{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T08:40:29Z","timestamp":1792658429459,"version":"4.5.0"},"reference-count":50,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Amyotrophic lateral sclerosis (ALS) has a markedly distinctive clinical and neuroradiological signature, with the preferential involvement of specific brain networks and the apparent sparing of others. The molecular underpinnings of the strikingly selective anatomical vulnerability have not been fully elucidated to date despite the potential therapeutic relevance of characterizing neurotransmitter receptor\u2010defined susceptibility to degeneration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A large neuroimaging study was undertaken with 258 participants to systematically evaluate topological associations between neurodegeneration and neurotransmitter expression distributions. Patients were stratified based on their genetic profile into sporadic and\n                      <jats:italic>C90rf72<\/jats:italic>\n                      hexanucleotide repeat expansion carriers. Anatomical associations were evaluated between patterns of atrophy and topological neurotransmitter receptor distributions. Cross\u2010sectional and longitudinal trends were comprehensively evaluated over 4 consecutive timepoints.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Our analyses reveal topological associations between neurodegeneration in sporadic ALS and GABA\u2010A receptor \u03b15\u2010selective component (GABAa5), serotonin 1a receptor, and kappa opioid receptor expression maps. In addition to these networks, neuronal loss in patients with GGGGCC hexanucleotide repeat expansions exhibit predilection to glutamatergic, endocannabinoid, and microglial systems. Our multi\u2010timepoint longitudinal analyses reveal dynamic temporal associations between focal volume loss and neurotransmitter expression with increasing spatial associations with noradrenaline transporter and GABAa5, but high attrition rates preclude definite longitudinal inferences.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>\n                      Our data suggest the preferential vulnerability of GABAergic, serotonergic, kappa opioid mediated networks in sporadic ALS. In\n                      <jats:italic>C9orf72<\/jats:italic>\n                      \u2010assocaited ALS, glutamatergic, endocannabinoid circuits are also susceptible and microglia\u2010mediated neuroinflammation is also implicated. The comprehensive evaluation of neurotransmitter\u2010receptor associations not only offer academic insights regarding pathophysiological processes in ALS, but may inform targeted therapy development strategies. ANN NEUROL 2026;100:948\u2013961\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.78316","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T19:07:36Z","timestamp":1784660856000},"page":"948-961","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Neurotransmitter\u2010Defined Degeneration Patterns in Sporadic and\n                    <i>C9orf72<\/i>\n                    \u2010Associated Amyotrophic Lateral Sclerosis: Predilection to\n                    <scp>GABAergic<\/scp>\n                    , Serotonergic, Opioid, Glutamatergic, Endocannabinoid, and Microglial Systems\u2014Implications for Therapy Development"],"prefix":"10.1002","volume":"100","author":[{"given":"Marlene","family":"Tahedl","sequence":"first","affiliation":[{"name":"Computational Neuroimaging Group (CNG), School of Medicine, Trinity College Dublin  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"We Fong","family":"Siah","sequence":"additional","affiliation":[{"name":"Computational Neuroimaging Group (CNG), School of Medicine, Trinity College Dublin  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmin","family":"Lope","sequence":"additional","affiliation":[{"name":"Computational Neuroimaging Group (CNG), School of Medicine, Trinity College Dublin  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer C.","family":"Hengeveld","sequence":"additional","affiliation":[{"name":"Smurfit Institute of Genetics Trinity College Dublin  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Doherty","sequence":"additional","affiliation":[{"name":"Smurfit Institute of Genetics Trinity College Dublin  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell L.","family":"McLaughlin","sequence":"additional","affiliation":[{"name":"Smurfit Institute of Genetics Trinity College Dublin  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orla","family":"Hardiman","sequence":"additional","affiliation":[{"name":"Computational Neuroimaging Group (CNG), School of Medicine, Trinity College Dublin  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ee Ling","family":"Tan","sequence":"additional","affiliation":[{"name":"Computational Neuroimaging Group (CNG), School of Medicine, Trinity College Dublin  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Toomey","sequence":"additional","affiliation":[{"name":"Computational Neuroimaging Group (CNG), School of Medicine, Trinity College Dublin  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8679-8516","authenticated-orcid":false,"given":"Jana","family":"Kleinerova","sequence":"additional","affiliation":[{"name":"Computational Neuroimaging Group (CNG), School of Medicine, Trinity College Dublin  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Bede","sequence":"additional","affiliation":[{"name":"Computational Neuroimaging Group (CNG), School of Medicine, Trinity College Dublin  Dublin Ireland"},{"name":"Department of Neurology St James's Hospital  Dublin Ireland"},{"name":"The Irish FTD\/FTLD Network  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-020-10289-5"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2020-323671"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-023-11764-5"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.70902"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2006.06.027"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2011.08.011"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2020-324416"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.3109\/21678421.2016.1173702"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.78099"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25706"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2026.107272"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000209623"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/gigascience\/giae049"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/hbm.25244"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2011.09.015"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410140103"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.30.1.98"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2013.234"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2019.04.014"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2012-304019"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1080\/00207450600754087"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3182563b57"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/bhq134"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2019.00179"},{"key":"e_1_2_10_26_1","article-title":"Gamma aminobutyric acid (GABA) modulators for amyotrophic lateral sclerosis\/motor neuron disease","volume":"1","author":"Diana A","year":"2017","journal-title":"Cochrane Database Syst Rev"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.2174\/1381612811319240013"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awh428"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.42.7.640"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1043661802002050"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1080\/14660820310009389"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1080\/21678421.2017.1392578"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.3109\/17482968.2010.544386"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00259-018-4179-9"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15515"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2017.06.020"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2008.06041.x"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1080\/14660820310016813"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.3109\/17482968.2012.687264"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2011.147"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1097\/WCO.0000000000001279"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf1064"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abq0651"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI90607"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-023-11682-6"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2021.04.031"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1111\/ene.70146"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-021-10801-5"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-020-10181-2"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2021.120079"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.31083\/j.jin2103087"}],"container-title":["Annals of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.78316","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ana.78316","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.78316","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T08:02:45Z","timestamp":1792656165000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ana.78316"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,21]]},"references-count":50,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,11]]}},"alternative-id":["10.1002\/ana.78316"],"URL":"https:\/\/doi.org\/10.1002\/ana.78316","archive":["Portico"],"relation":{},"ISSN":["0364-5134","1531-8249"],"issn-type":[{"value":"0364-5134","type":"print"},{"value":"1531-8249","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,21]]},"assertion":[{"value":"2026-05-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-10","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-21","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}