{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:36:42Z","timestamp":1790743002555,"version":"4.1.0"},"reference-count":65,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2021,5,21]],"date-time":"2021-05-21T00:00:00Z","timestamp":1621555200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS003034"],"award-info":[{"award-number":["NS003034"]}],"id":[{"id":"10.13039\/100000065","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":[[2021,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label\/><jats:p>The synucleinopathies Parkinson's disease (PD), multiple system atrophy (MSA), and pure autonomic failure (PAF) are characterized by intra\u2010cytoplasmic deposition of the protein alpha\u2010synuclein and by catecholamine depletion. PAF, which manifests with neurogenic orthostatic hypotension (nOH) and no motor signs of central neurodegeneration, can evolve into PD+nOH. The cerebrospinal fluid (CSF) levels of catecholamine metabolites may indicate central catecholamine deficiency in these synucleinopathies, but the literature is inconsistent and incomplete. In this retrospective cohort study we reviewed data about CSF catecholamines, the dopamine metabolites 3,4\u2010dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the norepinephrine metabolites 3,4\u2010dihydroxyphenylglycol (DHPG) and 3\u2010methoxy\u20104\u2010hydroxyphenylglycol (MHPG). The compounds were measured in 36 patients with PD, 37 patients with MSA, and 19 patients with PAF and in 38 controls. Compared to the control group, the PD, MSA, and PAF groups had decreased CSF MHPG (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a0.0001 each by Dunnett's post hoc test), DHPG (<jats:italic>p<\/jats:italic>\u00a0=\u00a0.004; <jats:italic>p<\/jats:italic>\u00a0&lt;\u00a0.0001; <jats:italic>p<\/jats:italic>\u00a0&lt;\u00a0.0001) and norepinephrine (<jats:italic>p<\/jats:italic>\u00a0=\u00a0.017; <jats:italic>p<\/jats:italic>\u00a0=\u00a0.0003; <jats:italic>p<\/jats:italic>\u00a0=\u00a0.044). CSF HVA and DOPAC were decreased in PD (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a0.0001 each) and MSA (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a0.0001 each) but not in PAF. The three synucleinopathies therefore have in common in vivo evidence of central noradrenergic deficiency but differ in the extents of central dopaminergic deficiency\u2014prominent in PD and MSA, less apparent in PAF. Data from putamen <jats:sup>18<\/jats:sup>F\u2010DOPA and cardiac <jats:sup>18<\/jats:sup>F\u2010dopamine neuroimaging in the same patients, post\u2010mortem tissue catecholamines in largely separate cohorts, and review of the neuropathology literature fit with these distinctions. The results suggest a \u2018norepinephrine first\u2019 ascending pathogenetic sequence in synucleinopathies, with degeneration of pontine locus ceruleus noradrenergic neurons preceding the loss of midbrain substantia nigra dopaminergic neurons.<\/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\/jnc15371-fig-0008-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.15371","type":"journal-article","created":{"date-parts":[[2021,4,24]],"date-time":"2021-04-24T13:23:49Z","timestamp":1619270629000},"page":"554-568","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Differential abnormalities of cerebrospinal fluid dopaminergic versus noradrenergic indices in synucleinopathies"],"prefix":"10.1111","volume":"158","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5709-9940","authenticated-orcid":false,"given":"David S.","family":"Goldstein","sequence":"first","affiliation":[{"name":"Autonomic Medicine Section Clinical Neurosciences Program Division of Intramural Research National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patti","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Autonomic Medicine Section Clinical Neurosciences Program Division of Intramural Research National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney","family":"Holmes","sequence":"additional","affiliation":[{"name":"Autonomic Medicine Section Clinical Neurosciences Program Division of Intramural Research National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillaume","family":"Lamotte","sequence":"additional","affiliation":[{"name":"Autonomic Medicine Section Clinical Neurosciences Program Division of Intramural Research National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhishek","family":"Lenka","sequence":"additional","affiliation":[{"name":"Autonomic Medicine Section Clinical Neurosciences Program Division of Intramural Research National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yehonatan","family":"Sharabi","sequence":"additional","affiliation":[{"name":"Autonomic Medicine Section Clinical Neurosciences Program Division of Intramural Research National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,5,21]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.13997"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(00)01623-2"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/90.4.725"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2017-02717"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1025067912199"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-008-0351-9"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.54.4.963"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.59.6.944"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.5774"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-004-0956-9"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.14965"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.37.1.42"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.24921"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2011-301817"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.65.8.1074"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.56.3.1"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0404.1995.tb01023.x"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1024255208563"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10286-006-0317-8"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2008.01.010"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2018.02.023"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1042\/CS20020315"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10286-011-0136-4"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/aws055"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.WNL.0000058766.46428.F3"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s004010050693"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410270405"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-013-7126-5"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/0378-4347(93)E0430-X"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaa238"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.1993.8"},{"key":"e_1_2_11_33_1","doi-asserted-by":"crossref","first-page":"6132","DOI":"10.1523\/JNEUROSCI.5188-10.2011","article-title":"Targeting 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