{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T00:49:36Z","timestamp":1793148576811,"version":"4.5.0"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,26]],"date-time":"2023-05-26T00:00:00Z","timestamp":1685059200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Currently, there are no disease-modifying pharmacological treatment options for dementia with Lewy bodies (DLB). The hallmark of DLB is pathological alpha-synuclein (aS) deposition. There are growing amounts of data suggesting that reduced aS clearance is caused by failure in endolysosomal and authophagic pathways, as well as and glucocerebrosidase (GCase) dysfunction and mutations in the GCase gene (GBA). The population\u2019s studies demonstrated that the incidence of GBA mutations is higher among Parkinson\u2019s disease (PD) patients, and carriers of such mutations have a higher risk of developing PD. The incidence of GBA mutations is even higher in DLB and a genome-wide association study (GWAS) confirmed the correlation between GBA mutations and DLB. <jats:italic>In vivo<\/jats:italic> experiments have shown that ambroxol (ABX) may increase GCase activity and GCase levels and therefore enhance aS autophagy-lysosome degradation pathways. Moreover, there is an emerging hypothesis that ABX may have an effect as a DLB modifying drug. The aims of the study \u201cAmbroxol in new and early Dementia with Lewy Bodies (ANeED) are to investigate the tolerability, safety and effects of ABX in patients with DLB.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This is a multicentre, phase IIa, double-blinded, randomised and placebo-controlled clinical trial, using a parallel arm design for 18\u2009months\u2019 follow-up. The allocation ratio is 1:1 (treatment:placebo).<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>The ANeED study is an ongoing clinical drug trial with ABX. The unique, but not fully understood mechanism of ABX on the enhancement of lysosomal aS clearance may be promising as a possible modifying treatment in DLB.<\/jats:p><\/jats:sec><jats:sec><jats:title>Trial Registration<\/jats:title><jats:p>The clinical trial is registered in the international trials register \u2013 <jats:ext-link>clinicaltrials.com<\/jats:ext-link> (NCT0458825) and nationally at the Current Research Information System in Norway (CRISTIN 2235504).<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnagi.2023.1163184","type":"journal-article","created":{"date-parts":[[2023,5,26]],"date-time":"2023-05-26T04:55:55Z","timestamp":1685076955000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":23,"title":["The ANeED study \u2013 ambroxol in new and early dementia with Lewy bodies (DLB): protocol for a phase IIa multicentre, randomised, double-blinded and placebo-controlled trial"],"prefix":"10.3389","volume":"15","author":[{"given":"Luiza Jadwiga","family":"Chwiszczuk","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica Haraldseid","family":"Breitve","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f8rn-Eivind Bordewick","family":"Kirsebom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Per","family":"Selnes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John Chr.","family":"Fl\u00f8vig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Brita","family":"Knapskog","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ragnhild E.","family":"Skogseth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Hubbers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elin","family":"Holst-Larsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arvid","family":"Rongve","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,26]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"3647","DOI":"10.3390\/cells10123547","article-title":"Autophagy-lysosomal pathway as potential therapeutic target in Parkinson's disease","volume":"10","author":"Bonam","year":"2021","journal-title":"Cells"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1186\/s13024-015-0010-2","article-title":"Selective loss of glucocerebrosidase activity in sporadic Parkinson's disease and dementia with Lewy bodies","volume":"10","author":"Chiasserini","year":"2015","journal-title":"Mol. Neurodegener."},{"key":"ref3","article-title":"MO: test Corporation of America","volume-title":"Multilingual Aphasia Examination","author":"City","year":"1986"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"940","DOI":"10.1002\/ana.22400","article-title":"Acid \u03b2-glucosidase mutants linked to gaucher disease, parkinson disease, and lewy body dementia alter \u03b1-synuclein processing","volume":"69","author":"Cullen","year":"2011","journal-title":"Ann. Neurol."