{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T05:30:34Z","timestamp":1789536634881,"version":"build-2803163510"},"reference-count":66,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:00:00Z","timestamp":1783468800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:00:00Z","timestamp":1783468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Stichting Woelse Waard"},{"DOI":"10.13039\/501100022222","name":"Parkinson Schweiz","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100022222","id-type":"DOI","asserted-by":"publisher"}]},{"name":"EPFL Lausanne"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Acta Neuropathol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Lewy body diseases, including Parkinson\u2019s disease (PD) and dementia with Lewy bodies (DLB), are defined by neuronal accumulation of misfolded \u03b1-synuclein (\u03b1-Syn), yet the ultrastructural diversity of these inclusions across brain regions and disease contexts remains unclear. Here, we applied large-scale correlative light and electron microscopy (CLEM) to map \u03b1-Syn pathology across cortical regions (entorhinal cortex, ENT; anterior cingulate cortex, AC; hippocampal CA2 region) and substantia nigra (SN) in clinically and pathologically confirmed PD and DLB donors. We identified pronounced regional heterogeneity in Lewy pathology, with cortical inclusions showing diverse maturation stages at the ultrastructural level, ranging from low-density fibrils interspersed with organelles to highly compact fibrillar inclusions. In the SN of DLB donors, we observed the full range of classical nigral LB morphologies previously described in PD. We additionally characterized diverse neuritic \u03b1-Syn pathologies in DLB and identified a distinct population of electron-dense, degenerating, \u03b1-Syn-positive cortical neurons not previously reported. Importantly, we found no significant difference in LB ultrastructure between PD and DLB in either cortical or nigral pathology. In contrast, quantitative analysis of\u2009&gt;\u200910,000 mitochondria revealed disease- and region-specific signatures of altered mitochondrial homeostasis. PD showed increased mitochondrial density and enlargement in the SN, whereas DLB showed increased mitochondrial density only in the ENT. Mitochondrial enlargement was exclusive to PD. These findings indicate that LB ultrastructure alone does not distinguish PD from DLB; instead, region-specific mitochondrial phenotypes may better reflect disease identity and regional susceptibility. Overall, we provide a high-resolution framework for human Lewy pathology in PD and DLB, revealing that ultrastructural responses to \u03b1-Syn pathology are driven primarily by neuronal identity and regional vulnerability. Our results highlight the need for disease- and region-specific models that capture human phenotypes to advance mechanistic understanding and therapeutic targeting of synucleinopathies.<\/jats:p>","DOI":"10.1007\/s00401-026-03039-w","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T18:59:59Z","timestamp":1783537199000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Correlative ultrastructural mapping of Lewy pathology reveals regional diversity in Parkinson\u2019s and dementia with Lewy bodies"],"prefix":"10.1007","volume":"152","author":[{"given":"Notash","family":"Shafiei","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daria","family":"Proniakova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marija","family":"Simjanoska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anniken Mathea Rafnum","family":"Sj\u00f8dal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"St\u00e4hli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukas","family":"van den Heuvel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Di Fabrizio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eve","family":"Aaron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandor","family":"Kasas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathis Solal","family":"Krause","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mallory","family":"Wittwer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julika","family":"Radecke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henning","family":"Stahlberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilma