease. Am J Pathol. 2000;157:895\u2013904.","journal-title":"Am J Pathol"},{"key":"1716_CR68","doi-asserted-by":"crossref","first-page":"4211","DOI":"10.1111\/j.1742-4658.2005.04833.x","volume":"272","author":"X Li","year":"2005","unstructured":"Li X, Alafuzoff I, Soininen H, Winblad B, Pei JJ. Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer\u2019s disease brain. FEBS J. 2005;272:4211\u201320.","journal-title":"FEBS J."},{"key":"1716_CR69","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/S1474-4422(15)70016-5","volume":"14","author":"MT Heneka","year":"2015","unstructured":"Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer\u2019s disease. Lancet Neurol. 2015;14:388\u2013405.","journal-title":"Lancet Neurol"},{"key":"1716_CR70","unstructured":"Kumar A, Fontana IC, Nordberg A. Reactive astrogliosis: a friend or foe in the pathogenesis of Alzheimer\u2019s disease. J Neurochem. 2021:1\u201316."},{"key":"1716_CR71","doi-asserted-by":"crossref","unstructured":"McLarnon JG. Chemokine interleukin-8 (IL-8) in Alzheimer\u2019s and other neurodegenerative diseases. J Alzheimer\u2019s Dis Parkinsonism. 2016;6:273.","DOI":"10.4172\/2161-0460.1000273"},{"key":"1716_CR72","doi-asserted-by":"crossref","first-page":"e72744","DOI":"10.1371\/journal.pone.0072744","volume":"8","author":"K Zhang","year":"2013","unstructured":"Zhang K, Tian L, Liu L, Feng Y, Dong YB, Li B, et al. CXCL1 contributes to beta-amyloid-induced transendothelial migration of monocytes in Alzheimer\u2019s disease. PLoS ONE. 2013;8:e72744.","journal-title":"PLoS ONE"},{"key":"1716_CR73","unstructured":"Cavazzoni P. FDA\u2019s decision to approve new treatment for Alzheimer\u2019s disease. 2021. https:\/\/www.fda.gov\/drugs\/news-events-human-drugs\/fdas-decision-approve-new-treatment-alzheimers-disease."},{"key":"1716_CR74","doi-asserted-by":"crossref","first-page":"e12179","DOI":"10.1002\/trc2.12179","volume":"7","author":"J Cummings","year":"2021","unstructured":"Cummings J, Lee G, Zhong K, Fonseca J, Taghva K. Alzheimer\u2019s disease drug development pipeline: 2021. Alzheimers Dement. 2021;7:e12179.","journal-title":"Alzheimers Dement"}],"container-title":["Molecular Psychiatry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41380-022-01716-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41380-022-01716-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41380-022-01716-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,25]],"date-time":"2023-11-25T08:12:50Z","timestamp":1700899970000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41380-022-01716-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,10]]},"references-count":74,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2022,11]]}},"alternative-id":["1716"],"URL":"https:\/\/doi.org\/10.1038\/s41380-022-01716-2","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.01.25.22269841","asserted-by":"object"}]},"ISSN":["1359-4184","1476-5578"],"issn-type":[{"value":"1359-4184","type":"print"},{"value":"1476-5578","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,10]]},"assertion":[{"value":"9 February 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 July 2022","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 July 2022","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 August 2022","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"SG has served as a scientific advisor to Cerveau Therapeutics. KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD\/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Prothena, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. HZ has served at scientific advisory boards and\/or as a consultant for Abbvie, Alector, Annexon, AZTherapies, CogRx, Denali, Eisai, Nervgen, Pinteon Therapeutics, Red Abbey Labs, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. All other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}