{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T02:48:23Z","timestamp":1788230903201,"version":"build-2803163510"},"reference-count":136,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2022,3,15]],"date-time":"2022-03-15T00:00:00Z","timestamp":1647302400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>There is clear, early noradrenergic dysfunction in Alzheimer's disease. This is likely secondary to pathological tau deposition in the locus coeruleus, the pontine nucleus that produces and releases noradrenaline, prior to involvement of cortical brain regions. Disruption of noradrenergic pathways affects cognition, especially attention, impacting memory and broader functioning. Additionally, it leads to autonomic and neuropsychiatric symptoms. Despite the strong evidence of noradrenergic involvement in Alzheimer's, there are no clear trial data supporting the clinical use of any noradrenergic treatments. Several approaches have been tried, including proof\u2010of\u2010principle studies and (mostly small scale) randomised controlled trials. Treatments have included pharmacotherapies as well as stimulation. The lack of clear positive findings is likely secondary to limitations in gauging locus coeruleus integrity and dysfunction at an individual level. However, the recent development of several novel biomarkers holds potential and should allow quantification of dysfunction. This may then inform inclusion criteria and stratification for future trials. Imaging approaches have improved greatly following the development of neuromelanin\u2010sensitive sequences, enabling the use of structural MRI to estimate locus coeruleus integrity. Additionally, functional MRI scanning has the potential to quantify network dysfunction. As well as neuroimaging, EEG, fluid biomarkers and pupillometry techniques may prove useful in assessing noradrenergic tone. Here, we review the development of these biomarkers and how they might augment clinical studies, particularly randomised trials, through identification of patients most likely to benefit from treatment. We outline the biomarkers with most potential, and how they may transform symptomatic therapy for people living with Alzheimer's disease.<\/jats:p>","DOI":"10.1002\/acn3.51539","type":"journal-article","created":{"date-parts":[[2022,3,16]],"date-time":"2022-03-16T06:00:49Z","timestamp":1647410449000},"page":"582-596","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["New approaches for the quantification and targeting of noradrenergic dysfunction in Alzheimer's disease"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8724-2840","authenticated-orcid":false,"given":"Michael","family":"David","sequence":"first","affiliation":[{"name":"Imperial College London and the University of Surrey UK Dementia Research Institute Care Research and Technology Centre Sir Michael Uren Hub, 86 Wood Lane London W12 0BZ UK"},{"name":"Imperial College London, Brain Sciences South Kensington London SW7 2AZ UK"},{"name":"Imperial College Healthcare NHS Trust, Clinical Neurosciences Charing Cross Hospital London W2 1NY UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paresh A.","family":"Malhotra","sequence":"additional","affiliation":[{"name":"Imperial College London and the University of Surrey UK Dementia Research Institute Care Research and Technology Centre Sir Michael Uren Hub, 86 Wood Lane London W12 0BZ UK"},{"name":"Imperial College London, Brain Sciences South Kensington London SW7 2AZ UK"},{"name":"Imperial College Healthcare NHS Trust, Clinical Neurosciences Charing Cross Hospital London W2 1NY UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,3,15]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awy132"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2018.01.001"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.copsyc.2018.11.002"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.2174\/156720508784533286"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abj2511"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab111"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/alzrt175"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.1989.00520400030015"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1097\/00002826-198904000-00007"},{"issue":"1","key":"e_1_2_8_11_1","first-page":"41","article-title":"Treatment of age\u2010associated memory impairment with Guanfacine","volume":"27","author":"McEntee W","year":"1991","journal-title":"Psychopharmacol Bull"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e31824b211b"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01309-6"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awy264"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awy282"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awr177"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2017.10.023"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-161078"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dadm.2015.08.004"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2004.03.008"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-006-0285-2"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2019.11.016"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3223(99)00232-2"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/0306-4522(86)90156-9"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.08.011"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nlm.2020.107327"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/0306-4522(93)90507-C"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1310025111"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2008.01.064"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