D. J.","family":"van de Berg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda J.","family":"Lewis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,8]]},"reference":[{"key":"3039_CR1","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1038\/s41572-021-00280-3","volume":"7","author":"D Aarsland","year":"2021","unstructured":"Aarsland D, Batzu L, Halliday GM, Geurtsen GJ, Ballard C, Ray Chaudhuri K et al (2021) Parkinson disease-associated cognitive impairment. Nat Rev Dis Primer 7:47. https:\/\/doi.org\/10.1038\/s41572-021-00280-3","journal-title":"Nat Rev Dis Primer"},{"key":"3039_CR2","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1111\/j.1750-3639.2008.00147.x","volume":"18","author":"I Alafuzoff","year":"2008","unstructured":"Alafuzoff I, Arzberger T, Al-Sarraj S, Bodi I, Bogdanovic N, Braak H et al (2008) Staging of neurofibrillary pathology in Alzheimer\u2019s disease: a study of the BrainNet Europe Consortium. Brain Pathol 18:484\u2013496. https:\/\/doi.org\/10.1111\/j.1750-3639.2008.00147.x","journal-title":"Brain Pathol"},{"key":"3039_CR3","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1007\/s00401-009-0523-2","volume":"117","author":"I Alafuzoff","year":"2009","unstructured":"Alafuzoff I, Ince PG, Arzberger T, Al-Sarraj S, Bell J, Bodi I et al (2009) Staging\/typing of Lewy body related \u03b1-synuclein pathology: a study of the BrainNet Europe Consortium. Acta Neuropathol (Berl) 117:635\u2013652. https:\/\/doi.org\/10.1007\/s00401-009-0523-2","journal-title":"Acta Neuropathol (Berl)"},{"key":"3039_CR4","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/S0006-8993(98)00734-3","volume":"808","author":"K Arima","year":"1998","unstructured":"Arima K, U\u00e9da K, Sunohara N, Hirai S, Izumiyama Y, Tonozuka-Uehara H et al (1998) Immunoelectron-microscopic demonstration of NACP\/\u03b1-synuclein-epitopes on the filamentous component of Lewy bodies in Parkinson\u2019s disease and in dementia with Lewy bodies. Brain Res 808:93\u2013100. https:\/\/doi.org\/10.1016\/S0006-8993(98)00734-3","journal-title":"Brain Res"},{"key":"3039_CR5","doi-asserted-by":"publisher","first-page":"12495","DOI":"10.3390\/ijerph191912495","volume":"19","author":"EA Ayeni","year":"2022","unstructured":"Ayeni EA, Aldossary AM, Ayejoto DA, Gbadegesin LA, Alshehri AA, Alfassam HA et al (2022) Neurodegenerative diseases: implications of environmental and climatic influences on neurotransmitters and neuronal hormones activities. Int J Environ Res Public Health 19:12495. https:\/\/doi.org\/10.3390\/ijerph191912495","journal-title":"Int J Environ Res Public Health"},{"key":"3039_CR6","first-page":"879","volume":"152","author":"M Baba","year":"1998","unstructured":"Baba M, Nakajo S, Tu PH, Tomita T, Nakaya K, Lee VM et al (1998) Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson\u2019s disease and dementia with Lewy bodies. Am J Pathol 152:879\u2013884","journal-title":"Am J Pathol"},{"key":"3039_CR7","doi-asserted-by":"publisher","first-page":"16878","DOI":"10.1038\/s41598-017-17204-5","volume":"7","author":"P Bankhead","year":"2017","unstructured":"Bankhead P, Loughrey MB, Fern\u00e1ndez JA, Dombrowski Y, McArt DG, Dunne PD et al (2017) QuPath: open source software for digital pathology image analysis. Sci Rep 7:16878. https:\/\/doi.org\/10.1038\/s41598-017-17204-5","journal-title":"Sci Rep"},{"key":"3039_CR8","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/S0197-4580(02)00065-9","volume":"24","author":"H Braak","year":"2003","unstructured":"Braak H, Tredici KD, R\u00fcb U, De Vos RAI, Jansen Steur ENH, Braak E (2003) Staging of brain pathology related to sporadic Parkinson\u2019s disease. Neurobiol Aging 24:197\u2013211. https:\/\/doi.org\/10.1016\/S0197-4580(02)00065-9","journal-title":"Neurobiol Aging"},{"key":"3039_CR9","doi-asserted-by":"publisher","first-page":"3587","DOI":"10.1093\/brain\/awad150","volume":"146","author":"P Calabresi","year":"2023","unstructured":"Calabresi P, Di Lazzaro G, Marino G, Campanelli F, Ghiglieri V (2023) Advances in understanding the function of alpha-synuclein: implications for Parkinson\u2019s disease. Brain 146:3587\u20133597. https:\/\/doi.org\/10.1093\/brain\/awad150","journal-title":"Brain"},{"key":"3039_CR10","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1038\/s41531-025-01048-2","volume":"11","author":"J