{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T22:33:25Z","timestamp":1793140405220,"version":"4.5.0"},"reference-count":88,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2013,6,19]],"date-time":"2013-06-19T00:00:00Z","timestamp":1371600000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2013,7]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>To see whether the distribution patterns of phosphorylated 43kDa TAR DNA\u2010binding protein (pTDP\u201043) intraneuronal inclusions in amyotrophic lateral sclerosis (ALS) permit recognition of neuropathological stages.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>pTDP\u201043 immunohistochemistry was performed on 70\u03bcm sections from ALS autopsy cases (N = 76) classified by clinical phenotype and genetic background.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>ALS cases with the lowest burden of pTDP\u201043 pathology were characterized by lesions in the agranular motor cortex, brainstem motor nuclei of cranial nerves V, VII, and X\u2013XII, and spinal cord \u03b1\u2010motoneurons (stage 1). Increasing burdens of pathology showed involvement of the prefrontal neocortex (middle frontal gyrus), brainstem reticular formation, precerebellar nuclei, and the red nucleus (stage 2). In stage 3, pTDP\u201043 pathology involved the prefrontal (gyrus rectus and orbital gyri) and then postcentral neocortex and striatum. Cases with the greatest burden of pTDP\u201043 lesions showed pTDP\u201043 inclusions in anteromedial portions of the temporal lobe, including the hippocampus (stage 4). At all stages, these lesions were accompanied by pTDP\u201043 oligodendroglial aggregates. Ten cases with <jats:italic>C9orf72<\/jats:italic> repeat expansion displayed the same sequential spreading pattern as nonexpansion cases but a greater regional burden of lesions, indicating a more fulminant dissemination of pTDP\u201043 pathology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>pTDP\u201043 pathology in ALS possibly disseminates in a sequential pattern that permits recognition of 4 neuropathological stages consistent with the hypothesis that pTDP\u201043 pathology is propagated along axonal pathways. Moreover, the finding that pTDP\u201043 pathology develops in the prefrontal cortex as part of an ongoing disease process could account for the development of executive cognitive deficits in ALS. Ann Neurol 2013;74:20\u201338<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.23937","type":"journal-article","created":{"date-parts":[[2013,5,20]],"date-time":"2013-05-20T08:10:51Z","timestamp":1369037451000},"page":"20-38","source":"Crossref","is-referenced-by-count":1032,"title":["Stages of pTDP\u201043 pathology in amyotrophic lateral sclerosis"],"prefix":"10.1002","volume":"74","author":[{"given":"Johannes","family":"Brettschneider","sequence":"first","affiliation":[{"name":"Center for Neurodegenerative Disease Research University of Pennsylvania School of Medicine Philadelphia PA"},{"name":"Clinical Neuroanatomy Section Department of Neurology Center for Biomedical Research University of Ulm Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Del Tredici","sequence":"additional","affiliation":[{"name":"Clinical Neuroanatomy Section Department of Neurology Center for Biomedical Research University of Ulm Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon B.","family":"Toledo","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease Research University of Pennsylvania School of Medicine Philadelphia PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John L.","family":"Robinson","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease Research University of Pennsylvania School of Medicine Philadelphia PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Irwin","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease Research University of Pennsylvania School of Medicine Philadelphia PA"},{"name":"Department of Neurology University of Pennsylvania School of Medicine Philadelphia PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murray","family":"Grossman","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Pennsylvania School of Medicine Philadelphia PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"EunRan","family":"Suh","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease Research University of Pennsylvania School of Medicine Philadelphia PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivianna M.","family":"Van Deerlin","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease Research University of Pennsylvania School of Medicine Philadelphia PA"},{"name":"Department of Pathology and Laboratory Medicine University of Pennsylvania School of Medicine Philadelphia PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth M.","family":"Wood","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease Research University of Pennsylvania School of Medicine Philadelphia PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young","family":"Baek","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease Research University of Pennsylvania School of Medicine Philadelphia PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Kwong","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease Research University of Pennsylvania School of Medicine Philadelphia PA"},{"name":"Department of Pathology and Laboratory Medicine University of Pennsylvania School of Medicine Philadelphia PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward B.","family":"Lee","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease Research University of Pennsylvania School of Medicine Philadelphia PA"},{"name":"Department of Pathology and Laboratory Medicine University of Pennsylvania School of Medicine Philadelphia PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren","family":"Elman","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Pennsylvania School of Medicine Philadelphia PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leo","family":"McCluskey","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Pennsylvania School of Medicine Philadelphia PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lubin","family":"Fang","sequence":"additional","affiliation":[{"name":"Clinical Neuroanatomy Section Department of Neurology Center for Biomedical Research University of Ulm Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Feldengut","sequence":"additional","affiliation":[{"name":"Clinical Neuroanatomy Section Department of Neurology Center for Biomedical Research University of Ulm Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert C.","family":"Ludolph","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Ulm Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia M.