{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T03:03:32Z","timestamp":1790996612931,"version":"4.1.0"},"reference-count":64,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2021,1,7]],"date-time":"2021-01-07T00:00:00Z","timestamp":1609977600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000864","name":"Michael J. Fox Foundation for Parkinson's Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001804","name":"Canada Research Chairs","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001804","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label\/><jats:p>The cholinergic system is a complex neurotransmitter system with functional involvement at multiple levels of the nervous system including the cerebral cortex, spinal cord, autonomic nervous system, and neuromuscular junction. Anticholinergic medications are among the most prescribed medications, making up one\u2010third to one\u2010half of all medications prescribed for seniors. Recent evidence has linked long\u2010term use of anticholinergic medications and dementia. Emerging evidence implicates the cholinergic system in the regulation of cerebral vasculature as well as neuroinflammation, suggesting that anticholinergic medications may contribute to absolute risk and progression of neurodegenerative diseases. In this review, we explore the involvement of the cholinergic system in various neurodegenerative diseases and the possible detrimental effects of anticholinergic medications on the onset and progression of these disorders. We identified references by searching the PubMed and Cochrane database between January 1990 and September 2019 for English\u2010language animal and human studies including randomized clinical trials (RCTs), meta\u2010analyses, systematic reviews, and observational studies. In addition, we conducted a manual search of reference lists from retrieved studies. Long\u2010term anticholinergic medication exposure may have detrimental consequences beyond well\u2010documented short\u2010term cognitive effects, through a variety of mechanisms either directly impacting cholinergic neurotransmission or through receptors expressed on the vasculature or immune cells, providing a pathophysiological framework for complex interactions across the entire neuroaxis.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15244-fig-0003-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.15244","type":"journal-article","created":{"date-parts":[[2020,11,22]],"date-time":"2020-11-22T04:41:47Z","timestamp":1606020107000},"page":"1334-1344","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Tardive neurotoxicity of anticholinergic drugs: A review"],"prefix":"10.1111","volume":"158","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4802-2391","authenticated-orcid":false,"given":"Sina","family":"Marzoughi","sequence":"first","affiliation":[{"name":"Division of Neurology Department of Medicine University of British Columbia Vancouver BC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ankur","family":"Banerjee","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Calgary Calgary AB Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine R.","family":"Jutzeler","sequence":"additional","affiliation":[{"name":"Department of Biosystems Science and Engineering ETH Zurich Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3028-5778","authenticated-orcid":false,"given":"Marco A.M.","family":"Prado","sequence":"additional","affiliation":[{"name":"Robarts Research Institute The University of Western Ontario London ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Rosner","sequence":"additional","affiliation":[{"name":"Collaboration for Outcomes Research and Evaluation (CORE) Faculty of Pharmaceutical Sciences University of British Columbia Vancouver BC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacquelyn J.","family":"Cragg","sequence":"additional","affiliation":[{"name":"Department of Biosystems Science and Engineering ETH Zurich Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil","family":"Cashman","sequence":"additional","affiliation":[{"name":"Division of Neurology Department of Medicine University of British Columbia Vancouver BC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,1,7]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/mp.2017.183"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/jgs.15767"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-20493-z"},{"key":"e_1_2_11_5_1","first-page":"791","article-title":"Chronic hM3Dq signaling in microglia ameliorates neuroinflammation in male mice","volume":"88","author":"Binning W.","year":"2020","journal-title":"bioRxiv"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.60.12.1745"},{"key":"e_1_2_11_7_1","doi-asserted-by":"crossref","unstructured":"Boustani M. Campbell N. Munger S. Maidment I. &Fox C.(2008).Impact of anticholinergics on the aging brain: A review and practical application.","DOI":"10.2217\/1745509X.4.3.311"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0197-4580(02)00065-9"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2013.06.003"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2016.00160"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270006292126"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1001\/archinternmed.2009.229"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000008696"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1532-5415.2008.01737.x"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.2174\/1570159X11311030006"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamainternmed.2019.0677"},{"key":"e_1_2_11_17_1","first-page":"349","article-title":"Inflammation as a therapeutic agent in cerebral infarction: Cellular inflammatory response and inflammatory mediators","volume":"50","author":"Cuenca\u2010L\u00f3pez M. D.","year":"2010","journal-title":"Revista De Neurologia"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.6393-09.2010"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-013-1499-3"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1474-8673.2006.00368.x"},{"key":"e_1_2_11_21_1","doi-asserted-by":"crossref","unstructured":"Eglen R. M.(2012)Overview of muscarinic receptor subtypes.","DOI":"10.1007\/978-3-642-23274-9_1"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.03.021"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2003.10.004"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1159\/000440864"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1296-1382"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyx265"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00982.2010"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1517\/14740338.2011.579899"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamainternmed.2014.7663"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbacli.2015.04.003"},{"key":"e_1_2_11_31_1","first-page":"3553","article-title":"Cholinergic surveillance over hippocampal RNA metabolism and Alzheimer\u2019s\u2010like pathology","volume":"27","author":"Kolisnyk B.","year":"2017","journal-title":"Cerebral Cortex"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.52.4.691"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1993.tb05838.x"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2007.09.009"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/0736-5748(94)90054-X"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2019.00403"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2011.04.041"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0091-3057(96)00431-5"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11910-013-0377-9"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005072-199804000-00004"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnbeh.2012.00024"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1827.1995.tb03418.x"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2016.09.013"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20121662"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-05384-z"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.111.187625"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2016.0580"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1001\/archinternmed.2007.106"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1588"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2004.01.004"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.06.001"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1184-19.2019"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1159\/000086679"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.2001.81.2.741"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2013.00074"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13395-016-0105-7"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neures.2018.08.005"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.1176\/ajp.149.10.1393"},{"key":"e_1_2_11_59_1","doi-asserted-by":"publisher","DOI":"10.1111\/nan.12472"},{"key":"e_1_2_11_60_1","volume-title":"Cholinergic deficiency involved in vascular dementia: Possible mechanism and strategy of treatment","author":"Wang J.","year":"2009"},{"key":"e_1_2_11_61_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.251542998"},{"key":"e_1_2_11_62_1","doi-asserted-by":"publisher","DOI":"10.1038\/sc.2014.41"},{"key":"e_1_2_11_63_1","doi-asserted-by":"publisher","DOI":"10.1159\/000381484"},{"key":"e_1_2_11_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2011.08.017"},{"key":"e_1_2_11_65_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01822-8"}],"container-title":["Journal of Neurochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jnc.15244","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/jnc.15244","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jnc.15244","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T07:58:35Z","timestamp":1693295915000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jnc.15244"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,7]]},"references-count":64,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2021,9]]}},"alternative-id":["10.1111\/jnc.15244"],"URL":"https:\/\/doi.org\/10.1111\/jnc.15244","archive":["Portico"],"relation":{},"ISSN":["0022-3042","1471-4159"],"issn-type":[{"value":"0022-3042","type":"print"},{"value":"1471-4159","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,7]]},"assertion":[{"value":"2020-06-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-11-17","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-01-07","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}