Chedid","year":"2025","unstructured":"Chedid J, Li Y, Labrador-Garrido A, Abu-Bonsrah D, Pavan C, Fraser T et al (2025) Dopamine and cortical neurons with different Parkinsonian mutations show variation in lysosomal and mitochondrial dysfunction. Npj Park Dis 11:177. https:\/\/doi.org\/10.1038\/s41531-025-01048-2","journal-title":"Npj Park Dis"},{"key":"3039_CR11","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1038\/s41531-023-00564-3","volume":"9","author":"C Chen","year":"2023","unstructured":"Chen C, McDonald D, Blain A, Mossman E, Atkin K, Marusich MF et al (2023) Parkinson\u2019s disease neurons exhibit alterations in mitochondrial quality control proteins. Npj Parkinsons Dis 9:120. https:\/\/doi.org\/10.1038\/s41531-023-00564-3","journal-title":"Npj Parkinsons Dis"},{"key":"3039_CR12","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1007\/BF00310030","volume":"83","author":"GE Dale","year":"1992","unstructured":"Dale GE, Probst A, Luthert P, Martin J, Anderton BH, Leigh PN (1992) Relationships between Lewy bodies and pale bodies in Parkinson\u2019s disease. Acta Neuropathol (Berl) 83:525\u2013529. https:\/\/doi.org\/10.1007\/BF00310030","journal-title":"Acta Neuropathol (Berl)"},{"key":"3039_CR13","doi-asserted-by":"publisher","first-page":"1244","DOI":"10.1002\/mds.25952","volume":"29","author":"AA Dijkstra","year":"2014","unstructured":"Dijkstra AA, Voorn P, Berendse HW, Groenewegen HJ, Bank NB, Rozemuller AJM et al (2014) Stage-dependent nigral neuronal loss in incidental Lewy body and Parkinson\u2019s disease. Mov Disord Off J Mov Disord Soc 29:1244\u20131251. https:\/\/doi.org\/10.1002\/mds.25952","journal-title":"Mov Disord Off J Mov Disord Soc"},{"key":"3039_CR14","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1007\/BF00688674","volume":"34","author":"LS Forno","year":"1976","unstructured":"Forno LS, Norville RL (1976) Ultrastructure of Lewy bodies in the stellate ganglion. Acta Neuropathol (Berl) 34:183\u2013197. https:\/\/doi.org\/10.1007\/BF00688674","journal-title":"Acta Neuropathol (Berl)"},{"key":"3039_CR15","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-025-01090-x","author":"Y Fu","year":"2025","unstructured":"Fu Y, Halliday GM (2025) Dementia with Lewy bodies and Parkinson disease dementia \u2014 the same or different and is it important? Nat Rev Neurol. https:\/\/doi.org\/10.1038\/s41582-025-01090-x","journal-title":"Nat Rev Neurol"},{"key":"3039_CR16","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1038\/s41582-022-00682-1","volume":"18","author":"I Fyfe","year":"2022","unstructured":"Fyfe I (2022) Vulnerable dopamine neurons identified. Nat Rev Neurol 18:381\u2013381. https:\/\/doi.org\/10.1038\/s41582-022-00682-1","journal-title":"Nat Rev Neurol"},{"key":"3039_CR17","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1006\/exnr.2000.7527","volume":"166","author":"WP Gai","year":"2000","unstructured":"Gai WP, Yuan HX, Li XQ, Power JTH, Blumbergs PC, Jensen PH (2000) In Situ and in vitro study of colocalization and segregation of \u03b1-synuclein, ubiquitin, and lipids in lewy bodies. Exp Neurol 166:324\u2013333. https:\/\/doi.org\/10.1006\/exnr.2000.7527","journal-title":"Exp Neurol"},{"key":"3039_CR18","first-page":"809","volume":"140","author":"PG Galloway","year":"1992","unstructured":"Galloway PG, Mulvihill P, Perryt G (1992) Filaments of Lewy Bodies contain insoluble cytoskeletal elements. Am J Pathol 140:809","journal-title":"Am J Pathol"},{"key":"3039_CR19","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1007\/BF00689769","volume":"41","author":"K Ikeda","year":"1978","unstructured":"Ikeda K, Ikeda S, Yoshimura T, Kato H, Namba M (1978) Idiopathic parkinsonism with lewy-type inclusions in cerebral cortex. A case report. Acta Neuropathol (Berl) 41:165\u2013168. https:\/\/doi.org\/10.1007\/BF00689769","journal-title":"Acta Neuropathol (Berl)"},{"key":"3039_CR20","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/j.jalz.2018.02.018","volume":"14","author":"CR Jack","year":"2018","unstructured":"Jack CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB et al (2018) NIA-AA research framework: toward a biological definition of Alzheimer\u2019s disease. Alzheimers Dement 14:535\u2013562. https:\/\/doi.org\/10.1016\/j.jalz.2018.02.018","journal-title":"Alzheimers