{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T12:29:28Z","timestamp":1786969768223,"version":"build-2736575974"},"reference-count":70,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Med. Sci.","Medical Sciences"],"abstract":"<jats:p>Background: Parkinson\u2019s disease (PD) exhibits remarkable clinical heterogeneity, with substantial variability in motor progression, cognitive decline, and the development of non-motor manifestations. Although the propagation of pathological alpha-synuclein is considered a central mechanism of PD pathogenesis, it does not fully explain why specific neuronal populations demonstrate differential susceptibility to degeneration. Emerging evidence suggests that selective neuronal vulnerability is determined by the interaction of multiple biological domains, including calcium homeostasis, mitochondrial bioenergetic capacity, lysosomal function, axonal architecture, synaptic resilience, and neuroinflammatory responses. Methods: A structured critical narrative review was performed using PubMed\/MEDLINE, Scopus, and Web of Science databases from inception to March 2025. Only full-text articles published in English and peer-reviewed journals were included. Evidence from human post-mortem studies, genetic analyses, biomarker investigations, experimental models, induced pluripotent stem cell studies, and longitudinal clinical cohorts were systematically synthesised to identify the principal mechanisms underlying selective neuronal vulnerability and their potential translational application. To capture evidence published after this electronic cut-off, a supplementary manual review of reference lists of key systematic reviews and landmark publications was conducted up to the date of manuscript submission; references with 2025 or 2026 publication dates entered through this supplementary process. The supplementary manual review was conducted as a targeted scan of reference lists of key systematic reviews and high-impact publications identified during the primary search and did not constitute an independent updated systematic search. Results: Five interconnected biological domains emerged as key determinants of neuronal susceptibility in PD: calcium-mediated metabolic stress associated with autonomous pacemaker activity, mitochondrial dysfunction and energetic failure, impaired lysosomal degradation and proteostasis (particularly involving the GBA1\u2013glucocerebrosidase pathway), vulnerability related to extensive axonal and synaptic architecture, and neuroinflammatory mechanisms involving microglial and astrocytic activation. Among these domains, the lysosomal pathway currently provides the strongest translational link between molecular mechanisms and measurable clinical outcomes. Based on this integrated framework, we propose the Parkinson\u2019s Vulnerability Index (PVI), a hypothesis-generating multidimensional model combining genetic, enzymatic, alpha-synuclein seeding, cognitive, olfactory, and neuroimaging biomarkers to facilitate biological stratification and improve the design of mechanism-targeted clinical trials. Conclusions: Selective neuronal vulnerability provides a complementary framework to alpha-synuclein propagation models for understanding the heterogeneity of PD. The proposed PVI is not intended as a diagnostic or prognostic clinical instrument but as a research tool requiring prospective validation. Future precision medicine approaches in PD may benefit from integrating vulnerability-related biomarkers with existing biological staging systems to identify patients most likely to benefit from targeted disease-modifying therapies.<\/jats:p>","DOI":"10.3390\/medsci14040489","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T12:01:26Z","timestamp":1786968086000},"page":"489","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Selective Neuronal Vulnerability to Alpha-Synuclein Pathology in Parkinson\u2019s Disease: A Critical Review of Mechanistic Rationale and Biomarker Stratification"],"prefix":"10.3390","volume":"14","author":[{"given":"Livia","family":"Livin\u021b-Popa","sequence":"first","affiliation":[{"name":"Department of Neuroscience, \u201cIuliu Ha\u021bieganu\u201d University of Medicine and Pharmacy, 400083 