1054-3589(08)60859-5"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/6031478"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1101\/lm.2302811"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jvs.2018.07.057"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/hipo.22436"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2573"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-020-0360-9"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tics.2021.10.009"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2020.117487"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.neuro.28.061604.135709"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/cne.920180503"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-8986.2011.01226.x"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-510X(81)90031-9"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awv236"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.wnr.0000227984.84927.a7"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dadm.2019.02.001"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1111\/ggi.12280"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(81)92657-X"},{"key":"e_1_2_8_48_1","first-page":"1","article-title":"Differential involvement of the locus Coeruleus in early\u2010 and late\u2010onset Alzheimer's disease: a potential mechanism of clinical differences?","author":"Bolton C","year":"2020","journal-title":"J Geriatr Psychiatry Neurol"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(86)90336-8"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1192\/bjp.135.3.216"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3223(01)01235-5"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1017\/S1355617700000102"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/122.3.383"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.ne.13.030190.000325"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-26268-x"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2018.05.051"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0140525X15000667"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2097-17.2017"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1712268115"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trci.2017.07.001"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-019-0437-x"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-2007-1014267"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.1988.00520350020008"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11011-012-9287-9"},{"key":"e_1_2_8_65_1","doi-asserted-by":"publisher","DOI":"10.1139\/y85-100"},{"key":"e_1_2_8_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-1838(81)90083-7"},{"key":"e_1_2_8_67_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00240508"},{"key":"e_1_2_8_68_1","doi-asserted-by":"publisher","DOI":"10.2174\/157015908785777193"},{"key":"e_1_2_8_69_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exger.2019.06.001"},{"key":"e_1_2_8_70_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-180688"},{"key":"e_1_2_8_71_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2019.06.3916"},{"key":"e_1_2_8_72_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-021-00902-8"},{"key":"e_1_2_8_73_1","volume-title":"BEST (Biomarkers, EndpointS, and Other Tools) Resource","author":"FDA\u2010NIH Biomarker Working Group","year":"2016"},{"key":"e_1_2_8_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ynstr.2015.09.002"},{"key":"e_1_2_8_75_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tics.2010.11.002"},{"key":"e_1_2_8_76_1","doi-asserted-by":"publisher","DOI":"10.1089\/104454603321666180"},{"key":"e_1_2_8_77_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awz149"},{"key":"e_1_2_8_78_1","first-page":"1","article-title":"Locus coeruleus integrity and the effect of atomoxetine on response inhibition in Parkinson's disease","volume":"144","author":"O'Callaghan C","year":"2020","journal-title":"Brain"},{"key":"e_1_2_8_79_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab107"},{"key":"e_1_2_8_80_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0033291700038782"},{"key":"e_1_2_8_81_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.52059"},{"key":"e_1_2_8_82_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2015.09.019"},{"key":"e_1_2_8_83_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnhum.2013.00623"},{"key":"e_1_2_8_84_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells10071829"},{"key":"e_1_2_8_85_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2018.00127"},{"key":"e_1_2_8_86_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awz193"},{"key":"e_1_2_8_87_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2020.583421"},{"key":"e_1_2_8_88_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2018.10.014"},{"key":"e_1_2_8_89_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2017.07.045"},{"key":"e_1_2_8_90_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-2011-0023"},{"key":"e_1_2_8_91_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2018.05.021"},{"key":"e_1_2_8_92_1","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/bhv172"},{"key":"e_1_2_8_93_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2014.10.041"},{"key":"e_1_2_8_94_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpsychires.2020.01.018"},{"key":"e_1_2_8_95_1","doi-asserted-by":"publisher","DOI":"10.1186\/alzrt106"},{"key":"e_1_2_8_96_1","doi-asserted-by":"publisher","DOI":"10.1186\/alzrt100"},{"key":"e_1_2_8_97_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2017.00211"},{"key":"e_1_2_8_98_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2018.08.012"},{"key":"e_1_2_8_99_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2010.03.001"},{"key":"e_1_2_8_100_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ynirp.2020.100002"},{"key":"e_1_2_8_101_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tics.2020.03.005"},{"key":"e_1_2_8_102_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2015.11.028"},{"key":"e_1_2_8_103_1","doi-asserted-by":"crossref","unstructured":"MegemontM