Dement"},{"key":"3039_CR21","doi-asserted-by":"publisher","first-page":"7674","DOI":"10.3390\/ijms26167674","volume":"26","author":"KA Jellinger","year":"2025","unstructured":"Jellinger KA (2025) Comorbid pathologies and their impact on dementia with Lewy bodies\u2014current view. Int J Mol Sci 26:7674. https:\/\/doi.org\/10.3390\/ijms26167674","journal-title":"Int J Mol Sci"},{"key":"3039_CR22","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/s0022-510x(03)00037-6","volume":"211","author":"O Katsuse","year":"2003","unstructured":"Katsuse O, Iseki E, Marui W, Kosaka K (2003) Developmental stages of cortical Lewy bodies and their relation to axonal transport blockage in brains of patients with dementia with Lewy bodies. J Neurol Sci 211:29\u201335. https:\/\/doi.org\/10.1016\/s0022-510x(03)00037-6","journal-title":"J Neurol Sci"},{"key":"3039_CR23","doi-asserted-by":"crossref","unstructured":"Kirillov A, Mintun E, Ravi N, Mao H, Rolland C, Gustafson L, Xiao T, Whitehead S, Berg AC, Lo W-Y, Doll\u00e1r P, Girshick R (2023) Segment anything. In: arXiv.org. https:\/\/arxiv.org\/abs\/2304.02643v1. Accessed 17 May 2026","DOI":"10.1109\/ICCV51070.2023.00371"},{"key":"3039_CR24","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1186\/s13024-021-00501-z","volume":"16","author":"S Koga","year":"2021","unstructured":"Koga S, Sekiya H, Kondru N, Ross OA, Dickson DW (2021) Neuropathology and molecular diagnosis of synucleinopathies. Mol Neurodegener 16:83. https:\/\/doi.org\/10.1186\/s13024-021-00501-z","journal-title":"Mol Neurodegener"},{"key":"3039_CR25","doi-asserted-by":"publisher","first-page":"2419","DOI":"10.1093\/brain\/awt192","volume":"136","author":"JH Kordower","year":"2013","unstructured":"Kordower JH, Olanow CW, Dodiya HB, Chu Y, Beach TG, Adler CH et al (2013) Disease duration and the integrity of the nigrostriatal system in Parkinson\u2019s disease. Brain J Neurol 136:2419\u20132431. https:\/\/doi.org\/10.1093\/brain\/awt192","journal-title":"Brain J Neurol"},{"key":"3039_CR26","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1007\/BF00690978","volume":"42","author":"K Kosaka","year":"1978","unstructured":"Kosaka K (1978) Lewy bodies in cerebral cortex. Report of three cases. Acta Neuropathol (Berl) 42:127\u2013134. https:\/\/doi.org\/10.1007\/BF00690978","journal-title":"Acta Neuropathol (Berl)"},{"key":"3039_CR27","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1007\/BF00685366","volume":"36","author":"K Kosaka","year":"1976","unstructured":"Kosaka K, Oyanagi S, Matsushita M, Hori A, Iwase S (1976) Presenile dementia with Alzheimer-, Pick- and Lewy-body changes. Acta Neuropathol (Berl) 36:221\u2013233. https:\/\/doi.org\/10.1007\/BF00685366","journal-title":"Acta Neuropathol (Berl)"},{"key":"3039_CR28","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1007\/s00401-015-1509-x","volume":"131","author":"GG Kovacs","year":"2016","unstructured":"Kovacs GG, Ferrer I, Grinberg LT, Alafuzoff I, Attems J, Budka H et al (2016) Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy. Acta Neuropathol (Berl) 131:87\u2013102. https:\/\/doi.org\/10.1007\/s00401-015-1509-x","journal-title":"Acta Neuropathol (Berl)"},{"key":"3039_CR29","doi-asserted-by":"publisher","first-page":"1241","DOI":"10.1093\/jnen\/62.12.1241","volume":"62","author":"E Kuusisto","year":"2003","unstructured":"Kuusisto E, Parkkinen L, Alafuzoff I (2003) Morphogenesis of Lewy bodies: dissimilar incorporation of \u03b1-synuclein, ubiquitin, and p62. J Neuropathol Exp Neurol 62:1241\u20131253. https:\/\/doi.org\/10.1093\/jnen\/62.12.1241","journal-title":"J Neuropathol Exp Neurol"},{"key":"3039_CR30","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1007\/BF00687787","volume":"75","author":"S Kuzuhara","year":"1988","unstructured":"Kuzuhara S, Mori H, Izumiyama N, Yoshimura M, Ihara Y (1988) Lewy bodies are ubiquitinated: a light and electron microscopic immunocytochemical study. Acta Neuropathol (Berl) 75:345\u2013353. https:\/\/doi.org\/10.1007\/BF00687787","journal-title":"Acta Neuropathol (Berl)"},{"key":"3039_CR31","first-page":"903","volume":"9","author":"JB Leverenz","year":"2009","unstructured":"Leverenz JB, Quinn JF, Zabetian C, Zhang J, Montine KS, Montine TJ (2009) Cognitive impairment and dementia in patients with Parkinson disease. Curr Top Med Chem 9:903\u2013912","journal-title":"Curr