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreea","family":"Nicolaie","sequence":"additional","affiliation":[{"name":"American University of the Caribbean School of Medicine, Miramar, FL 33025, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0008-9696","authenticated-orcid":false,"given":"Alexandra","family":"Mastaleru","sequence":"additional","affiliation":[{"name":"Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u0218tefan","family":"Socolov","sequence":"additional","affiliation":[{"name":"Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihaela","family":"Mitrea","sequence":"additional","affiliation":[{"name":"Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7004-6846","authenticated-orcid":false,"given":"Gabriela","family":"Popescu","sequence":"additional","affiliation":[{"name":"Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4495-4004","authenticated-orcid":false,"given":"Thomas Gabriel","family":"Schreiner","sequence":"additional","affiliation":[{"name":"Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7386-0859","authenticated-orcid":false,"given":"Roxana","family":"Covali","sequence":"additional","affiliation":[{"name":"Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1544-1325","authenticated-orcid":false,"given":"Laura-Elena","family":"Cucu","sequence":"additional","affiliation":[{"name":"Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia Corina","family":"Dima-Cozma","sequence":"additional","affiliation":[{"name":"Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3768-6232","authenticated-orcid":false,"given":"Romica Sebastian","family":"Cozma","sequence":"additional","affiliation":[{"name":"Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2079-2383","authenticated-orcid":false,"given":"Alin","family":"Ciubotaru","sequence":"additional","affiliation":[{"name":"Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1221-5397","authenticated-orcid":false,"given":"Raluca","family":"Olariu","sequence":"additional","affiliation":[{"name":"Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6428-4071","authenticated-orcid":false,"given":"Cosmin Mihai","family":"Ciurumelea","sequence":"additional","affiliation":[{"name":"Prevent Institute, 020021 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liana Rada","family":"Borza","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Imperial College London, London SW7 2AZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Vamanu","sequence":"additional","affiliation":[{"name":"Basic and Clinical Neuroscience Department, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London SE5 8AF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"key":"ref_1","unstructured":"GBD 2016 Parkinson\u2019s Disease Collaborators (2018). Global, Regional, and National Burden of Parkinson\u2019s Disease, 1990\u20132016: A Systematic Analysis for the Global Burden of Disease Study 2016. Lancet Neurol., 17, 939\u2013953."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1056\/NEJMra2401857","article-title":"Parkinson\u2019s Disease","volume":"391","author":"Tanner","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/S0197-4580(02)00065-9","article-title":"Staging of Brain Pathology Related to Sporadic Parkinson\u2019s Disease","volume":"24","author":"Braak","year":"2003","journal-title":"Neurobiol. Aging"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1126\/science.1227157","article-title":"Pathological \u03b1-Synuclein Transmission Initiates Parkinson-like Neurodegeneration in Nontransgenic Mice","volume":"338","author":"Luk","year":"2012","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/nm1747","article-title":"Lewy Body-like Pathology in Long-Term Embryonic Nigral Transplants in Parkinson\u2019s Disease","volume":"14","author":"Kordower","year":"2008","journal-title":"Nat. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1007\/978-3-7091-6842-4_9","article-title":"Neuronal Vulnerability in Parkinson\u2019s Disease","volume":"50","author":"Hirsch","year":"1997","journal-title":"J. Neural Transm. Suppl."