McburneyJ.Pupil diameter is not an accurate real\u2010 \u00ad time readout of locus coeruleus activity.2022;1\u201317.","DOI":"10.7554\/eLife.70510"},{"key":"e_1_2_8_104_1","doi-asserted-by":"publisher","DOI":"10.3758\/CABN.10.2.252"},{"key":"e_1_2_8_105_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2017.06.021"},{"key":"e_1_2_8_106_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cortex.2017.09.025"},{"key":"e_1_2_8_107_1","doi-asserted-by":"publisher","DOI":"10.1002\/hbm.22466"},{"key":"e_1_2_8_108_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-08246-w"},{"key":"e_1_2_8_109_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.11-10-03135.1991"},{"key":"e_1_2_8_110_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2007.05.001"},{"key":"e_1_2_8_111_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1934854100"},{"key":"e_1_2_8_112_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-4886(80)90141-7"},{"key":"e_1_2_8_113_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.npp.1300116"},{"key":"e_1_2_8_114_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00429-017-1531-y"},{"key":"e_1_2_8_115_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1361-20.2020"},{"issue":"160","key":"e_1_2_8_116_1","first-page":"381","article-title":"Polysomnography","volume":"2019","author":"Rundo JV","year":"1877","journal-title":"Handb Clin Neurol"},{"issue":"1","key":"e_1_2_8_117_1","first-page":"1","article-title":"Sleep dysregulation, memory impairment, and CSF biomarkers during different levels of neurocognitive functioning in Alzheimer's disease course","volume":"12","author":"Liguori C","year":"2020","journal-title":"Alzheimer's Res Ther."},{"key":"e_1_2_8_118_1","doi-asserted-by":"publisher","DOI":"10.1111\/jsr.12821"},{"key":"e_1_2_8_119_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12304"},{"key":"e_1_2_8_120_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.056018"},{"key":"e_1_2_8_121_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-020-0841-7"},{"key":"e_1_2_8_122_1","doi-asserted-by":"publisher","DOI":"10.1097\/JGP.0b013e3181ab8c61"},{"key":"e_1_2_8_123_1","doi-asserted-by":"publisher","DOI":"10.1097\/00002093-199509040-00010"},{"issue":"1","key":"e_1_2_8_124_1","first-page":"67","article-title":"Noradrenergic intervention in Alzheimer's disease","volume":"28","author":"Crook T","year":"1992","journal-title":"Psychopharmacol Bull"},{"key":"e_1_2_8_125_1","unstructured":"HoangK WattH GolemmeM PerryRJ RitchieC WilsonD et\u00a0al.Noradrenergic add\u2010on therapy with extended\u2010release Guanfacine in Alzheimer's disease: study protocol for a randomised clinical trial (NorAD) and COVID\u201019 amendments. Submiss."},{"key":"e_1_2_8_126_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2008.04.037"},{"key":"e_1_2_8_127_1","first-page":"1","article-title":"Effect of methylphenidate on apathy in patients with Alzheimer disease the ADMET 2 randomized clinical trial","volume":"29403","author":"Mintzer J","year":"2021","journal-title":"JAMA Neurol"},{"key":"e_1_2_8_128_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.22307"},{"key":"e_1_2_8_129_1","doi-asserted-by":"publisher","DOI":"10.1097\/JGP.0b013e3181aad585"},{"key":"e_1_2_8_130_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab452"},{"key":"e_1_2_8_131_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2011.11.001"},{"key":"e_1_2_8_132_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-17344-9"},{"key":"e_1_2_8_133_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.106.104166"},{"key":"e_1_2_8_134_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2015.02.023"},{"issue":"4","key":"e_1_2_8_135_1","first-page":"143","article-title":"Activation of the dorsal raphe nucleus and locus coeruleus by transcutaneous electrical nerve stimulation in Alzheimer's disease: a reconsideration of stimulation\u2010parameters derived from animal studies","volume":"46","author":"Scherder EJA","year":"2003","journal-title":"Chin J Physiol"},{"key":"e_1_2_8_136_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autneu.2021.102900"},{"key":"e_1_2_8_137_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnpbp.2017.08.004"}],"container-title":["Annals of Clinical and Translational Neurology"],"original-title":[],"language":"es","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acn3.51539","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/acn3.51539","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acn3.51539","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T09:09:59Z","timestamp":1692954599000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/acn3.51539"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,15]]},"references-count":136,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2022,4]]}},"alternative-id":["10.1002\/acn3.51539"],"URL":"https:\/\/doi.org\/10.1002\/acn3.51539","archive":["Portico"],"relation":{},"ISSN":["2328-9503","2328-9503"],"issn-type":[{"value":"2328-9503","type":"print"},{"value":"2328-9503","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,15]]},"assertion":[{"value":"2022-01-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-02-25","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-03-15","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}