Top Med Chem"},{"key":"3039_CR32","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.sbi.2019.06.003","volume":"58","author":"AJ Lewis","year":"2019","unstructured":"Lewis AJ, Genoud C, Pont M, van de Berg WD, Frank S, Stahlberg H et al (2019) Imaging of post-mortem human brain tissue using electron and X-ray microscopy. Curr Opin Struct Biol 58:138\u2013148. https:\/\/doi.org\/10.1016\/j.sbi.2019.06.003","journal-title":"Curr Opin Struct Biol"},{"key":"3039_CR33","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-026-74083-z","author":"AJ Lewis","year":"2026","unstructured":"Lewis AJ, Heuvel L van den, Fabrizio M di, Bandelier K, Proniakova D, Burger D, Shafiei N, Ekundayo K, Offringa S, Huisman E, Bol JG, Berg WDV de, Stahlberg H (2026) Ultrastructural diversity and subcellular organization of nigral Lewy pathology in Parkinson\u2019s disease. Nat Commun. https:\/\/doi.org\/10.1038\/s41467-026-74083-z","journal-title":"Nat Commun"},{"key":"3039_CR34","doi-asserted-by":"publisher","first-page":"4971","DOI":"10.1073\/pnas.1913904117","volume":"117","author":"A-L Mahul-Mellier","year":"2020","unstructured":"Mahul-Mellier A-L, Burtscher J, Maharjan N, Weerens L, Croisier M, Kuttler F et al (2020) The process of Lewy body formation, rather than simply \u03b1-synuclein fibrillization, is one of the major drivers of neurodegeneration. Proc Natl Acad Sci 117:4971\u20134982. https:\/\/doi.org\/10.1073\/pnas.1913904117","journal-title":"Proc Natl Acad Sci"},{"key":"3039_CR35","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aed8851","author":"A-L Mahul-Mellier","year":"2026","unstructured":"Mahul-Mellier A-L, Van Den Heuvel L, Teixeira M, Boussouf MLN, Oudinot G, Thonet A, Speri D, Jasiqi Y, Ulrich C, Sheta R, Idi W, Croisier M, Clerc-Rosset S, Blanc J, Knott G, Oueslati A, Lashuel HA (2026) Recapitulating Parkinson\u2019s pathology in human iPSC dopaminergic neurons reveals new mechanistic insights into Lewy body formation and heterogeneity. Sci Adv. https:\/\/doi.org\/10.1126\/sciadv.aed8851","journal-title":"Sci Adv"},{"key":"3039_CR36","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1016\/S1474-4422(25)00085-7","volume":"24","author":"E Matar","year":"2025","unstructured":"Matar E, Halliday GM (2025) Biological effects of pathologies in Lewy body diseases: why timing matters. Lancet Neurol 24:441\u2013455. https:\/\/doi.org\/10.1016\/S1474-4422(25)00085-7","journal-title":"Lancet Neurol"},{"key":"3039_CR37","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00401-011-0910-3","volume":"123","author":"TJ Montine","year":"2012","unstructured":"Montine TJ, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Dickson DW et al (2012) National Institute on Aging\u2013Alzheimer\u2019s Association guidelines for the neuropathologic assessment of Alzheimer\u2019s disease: a practical approach. Acta Neuropathol (Berl) 123:1\u201311. https:\/\/doi.org\/10.1007\/s00401-011-0910-3","journal-title":"Acta Neuropathol (Berl)"},{"key":"3039_CR38","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/s13024-019-0306-8","volume":"14","author":"TF Outeiro","year":"2019","unstructured":"Outeiro TF, Koss DJ, Erskine D, Walker L, Kurzawa-Akanbi M, Burn D et al (2019) Dementia with Lewy bodies: an update and outlook. Mol Neurodegener 14:5. https:\/\/doi.org\/10.1186\/s13024-019-0306-8","journal-title":"Mol Neurodegener"},{"key":"3039_CR39","doi-asserted-by":"publisher","first-page":"1634","DOI":"10.1038\/s41592-022-01663-4","volume":"19","author":"M Pachitariu","year":"2022","unstructured":"Pachitariu M, Stringer C (2022) Cellpose 2.0: how to train your own model. Nat Methods 19:1634\u20131641. https:\/\/doi.org\/10.1038\/s41592-022-01663-4","journal-title":"Nat Methods"},{"key":"3039_CR40","doi-asserted-by":"publisher","unstructured":"Pachitariu M, Rariden M, Stringer C (2025) Cellpose-SAM: superhuman generalization for cellular segmentation.  