\u2010Y.","family":"Lee","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease Research University of Pennsylvania School of Medicine Philadelphia PA"},{"name":"Department of Pathology and Laboratory Medicine University of Pennsylvania School of Medicine Philadelphia PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heiko","family":"Braak","sequence":"additional","affiliation":[{"name":"Clinical Neuroanatomy Section Department of Neurology Center for Biomedical Research University of Ulm Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John Q.","family":"Trojanowski","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease Research University of Pennsylvania School of Medicine Philadelphia PA"},{"name":"Department of Pathology and Laboratory Medicine University of Pennsylvania School of Medicine Philadelphia PA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,6,19]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(10)61156-7"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1134108"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3121"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e318232a379"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/WCO.0b013e32835a3432"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0197-4580(02)00065-9"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20120741"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1901"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1746"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e318217d95f"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2011.08.033"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20112457"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1227157"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.051672"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1080\/146608200300079536"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-510X(99)00210-5"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-3956(75)90026-6"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2010.08.233"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2011-301826"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.51.6.1546"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awr179"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e31821103e6"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.10279"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-008-0477-9"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M511018200"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e31817713b5"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.65.5.636"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2013.03.010"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-012-0970-z"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10353"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(08)70071-1"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2990.2003.00432.x"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00210889"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/hipo.450030407"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00308809"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awh303"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3181b6bbbd"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000260965.20021.47"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000261045.57095.56"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-008-0396-9"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-008-0443-6"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-011-0932-x"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-008-0396-9"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11314"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/aws339"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21147"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.47.4_Suppl_2.63S"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-012-1022-4"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00230482"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneurpsyc.1953.02320260029002"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneurol.2011.130"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0079-6123(05)51004-5"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0857-12.2012"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.23200"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.2010.212407"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.1982.00510230010003"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(07)70265-X"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.53.8.1665"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.WNL.0000152047.58767.9D"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0404.1992.tb04003.x"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.1002\/cne.20665"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.1002\/1096-9861(20000717)423:1<140::AID-CNE12>3.0.CO;2-3"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(79)90001-6"},{"key":"e_1_2_8_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(79)90928-4"},{"key":"e_1_2_8_66_1","doi-asserted-by":"publisher","DOI":"10.1002\/cne.903330206"},{"key":"e_1_2_8_67_1","doi-asserted-by":"publisher","DOI":"10.1002\/cne.903410308"},{"key":"e_1_2_8_68_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750-3639.2003.tb00002.x"},{"key":"e_1_2_8_69_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.1986.00520040026013"},{"key":"e_1_2_8_70_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.36.6.796"},{"key":"e_1_2_8_71_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cortex.2011.10.001"},{"key":"e_1_2_8_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-0102(84)80007-3"},{"key":"e_1_2_8_73_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-007-0285-7"},{"key":"e_1_2_8_74_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1789.2009.01046.x"},{"key":"e_1_2_8_75_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0079-6123(03)43043-4"},{"key":"e_1_2_8_76_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0079-6123(08)61886-5"},{"key":"e_1_2_8_77_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.2009.204081"},{"key":"e_1_2_8_78_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/116.3.655"},{"key":"e_1_2_8_79_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2010.145"},{"key":"e_1_2_8_80_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02778005"},{"key":"e_1_2_8_81_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-10-03606.2000"},{"key":"e_1_2_8_82_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2011.06.022"},{"key":"e_1_2_8_83_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0615-12.2012"},{"key":"e_1_2_8_84_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0010627"},{"key":"e_1_2_8_85_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.231209"},{"key":"e_1_2_8_86_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds205"},{"key":"e_1_2_8_87_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2011.09.011"},{"key":"e_1_2_8_88_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2011.09.010"},{"key":"e_1_2_8_89_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(12)70014-5"}],"container-title":["Annals of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fana.23937","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.23937","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,6]],"date-time":"2023-10-06T11:01:15Z","timestamp":1696590075000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ana.23937"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,6,19]]},"references-count":88,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2013,7]]}},"alternative-id":["10.1002\/ana.23937"],"URL":"https:\/\/doi.org\/10.1002\/ana.23937","archive":["Portico"],"relation":{},"ISSN":["0364-5134","1531-8249"],"issn-type":[{"value":"0364-5134","type":"print"},{"value":"1531-8249","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,6,19]]}}}