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"S3","DOI":"10.3233\/JAD-179901","article-title":"Clinical trials for disease-modifying therapies in Alzheimer's disease: a primer, lessons learned, and a blueprint for the future","volume":"64","author":"Cummings","year":"2018","journal-title":"J. Alzheimers Dis."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"1130","DOI":"10.1002\/mds.27403","article-title":"Clinical and imaging correlates of amyloid deposition in dementia with Lewy bodies","volume":"33","author":"Donaghy","year":"2018","journal-title":"Mov. Disord."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1038\/s41582-019-0155-7","article-title":"Okun MS. emerging therapies in Parkinson disease - repurposed drugs and new approaches","volume":"15","author":"Elkouzi","year":"2013","journal-title":"Nat. Rev. Neurol."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.jalz.2007.08.005","article-title":"Consortium to establish a Registry for Alzheimer\u2019s disease (CERAD): the first twenty years","volume":"4","author":"Fillenbaum","year":"2008","journal-title":"Alzheimers Dement."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/0022-3956(75)90026-6","article-title":"Mini-mental state. A practical method for grading the cognitive state of patients for the clinician","volume":"12","author":"Folstein","year":"1975","journal-title":"J. Psychiatr. Res."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1002\/ana.23614","article-title":"Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains","volume":"72","author":"Gegg","year":"2012","journal-title":"Ann. Neurol."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"937","DOI":"10.1136\/jmg.2004.024455","article-title":"Parkinsonism among Gaucher disease carriers. Journal of medical genetics","volume":"41","author":"Goker-Alpan","year":"2004","journal-title":"BMJ"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1186\/s13195-020-00703-5","article-title":"Challenges and opportunities for improving the landscape for Lewy body dementia clinical trials","volume":"12","author":"Goldman","year":"2020","journal-title":"Alz. Res. Therapy"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"271","DOI":"10.3389\/fcell.2020.00271","article-title":"Small molecule chaperones for the treatment of Gaucher disease and GBA1-associated Parkinson disease","volume":"8","author":"Han","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1212\/WNL.0000000000009323","article-title":"Research criteria for the diagnosis of prodromal dementia with Lewy bodies","volume":"94","author":"IG","year":"2020","journal-title":"Neurology"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1136\/jmedgenet-2019-106132","article-title":"Pharmacologic properties of high-dose ambroxol in four patients with Gaucher disease and myoclonic epilepsy","volume":"57","author":"Kim","year":"2020","journal-title":"J. Med. Genet."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1080\/13543784.2019.1681398","article-title":"Clinical drug development for dementia with Lewy bodies: past and present","volume":"28","author":"Lee","year":"2019","journal-title":"Expert. Opin. Investig. Drugs"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.ymgme.2003.11.004","article-title":"Glucocerebrosidase mutations in subjects with parkinsonism","volume":"81","author":"Lwin","year":"2004","journal-title":"Mol. Genet. Metab."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1212\/WNL.0000000000004058","article-title":"Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB consortium","volume":"89","author":"McKeith","year":"2017","journal-title":"Neurology"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"1481","DOI":"10.1093\/brain\/awu020","article-title":"Ambroxol improves lysosomal biochemistry in glucocerebrosidase mutation-linked Parkinson disease cells","volume":"137","author":"McNeill","year":"2014","journal-title":"Brain"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1001\/jamaneurol.2019.4611","article-title":"Ambroxol for the treatment of patients with Parkinson disease with and without Glucocerebrosidase gene mutations: a nonrandomized, noncontrolled trial","volume":"77","author":"Mullin","year":"2020","journal-title":"JAMA Neurol."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1001\/jamaneurol.2013.1925","article-title":"A multicenter study of Glucocerebrosidase mutations in dementia with Lewy bodies","volume":"70","author":"Nalls","year":"2013","journal-title":"JAMA Neurol."