https:\/\/doi.org\/10.1101\/2025.04.28.651001","DOI":"10.1101\/2025.04.28.651001"},{"key":"3039_CR41","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1111\/bpa.12344","volume":"27","author":"JHT Power","year":"2017","unstructured":"Power JHT, Barnes OL, Chegini F (2017) Lewy bodies and the mechanisms of neuronal cell death in Parkinson\u2019s Disease and dementia with lewy bodies. Brain Pathol Zurich Switz 27:3\u201312. https:\/\/doi.org\/10.1111\/bpa.12344","journal-title":"Brain Pathol Zurich Switz"},{"key":"3039_CR42","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1007\/s00401-002-0546-4","volume":"104","author":"K Sasaki","year":"2002","unstructured":"Sasaki K, Doh-ura K, Wakisaka Y, Iwaki T (2002) Clusterin\/apolipoprotein J is associated with cortical Lewy bodies: immunohistochemical study in cases with \u03b1-synucleinopathies. Acta Neuropathol (Berl) 104:225\u2013230. https:\/\/doi.org\/10.1007\/s00401-002-0546-4","journal-title":"Acta Neuropathol (Berl)"},{"key":"3039_CR43","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1038\/nmeth.2019","volume":"9","author":"J Schindelin","year":"2012","unstructured":"Schindelin J (2012) Fiji: an open-source platform for biological-image analysis. Nat Methods 9:676\u2013682. https:\/\/doi.org\/10.1038\/nmeth.2019","journal-title":"Nat Methods"},{"key":"3039_CR44","first-page":"53","volume":"139","author":"ML Schmidt","year":"1991","unstructured":"Schmidt ML, Murray J, Lee VM, Hill WD, Wertkin A, Trojanowski JQ (1991) Epitope map of neurofilament protein domains in cortical and peripheral nervous system Lewy bodies. Am J Pathol 139:53\u201365","journal-title":"Am J Pathol"},{"issue":"25","key":"3039_CR45","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.1016\/S1474-4422(25)00363-1","volume":"4422","author":"SW Scholz","year":"2025","unstructured":"Scholz SW, Okubadejo NU, Prakash P, Liddelow SA, Ryten M, Halliday GM (2025) Advances in the genetics and pathology of Lewy body dementia. Lancet Neurol 4422(25):1026\u20131037. https:\/\/doi.org\/10.1016\/S1474-4422(25)00363-1","journal-title":"Lancet Neurol"},{"key":"3039_CR46","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1186\/s13024-025-00900-6","volume":"20","author":"H Sekiya","year":"2025","unstructured":"Sekiya H, Matsubara T, DeTure MA, Dickson DW (2025) Neuropathology of Lewy body dementia: Lewy-related pathology, \u03b1-synuclein oligomers, and comorbid pathologies. Mol Neurodegener 20:117. https:\/\/doi.org\/10.1186\/s13024-025-00900-6","journal-title":"Mol Neurodegener"},{"key":"3039_CR47","doi-asserted-by":"publisher","first-page":"1443","DOI":"10.1038\/s41592-023-01990-0","volume":"20","author":"GJ Selzer","year":"2023","unstructured":"Selzer GJ, Rueden CT, Hiner MC, Evans EL, Harrington KIS, Eliceiri KW (2023) napari-imagej: ImageJ ecosystem access from napari. Nat Methods 20:1443\u20131444. https:\/\/doi.org\/10.1038\/s41592-023-01990-0","journal-title":"Nat Methods"},{"key":"3039_CR48","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-025-01153-9","author":"N Shafiei","year":"2025","unstructured":"Shafiei N, St\u04d3hli D, Burger D, Di Fabrizio M, Van Den Heuvel L, Daraspe J et al (2025) Correlative light and electron microscopy for human brain and other biological models. Nat Protoc. https:\/\/doi.org\/10.1038\/s41596-025-01153-9","journal-title":"Nat Protoc"},{"key":"3039_CR49","doi-asserted-by":"publisher","first-page":"1099","DOI":"10.1038\/s41593-019-0423-2","volume":"22","author":"SH Shahmoradian","year":"2019","unstructured":"Shahmoradian SH, Lewis AJ, Genoud C, Hench J, Moors TE, Navarro PP et al (2019) Lewy pathology in Parkinson\u2019s disease consists of crowded organelles and lipid membranes. Nat Neurosci 22:1099\u20131109. https:\/\/doi.org\/10.1038\/s41593-019-0423-2","journal-title":"Nat Neurosci"},{"key":"3039_CR50","doi-asserted-by":"publisher","first-page":"847","DOI":"10.1016\/j.stemcr.2015.02.019","volume":"4","author":"A Shaltouki","year":"2015","unstructured":"Shaltouki A, Sivapatham R, Pei Y, Gerencser AA, Mom\u010dilovi\u0107 O, Rao MS et al (2015) Mitochondrial alterations by PARKIN in dopaminergic neurons using PARK2 patient-specific and PARK2 knockout isogenic iPSC lines. Stem Cell Rep 4:847\u2013859. https:\/\/doi.org\/10.1016\/j.stemcr.2015.02.019","journal-title":"Stem Cell Rep"},{"key":"3039_CR51","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1016\/S1474-4422(23)00405-2","volume":"23","author":"T Simuni","year":"2024","unstructured":"Simuni T, Chahine LM, Poston K, Brumm M, Buracchio T, Campbell M et al (2024) A biological definition of neuronal \u03b1-synuclein disease: towards an integrated staging system for research. Lancet Neurol 23:178\u2013190. https:\/\/doi.org\/10.1016\/S1474-4422(23)00405-2","journal-title":"Lancet