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1016\/S1474-4422(09)70238-8","article-title":"Neuropathological Assessment of Parkinson\u2019s Disease: Refining the Diagnostic Criteria","volume":"8","author":"Dickson","year":"2009","journal-title":"Lancet Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/S1474-4422(23)00405-2","article-title":"A Biological Definition of Neuronal \u03b1-Synuclein Disease: Towards an Integrated Staging System for Research","volume":"23","author":"Simuni","year":"2024","journal-title":"Lancet Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/S1474-4422(23)00404-0","article-title":"A Biological Classification of Parkinson\u2019s Disease: The SynNeurGe Research Diagnostic Criteria","volume":"23","author":"Adler","year":"2024","journal-title":"Lancet Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1002\/mds.29683","article-title":"A Statement of the MDS on Biological Definition, Staging, and Classification of Parkinson\u2019s Disease","volume":"39","author":"Cardoso","year":"2024","journal-title":"Mov. Disord."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1038\/s41531-024-00789-w","article-title":"Neuronal Alpha-Synuclein Disease Integrated Staging System Performance in PPMI, PASADENA, and SPARK Baseline Cohorts","volume":"10","author":"Dam","year":"2024","journal-title":"npj Park. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1038\/nature05865","article-title":"\u2018Rejuvenation\u2019 Protects Neurons in Mouse Models of Parkinson\u2019s Disease","volume":"447","author":"Chan","year":"2007","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.neuroscience.2011.08.045","article-title":"The Role of Calcium and Mitochondrial Oxidant Stress in the Loss of substantia nigra pars compacta Dopaminergic Neurons","volume":"198","author":"Surmeier","year":"2011","journal-title":"Neuroscience"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Brichta, L., and Greengard, P. (2014). Molecular Determinants of Selective Dopaminergic Vulnerability in Parkinson\u2019s Disease. Front. Neuroanat., 8.","DOI":"10.3389\/fnana.2014.00152"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"(2020). Parkinson Study Group STEADY-PD III Investigators. Isradipine versus Placebo in Early Parkinson Disease: A Randomized Trial. Ann. Intern. Med., 172, 591\u2013598.","DOI":"10.7326\/M19-2534"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1002\/mds.25135","article-title":"Living on the Edge with Too Many Mouths to Feed: Why Dopamine Neurons Die","volume":"27","author":"Bolam","year":"2012","journal-title":"Mov. Disord."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1111\/j.1471-4159.1990.tb02325.x","article-title":"Mitochondrial Complex I Deficiency in Parkinson\u2019s Disease","volume":"54","author":"Schapira","year":"1990","journal-title":"J. Neurochem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9089","DOI":"10.1074\/jbc.M710012200","article-title":"Mitochondrial Import and Accumulation of \u03b1-Synuclein Impair Complex I in Human Dopaminergic Neuronal Cultures and Parkinson Disease Brain","volume":"283","author":"Devi","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2349","DOI":"10.1016\/j.cub.2015.07.050","article-title":"Elevated Mitochondrial Bioenergetics and Axonal Arborization Size Are Key Contributors to the Vulnerability of Dopamine Neurons","volume":"25","author":"Pacelli","year":"2015","journal-title":"Curr. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1126\/science.aam9080","article-title":"Dopamine Oxidation Mediates Mitochondrial and Lysosomal Dysfunction in Parkinson\u2019s Disease","volume":"357","author":"Burbulla","year":"2017","journal-title":"Science"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Gigu\u00e8re, N., Burke Nanni, S., and Trudeau, L.E. (2018). On Cell Loss and Selective Vulnerability of Neuronal Populations in Parkinson\u2019s Disease. Front. Neurol., 9.","DOI":"10.3389\/fneur.2018.00455"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1038\/s41419-023-05672-9","article-title":"Alpha-Synuclein in Parkinson\u2019s Disease and Other Synucleinopathies: From Overt Neurodegeneration Back to Early Synaptic Dysfunction","volume":"14","author":"Calabresi","year":"2023","journal-title":"Cell Death Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1126\/science.1101738","article-title":"Impaired Degradation of Mutant \u03b1-Synuclein by Chaperone-Mediated Autophagy","volume":"305","author":"Cuervo","year":"2004","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1056\/NEJMoa0901281","article-title":"Multicenter