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1002\/acn3.292","article-title":"Ambroxol chaperone therapy for neuronopathic Gaucher disease: a pilot study","volume":"3","author":"Narita","year":"2016","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"1783","DOI":"10.1093\/brain\/awp044","article-title":"Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease","volume":"132","author":"Neumann","year":"2009","journal-title":"Brain"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1093\/hmg\/ddy075","article-title":"Modulation of \u0392-glucocerebrosidase increases \u0391-synuclein secretion and exosome release in mouse models of Parkinson\u2019s disease","volume":"27","author":"Papadopoulos","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/s13195-019-0476-1","article-title":"Lewy body dementia Association's research centers of excellence program: inaugural meeting","volume":"11","author":"Peterson","year":"2019","journal-title":"Alz. Res. Therapy"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1300\/J018v05n01_03","article-title":"The Halstead-Reitan neuropsychological test battery","volume":"5","author":"Reitan","year":"1985","journal-title":"Neuropsychology"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"766","DOI":"10.1002\/ana.24790","article-title":"Ambroxol effects in glucocerebrosidase and \u03b1-synuclein transgenic mice","volume":"80","author":"Richards","year":"2016","journal-title":"Ann. Neurol."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1002\/gps.4015","article-title":"Time until nursing home admission in people with mild dementia: comparison of dementia with Lewy bodies and Alzheimer's dementia","volume":"29","author":"Rongve","year":"2013","journal-title":"Int. J. Geriatr. Psychiatry"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1007\/s00401-020-02160-8","article-title":"Ultrasensitive RT-QuIC assay with high sensitivity and specificity for Lewy body-associated synucleinopathies","volume":"140","author":"Rossi","year":"2020","journal-title":"Acta Neuropathol."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"12101","DOI":"10.1073\/pnas.1108197108","article-title":"CNS expression of glucocerebrosidase corrects alpha-synuclein pathology and memory in a mouse model of Gaucher-related synucleinopathy","volume":"108","author":"Sardi","year":"2011","journal-title":"Proc Natl Acad Sci U. S. A."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12883-019-1252-3","article-title":"Ambroxol as a novel disease-modifying treatment for Parkinson\u2019s disease dementia: protocol for a single-Centre, randomized, double-blind, placebo-controlled trial","volume":"19","author":"Silveira","year":"2019","journal-title":"BMC Neurol."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1016\/S1096-7192(03)00071-4","article-title":"Gaucher disease with parkinsonian manifestations: does glucocerebrosidase deficiency contribute to a vulnerability to parkinsonism?","volume":"79","author":"Tayebi","year":"2003","journal-title":"Mol. Genet. Metab."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1007\/s11910-010-0102-x","article-title":"The role of glucocerebrosidase mutations in Parkinson disease and Lewy body disorders","volume":"10","author":"Velayati","year":"2010","journal-title":"Curr. Neurol. Neurosci. rep."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"23542","DOI":"10.1074\/jbc.M801992200","article-title":"Wild type alpha-synuclein is degraded by chaperone-mediated autophagy and macroautophagy in neuronal cells","volume":"283","author":"Vogiatzi","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref35","volume-title":"The Visual Object and Space Perception Battery","author":"Warrington","year":"1991"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"25009","DOI":"10.1074\/jbc.M300227200","article-title":"Alpha-Synuclein is degraded by both autophagy and the proteasome","volume":"278","author":"Webb","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"598446","DOI":"10.3389\/fcell.2020.598446","article-title":"Current evidence for a bidirectional loop between the lysosome and alpha-Synuclein Proteoforms","volume":"8","author":"Wildburger","year":"2020","journal-title":"Front Cell Dev. Biol."}],"container-title":["Frontiers in Aging Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2023.1163184\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,26]],"date-time":"2023-05-26T04:56:00Z","timestamp":1685076960000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2023.1163184\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,26]]},"references-count":37,"alternative-id":["10.3389\/fnagi.2023.1163184"],"URL":"https:\/\/doi.org\/10.3389\/fnagi.2023.1163184","relation":{},"ISSN":["1663-4365"],"issn-type":[{"value":"1663-4365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,26]]},"article-number":"1163184"}}