Neurol"},{"key":"3039_CR52","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000009434","author":"DS Smirnov","year":"2020","unstructured":"Smirnov DS, Galasko D, Edland SD, Filoteo JV, Hansen LA, Salmon DP (2020) Cognitive decline profiles differ in Parkinson disease dementia and dementia with Lewy bodies. Neurology. https:\/\/doi.org\/10.1212\/WNL.0000000000009434","journal-title":"Neurology"},{"key":"3039_CR53","doi-asserted-by":"publisher","first-page":"6469","DOI":"10.1073\/pnas.95.11.6469","volume":"95","author":"MG Spillantini","year":"1998","unstructured":"Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M (1998) \u03b1-Synuclein in filamentous inclusions of Lewy bodies from Parkinson\u2019s disease and dementia with Lewy bodies. Proc Natl Acad Sci 95:6469\u20136473. https:\/\/doi.org\/10.1073\/pnas.95.11.6469","journal-title":"Proc Natl Acad Sci"},{"key":"3039_CR54","doi-asserted-by":"publisher","first-page":"451","DOI":"10.3390\/cells15050451","volume":"15","author":"F Su","year":"2026","unstructured":"Su F, Kim WS, Halliday GM, Fu Y (2026) Alpha-synuclein in neurodegeneration: from shared biology to disease-specific phenotypes. Cells 15:451. https:\/\/doi.org\/10.3390\/cells15050451","journal-title":"Cells"},{"key":"3039_CR55","doi-asserted-by":"publisher","first-page":"a009290","DOI":"10.1101\/cshperspect.a009290","volume":"2","author":"DJ Surmeier","year":"2012","unstructured":"Surmeier DJ, Guzman JN, Sanchez J, Schumacker PT (2012) Physiological phenotype and vulnerability in Parkinson\u2019s disease. Cold Spring Harb Perspect Med 2:a009290. https:\/\/doi.org\/10.1101\/cshperspect.a009290","journal-title":"Cold Spring Harb Perspect Med"},{"key":"3039_CR56","doi-asserted-by":"publisher","first-page":"10736","DOI":"10.1074\/jbc.R112.410530","volume":"288","author":"DJ Surmeier","year":"2013","unstructured":"Surmeier DJ, Schumacker PT (2013) Calcium, bioenergetics, and neuronal vulnerability in Parkinson\u2019s disease. J Biol Chem 288:10736\u201310741. https:\/\/doi.org\/10.1074\/jbc.R112.410530","journal-title":"J Biol Chem"},{"key":"3039_CR57","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1111\/j.1440-1789.1994.tb00242.x","volume":"14","author":"H Takahashi","year":"1994","unstructured":"Takahashi H, Iwanaga K, Egawa S, Ikuta F (1994) Ultrastructural relationship between Lewy bodies and pale bodies studied in locus ceruleus neurons of a non-Parkinsonian patient. Neuropathology 14:73\u201380. https:\/\/doi.org\/10.1111\/j.1440-1789.1994.tb00242.x","journal-title":"Neuropathology"},{"key":"3039_CR58","doi-asserted-by":"publisher","first-page":"1791","DOI":"10.1212\/WNL.58.12.1791","volume":"58","author":"DR Thal","year":"2002","unstructured":"Thal DR, R\u00fcb U, Orantes M, Braak H (2002) Phases of A\u03b2-deposition in the human brain and its relevance for the development of AD. Neurology 58:1791\u20131800. https:\/\/doi.org\/10.1212\/WNL.58.12.1791","journal-title":"Neurology"},{"key":"3039_CR59","doi-asserted-by":"publisher","first-page":"1287","DOI":"10.1093\/jnen\/62.12.1287","volume":"62","author":"DR Thal","year":"2003","unstructured":"Thal DR, Ghebremedhin E, Orantes M, Wiestler OD (2003) Vascular pathology in Alzheimer disease: correlation of cerebral amyloid Angiopathy and arteriosclerosis\/lipohyalinosis with cognitive decline. J Neuropathol Exp Neurol 62:1287\u20131301. https:\/\/doi.org\/10.1093\/jnen\/62.12.1287","journal-title":"J Neuropathol Exp Neurol"},{"key":"3039_CR60","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1007\/s00401-008-0366-2","volume":"115","author":"DR Thal","year":"2008","unstructured":"Thal DR, Griffin WST, De Vos RAI, Ghebremedhin E (2008) Cerebral amyloid angiopathy and its relationship to Alzheimer\u2019s disease. Acta Neuropathol (Berl) 115:599\u2013609. https:\/\/doi.org\/10.1007\/s00401-008-0366-2","journal-title":"Acta Neuropathol (Berl)"},{"key":"3039_CR61","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1007\/s004010051025","volume":"97","author":"SG Van Duinen","year":"1999","unstructured":"Van Duinen SG, Lammers G-J, Maat-Schieman MLC, Roos RAC (1999) Numerous and widespread \u03b1-synuclein-negative Lewy bodies in an asymptomatic patient. Acta Neuropathol (Berl) 97:533\u2013539. https:\/\/doi.org\/10.1007\/s004010051025","journal-title":"Acta Neuropathol (Berl)"},{"key":"3039_CR62","doi-asserted-by":"publisher","first-page":"1054","DOI":"10.1016\/S1474-4422(15)00186-6","volume":"14","author":"M Volta","year":"2015","unstructured":"Volta M, Milnerwood AJ, Farrer MJ (2015) Insights from late-onset familial parkinsonism on the pathogenesis of idiopathic Parkinson\u2019s disease. Lancet Neurol 14:1054\u20131064. https:\/\/doi.org\/10.1016\/S1474-4422(15)00186-6","journal-title":"Lancet Neurol"},{"key":"3039_CR63","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1007\/BF00703325","volume":"39","author":"I Watanabe","year":"1977","unstructured":"Watanabe I, Vachal E, Tomita T (1977) Dense core vesicles around the Lewy body in incidental Parkinson\u2019s disease: an electron microscopic study. Acta Neuropathol (Berl) 39:173\u2013175. https:\/\/doi.org\/10.1007\/BF00703325","journal-title":"Acta Neuropathol (Berl)"},{"key":"3039_CR64","doi-asserted-by":"publisher","unstructured":"Wiseman JA, Reddy K, Halliday G, Dieriks BV Setting shapes the strain: untangling alpha-synuclein heterogeneity. Neural Regen Res. https:\/\/doi.org\/10.4103\/NRR.NRR-D-25-01287","DOI":"10.4103\/NRR.NRR-D-25-01287"},{"key":"3039_CR65","doi-asserted-by":"publisher","first-page":"1","DOI":"10.14802\/jmd.19052","volume":"13","author":"M Yamada","year":"2020","unstructured":"Yamada M, Komatsu J, Nakamura K, Sakai K, Samuraki-Yokohama M, Nakajima K et al (2020) Diagnostic criteria for dementia with Lewy bodies: updates and future directions. J Mov Disord 13:1\u201310. https:\/\/doi.org\/10.14802\/jmd.19052","journal-title":"J Mov Disord"},{"key":"3039_CR66","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1038\/s41586-022-05319-3","volume":"610","author":"Y Yang","year":"2022","unstructured":"Yang Y, Shi Y, Schweighauser M, Zhang X, Kotecha A, Murzin AG et al (2022) Structures of \u03b1-synuclein filaments from human brains with Lewy pathology. Nature 610:791\u2013795. https:\/\/doi.org\/10.1038\/s41586-022-05319-3","journal-title":"Nature"}],"container-title":["Acta Neuropathologica"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00401-026-03039-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00401-026-03039-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00401-026-03039-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T19:00:02Z","timestamp":1783537202000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00401-026-03039-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,8]]},"references-count":66,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["3039"],"URL":"https:\/\/doi.org\/10.1007\/s00401-026-03039-w","relation":{},"ISSN":["1432-0533"],"issn-type":[{"value":"1432-0533","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,8]]},"assertion":[{"value":"19 December 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 June 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 June 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 July 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"All donors provided written informed consent for a brain autopsy and the use of the material and clinical information for research purposes. Detailed neuropathological and clinical information was made available, in compliance with local ethical and legal guidelines, and all protocols were approved by the Amsterdam UMC institutional review board. Demographic features and clinical symptoms were abstracted from the clinical files, including sex, age at symptom onset, age at death, disease duration, presence of dementia, core and supportive clinical features for Parkinson\u2019s disease and Dementia with Lewy bodies. All protocols were approved by VU University Medical Center institutional ethics review board (reference number 2019\/148). This study was approved by the Cantonal Ethics Committee (Canton de Vaud, Project-ID CER-VD 2025\u201301061).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval and consent to participate"}},{"value":"All donors provided written informed consent for the use of the material and clinical information for publication. All protocols were approved by Vrije University Medical Center Institutional Review Board. Figure\u00a0\n                      \n                      was created with BioRender.com with agreement number ZY294VGV08.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}],"article-number":"5"}}