Analysis of Glucocerebrosidase Mutations in Parkinson\u2019s Disease","volume":"361","author":"Sidransky","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.cell.2011.06.001","article-title":"Gaucher Disease Glucocerebrosidase and \u03b1-Synuclein Form a Bidirectional Pathogenic Loop","volume":"146","author":"Mazzulli","year":"2011","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1073\/pnas.1520335113","article-title":"\u03b1-Synuclein-Induced Lysosomal Dysfunction Occurs through Disruptions in Protein Trafficking in Human Midbrain Synucleinopathy Models","volume":"113","author":"Mazzulli","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/s40035-024-00437-6","article-title":"Clinical, Mechanistic, Biomarker, and Therapeutic Advances in GBA1-Associated Parkinson\u2019s Disease","volume":"13","author":"Zhang","year":"2024","journal-title":"Transl. Neurodegener."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1093\/brain\/aws318","article-title":"Glucocerebrosidase Mutations Influence the Natural History of Parkinson\u2019s Disease in a Community-Based Incident Cohort","volume":"136","author":"Evans","year":"2013","journal-title":"Brain"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2106","DOI":"10.1002\/mds.28195","article-title":"GBA1-Related Parkinson\u2019s Disease: Genotype-Phenotype Correlates in a Large Italian Cohort","volume":"35","author":"Petrucci","year":"2020","journal-title":"Mov. Disord."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s40035-022-00281-6","article-title":"LRRK2, GBA and Their Interaction in the Regulation of Autophagy in Parkinson\u2019s Disease","volume":"11","author":"Pang","year":"2022","journal-title":"Transl. Neurodegener."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Skrahin, A., Horowitz, M., Istaiti, M., Skrahina, V., Lukas, J., Yahalom, G., Cohen, M.E., Revel-Vilk, S., Goker-Alpan, O., and Becker-Cohen, M. (2024). GBA1-Associated Parkinson\u2019s Disease Is a Distinct Entity. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25137102"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1038\/s41531-025-01060-6","article-title":"Classification of GBA1 Variants and Their Impact on Parkinson\u2019s Disease: An In Silico Score Analysis","volume":"11","author":"Lanore","year":"2025","journal-title":"npj Park. Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/s41531-024-00706-1","article-title":"Longitudinal Cognitive Decline Characterizes the Profile of Non-PD-Manifest GBA1 Mutation Carriers","volume":"10","author":"Lerche","year":"2024","journal-title":"npj Park. Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/s41531-025-00883-7","article-title":"Male Sex Accelerates Cognitive Decline in GBA1 Parkinson\u2019s Disease","volume":"11","author":"Caminiti","year":"2025","journal-title":"npj Park. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Li, Q., Bi, Z., Liang, W., Yin, S., Li, H., Liang, Z., Wu, M., Quan, J., and Li, C. (2025). Effects of Glucocerebrosidase Gene Variations on the Risk of Parkinson\u2019s Disease Dementia: A Meta-Analysis. Front. Aging Neurosci., 17.","DOI":"10.3389\/fnagi.2025.1671760"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s13024-026-00931-7","article-title":"Multi-Omics Insights into GBA1-Associated Parkinson\u2019s Disease: Interplay of Genomics, Transcriptomics, Proteomics, and Lipidomics","volume":"21","author":"Ni","year":"2026","journal-title":"Mol. Neurodegener."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Hanff, A.M., McCrum, C., Rauschenberger, A., Pachchek, S., Aguayo, G.A., Pauly, C., J\u00f3nsd\u00f3ttir, S.R., Tsurkalenko, O., Pauly, L., and Landoulsi, Z. (2026). Progression of GBA1 Severe and Risk Variants: A Longitudinal Mixed Model Analysis. Front. Aging Neurosci., 18.","DOI":"10.3389\/fnagi.2026.1771789"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/s41531-018-0044-6","article-title":"Mitochondrial Dysfunction within the Synapses of Substantia Nigra Neurons in Parkinson\u2019s Disease","volume":"4","author":"Reeve","year":"2018","journal-title":"npj Park. Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1007\/s00401-010-0711-0","article-title":"The Synaptic Pathology of \u03b1-Synuclein Aggregation in Dementia with Lewy Bodies, Parkinson\u2019s Disease and Parkinson\u2019s Disease Dementia","volume":"120","year":"2010","journal-title":"Acta Neuropathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"eabc2487","DOI":"10.1126\/sciadv.abc2487","article-title":"Determinants of Seeding and Spreading of \u03b1-Synuclein Pathology in the Brain","volume":"6","author":"Henrich","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"eadi8287","DOI":"10.1126\/sciadv.adi8287","article-title":"Molecular Profiling of Human Substantia Nigra Identifies Diverse Neuron Types Associated with Vulnerability in Parkinson\u2019s Disease","volume":"10","author":"Wang","year":"2024","journal-title":"Sci. Adv."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s13024-023-00699-0","article-title":"Unravelling Cell Type-Specific Responses to Parkinson\u2019s Disease at Single Cell Resolution","volume":"19","author":"Martirosyan","year":"2024","journal-title":"Mol. Neurodegener."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1562","DOI":"10.1038\/ncomms2534","article-title":"Neuron-Released Oligomeric \u03b1-Synuclein Is an Endogenous Agonist of TLR2 for Paracrine Activation of Microglia","volume":"4","author":"Kim","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Eo, H., Kim, S., Jung, U.J., and Kim, S.R. (2024). Alpha-Synuclein and Microglia in Parkinson\u2019s Disease. J. Clin. Med., 13.","DOI":"10.3390\/jcm13237243"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1093\/brain\/awab446","article-title":"Single-Cell Sequencing of Human Midbrain Reveals Glial Activation and a Parkinson-Specific Neuronal State","volume":"145","author":"Landoulsi","year":"2022","journal-title":"Brain"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/nature21029","article-title":"Neurotoxic Reactive Astrocytes Are Induced by Activated Microglia","volume":"541","author":"Liddelow","year":"2017","journal-title":"Nature"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1038\/s41531-025-01005-z","article-title":"Complement C4 Exacerbates Astrocyte-Mediated Neuroinflammation and Promotes \u03b1-Synuclein Pathology in Parkinson\u2019s Disease","volume":"11","author":"Zou","year":"2025","journal-title":"npj Park. Dis."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1002\/mds.28472","article-title":"The Mutation Matters: CSF Profiles of GCase, Sphingolipids, \u03b1-Synuclein in PDGBA","volume":"36","author":"Lerche","year":"2021","journal-title":"Mov. Disord."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1002\/mds.25772","article-title":"Cerebrospinal Fluid Lysosomal Enzymes and \u03b1-Synuclein in Parkinson\u2019s Disease","volume":"29","author":"Parnetti","year":"2014","journal-title":"Mov. Disord."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2648","DOI":"10.1093\/brain\/awv179","article-title":"Glucocerebrosidase Activity in Parkinson\u2019s Disease with and without GBA Mutations","volume":"138","author":"Alcalay","year":"2015","journal-title":"Brain"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/S1474-4422(23)00109-6","article-title":"Assessment of Heterogeneity among Participants in the Parkinson\u2019s Progression Markers Initiative Cohort Using \u03b1-Synuclein Seed Amplification: A Cross-Sectional Study","volume":"22","author":"Siderowf","year":"2023","journal-title":"Lancet Neurol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1002\/mds.27646","article-title":"Comparative Study of Cerebrospinal Fluid \u03b1-Synuclein Seeding Aggregation Assay in Parkinson\u2019s Disease","volume":"34","author":"Kang","year":"2019","journal-title":"Mov. Disord."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e210279","DOI":"10.1212\/WNL.0000000000210279","article-title":"\u03b1-Synuclein Seed Amplification Assay Amplification Parameters and the Risk of Progression in Prodromal Parkinson Disease","volume":"104","author":"Coughlin","year":"2025","journal-title":"Neurology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1016\/S1474-4422(25)00157-7","article-title":"Diagnostic and Prognostic Value of \u03b1-Synuclein Seed Amplification Assay Kinetic Measures in Parkinson\u2019s Disease: A Longitudinal Cohort Study","volume":"24","author":"Vaughan","year":"2025","journal-title":"Lancet Neurol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/s41531-026-01346-3","article-title":"Clinical Correlates of a Negative Cerebrospinal Fluid \u03b1-Synuclein Seed Amplification Assay Result in Parkinson\u2019s Disease","volume":"12","author":"Mastrangelo","year":"2026","journal-title":"npj Park. Dis."