{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T01:54:43Z","timestamp":1791338083124,"version":"4.3.1"},"reference-count":78,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2021,5,22]],"date-time":"2021-05-22T00:00:00Z","timestamp":1621641600000},"content-version":"vor","delay-in-days":51,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P01 NS015655"],"award-info":[{"award-number":["P01 NS015655"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RO1 NS070856"],"award-info":[{"award-number":["RO1 NS070856"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P50 NS091856"],"award-info":[{"award-number":["P50 NS091856"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,4,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Clinical effects of anti-cholinergic drugs implicate cholinergic systems alterations in the pathophysiology of some cardinal motor impairments in Parkinson\u2019s disease. The topography of affected cholinergic systems deficits and motor domain specificity are poorly understood. Parkinson's disease patients (n\u2009=\u2009108) underwent clinical and motor assessment and vesicular acetylcholine transporter [18F]-fluoroethoxybenzovesamicol PET imaging. Volumes-of-interest-based analyses included detailed thalamic and cerebellar parcellations. Successful PET sampling for most of the small-sized parcellations was available in 88 patients. A data-driven approach, stepwise regression using the forward selection method, was used to identify cholinergic brain regions associating with cardinal domain-specific motor ratings. Regressions with motor domain scores for model-selected regions followed by confounder analysis for effects of age of onset, duration of motor disease and levodopa equivalent dose were performed. Among 7 model-derived regions associating with postural instability and gait difficulties domain scores three retained significance in confounder variable analysis: medial geniculate nucleus (standardized \u03b2 = \u22120.34, t = \u22123.78, P\u2009=\u20090.0003), lateral geniculate nucleus (\u03b2 = \u22120.32, t = \u22123.4, P\u2009=\u20090.001) and entorhinal cortex (\u03b2 = \u22120.23, t = \u22122.6, P\u2009=\u20090.011). A sub-analysis of non-episodic postural instability and gait difficulties scores demonstrated significant effects of the medial geniculate nucleus, entorhinal cortex and globus pallidus pars interna. Among 6 tremor domain model-selected regions two regions retained significance in confounder variable analysis: cerebellar vermis section of lobule VIIIb (\u03b2 = \u22120.22, t = \u22122.4, P\u2009=\u20090.021) and the putamen (\u03b2 = \u22120.23, t = \u22122.3, P\u2009=\u20090.024). None of the three model-selected variables for the rigidity domain survived confounder analysis. Two out of the four model-selected regions for the distal limb bradykinesia domain survived confounder analysis: globus pallidus pars externa (\u03b2\u2009=\u20090.36, t\u2009=\u20093.9, P\u2009=\u20090.0097) and the paracentral lobule (\u03b2\u2009=\u20090.26, t\u2009=\u20092.5, P\u2009=\u20090.013). Emphasizing the utility of a systems-network conception of the pathophysiology of Parkinson's disease cardinal motor features, our results are consistent with specific deficits in basal forebrain corticopetal, peduncupontine-laterodorsal tegmental complex, and medial vestibular nucleus cholinergic pathways, against the background of nigrostriatal dopaminergic deficits, contributing significantly to postural instability, gait difficulties, tremor and distal limb bradykinesia cardinal motor features of Parkinson\u2019s disease. Our results suggest significant and distinct consequences of degeneration of cholinergic peduncupontine-laterodorsal tegmental complex afferents to both segments of the globus pallidus. Non-specific regional cholinergic nerve terminal associations with rigidity scores likely reflect more complex multifactorial signalling mechanisms with smaller contributions from cholinergic pathways.<\/jats:p>","DOI":"10.1093\/braincomms\/fcab109","type":"journal-article","created":{"date-parts":[[2021,5,21]],"date-time":"2021-05-21T11:10:52Z","timestamp":1621595452000},"source":"Crossref","is-referenced-by-count":53,"title":["Regional cerebral cholinergic nerve terminal integrity and cardinal motor features in Parkinson\u2019s disease"],"prefix":"10.1093","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0352-6414","authenticated-orcid":false,"given":"Nicolaas I","family":"Bohnen","sequence":"first","affiliation":[{"name":"Department of Radiology, University of Michigan, Ann Arbor, MI 48105, USA"},{"name":"Department of Neurology, University of Michigan, Ann Arbor, MI 48105, USA"},{"name":"Neurology Service and GRECC, Veterans Administration Ann Arbor Healthcare System, Ann Arbor, MI 48105, USA"},{"name":"Morris K. Udall Center of Excellence for Parkinson's Disease Research, University of Michigan, Ann Arbor, MI 48105, USA"},{"name":"Parkinson\u2019s Foundation Research Center of Excellence, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1418-2960","authenticated-orcid":false,"given":"Prabesh","family":"Kanel","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Michigan, Ann Arbor, MI 48105, USA"},{"name":"Morris K. Udall Center of Excellence for Parkinson's Disease Research, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A","family":"Koeppe","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Michigan, Ann Arbor, MI 48105, USA"},{"name":"Morris K. Udall Center of Excellence for Parkinson's Disease Research, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos A","family":"Sanchez-Catasus","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Michigan, Ann Arbor, MI 48105, USA"},{"name":"Morris K. Udall Center of Excellence for Parkinson's Disease Research, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirk A","family":"Frey","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Michigan, Ann Arbor, MI 48105, USA"},{"name":"Department of Neurology, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Scott","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory M","family":"Constantine","sequence":"additional","affiliation":[{"name":"Department of Mathematics, University of Pittsburgh, Pittsburgh, PA 15260, USA"},{"name":"Department of Statistics, University of Pittsburgh, Pittsburgh, PA 15260, USA"},{"name":"The McGowen Institute for Regenerative Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15260, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger L","family":"Albin","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Michigan, Ann Arbor, MI 48105, USA"},{"name":"Neurology Service and GRECC, Veterans Administration Ann Arbor Healthcare System, Ann Arbor, MI 48105, USA"},{"name":"Morris K. Udall Center of Excellence for Parkinson's Disease Research, University of Michigan, Ann Arbor, MI 48105, USA"},{"name":"Parkinson\u2019s Foundation Research Center of Excellence, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martijn L T M","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Michigan, Ann Arbor, MI 48105, USA"},{"name":"Morris K. Udall Center of Excellence for Parkinson's Disease Research, University of Michigan, Ann Arbor, MI 48105, USA"},{"name":"Parkinson\u2019s Foundation Research Center of Excellence, University of Michigan, Ann Arbor, MI 48105, USA"},{"name":"Critical Path Institute, Tucson, AZ 85718, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,5,22]]},"reference":[{"issue":"1","key":"2021121111082664000_fcab109-B1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1001\/archneur.56.1.33","article-title":"Diagnostic criteria for Parkinson disease","volume":"56","author":"Gelb","year":"1999","journal-title":"Arch Neurol"},{"issue":"2","key":"2021121111082664000_fcab109-B2","first-page":"39","article-title":"Anticholinergic drugs used in Parkinson's disease: An overlooked class of drugs from a pharmacokinetic perspective","volume":"2","author":"Brocks","year":"1999","journal-title":"J Pharm Pharm 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