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Parkinson Study Group Biomarkers Working Group (2026). CSF \u03b1-Synuclein Seed Amplification Assays and Skin Immunofluorescence: Clinical Applications, Research Opportunities, and Knowledge Gaps. Neurology, 106, e214648.","DOI":"10.1212\/WNL.0000000000214648"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1111\/j.1532-5415.2005.53221.x","article-title":"The Montreal Cognitive Assessment, MoCA: A Brief Screening Tool for Mild Cognitive Impairment","volume":"53","author":"Nasreddine","year":"2005","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_58","unstructured":"Doty, R.L. (1995). The Smell Identification Test Administration Manual, Sensonics. [3rd ed.]."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1056\/NEJMoa2202867","article-title":"Trial of Prasinezumab in Early-Stage Parkinson\u2019s Disease","volume":"387","author":"Pagano","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1038\/s41591-024-02886-y","article-title":"Prasinezumab Slows Motor Progression in Rapidly Progressing Early-Stage Parkinson\u2019s Disease","volume":"30","author":"Pagano","year":"2024","journal-title":"Nat. Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3669","DOI":"10.1038\/s41591-024-03270-6","article-title":"Sustained Effect of Prasinezumab on Parkinson\u2019s Disease Motor Progression in the Open-Label Extension of the PASADENA Trial","volume":"30","author":"Pagano","year":"2024","journal-title":"Nat. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1056\/NEJMoa2312323","article-title":"Trial of Lixisenatide in Early Parkinson\u2019s Disease","volume":"390","author":"Meissner","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_63","doi-asserted-by":"crossref","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":"ref_64","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1001\/jamaneurol.2025.1687","article-title":"Ambroxol as a Treatment for Parkinson Disease Dementia: A Randomized Clinical Trial","volume":"82","author":"Silveira","year":"2025","journal-title":"JAMA Neurol."},{"key":"ref_65","unstructured":"(2015). Writing Group for the NINDS Exploratory Trials in Parkinson Disease (NET-PD) Investigators. Effect of Creatine Monohydrate on Clinical Progression in Patients with Parkinson Disease: A Randomized Clinical Trial. JAMA, 313, 584\u2013593."},{"key":"ref_66","unstructured":"(2014). Parkinson Study Group QE3 Investigators. A Randomized Clinical Trial of High-Dosage Coenzyme Q10 in Early Parkinson Disease: No Evidence of Benefit. JAMA Neurol., 71, 543\u2013552."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1056\/NEJMoa2203395","article-title":"Trial of Cinpanemab in Early Parkinson\u2019s Disease","volume":"387","author":"Lang","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/j.pneurobio.2011.09.005","article-title":"The Parkinson Progression Marker Initiative (PPMI)","volume":"95","author":"Marek","year":"2011","journal-title":"Prog. Neurobiol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1016\/S0002-9440(10)65226-1","article-title":"Widespread Alterations of \u03b1-Synuclein in Multiple System Atrophy","volume":"155","author":"Dickson","year":"1999","journal-title":"Am. J. Pathol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/s00401-020-02255-2","article-title":"Neuropathological Consensus Criteria for the Evaluation of Lewy Pathology in Post-Mortem Brains","volume":"141","author":"Attems","year":"2021","journal-title":"Acta Neuropathol."}],"container-title":["Medical Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3271\/14\/4\/489\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T12:18:23Z","timestamp":1786969103000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3271\/14\/4\/489"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,17]]},"references-count":70,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["medsci14040489"],"URL":"https:\/\/doi.org\/10.3390\/medsci14040489","relation":{},"ISSN":["2076-3271"],"issn-type":[{"value":"2076-3271","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,17]]}}}