Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons and α-synuclein accumulation. Despite extensive research, there remains a shortage of effective disease-modifying medicines, which is due in part to the failure to translate molecular insights into clinically useful models and diagnostics.
Objectives
This review will summarize recent developments in the PD pathophysiology and diagnostic, therapeutic and experimental models and will focus on the newer in vivo, in vitro and bioengineered in vivo platforms.
Methods
Recent studies on animal models, patient-induced pluripotent stem cell (iPSC) systems, three-dimensional (3D) bioprinting, neuroimaging, and biomarker discovery have been critically examined to determine their translational potential and limitations.
Results
Traditional animal models are effective at replicating dopaminergic degradation but fall short of fully replicating progressive and systemic elements of Parkinson's disease. iPSC-derived neurons and 3D-bioprinted constructs are more genetically specific and cellularly complex, allowing for patient-relevant modeling and medication screening. Advances in imaging and molecular biomarkers aid in earlier detection; nevertheless, no cross-validation or platform standards has been established.
Conclusion
Combining cellular, molecular, and bioengineered models with clinical diagnostics has the potential to improve translational accuracy and accelerate the development of disease-modifying treatments. A cross-platform system is critical for improving the predictive validity of preclinical studies in Parkinson's disease.
AbusrairA. H.ElsekailyW.BohlegaS. (2022). Tremor in Parkinson’s disease: From pathophysiology to advanced therapies. Tremor and Other Hyperkinetic Movements, 12, 29. https://doi.org/10.5334/tohm.712
2.
AdamiecK.TrojanowskiD.RodakM.Smorońska-RypelJ.SzymczukB.KajzarM.NitkaK.IwanM.PiątkowskaN.MilczarekJ. (2024). Moving beyond medication: Harnessing the power of physical therapy and dance therapy in Parkinson's disease management. Quality in Sport, 15, 52373–52373. https://doi.org/10.12775/QS.2024.15.52373
3.
AlameerA. A. H.AlhuraysiM. A. M.AlhazmiM. I.Al-GhamdiW. A. M.AlshehriS. A. A.MaashiS. M.Al-GhashmariK. H. A. (2024). Parkinson disease: An overview for the management techniques via physical therapy. Journal of Ecohumanism, 3(8), 12698–12707. https://doi.org/10.62754/joe.v3i8.6023
4.
AliB.RiazB.ButtM. S.MehmoodA.KhanS. A.MahmoodU. (2023). Effectiveness of virtual reality rehabilitation versus conventional physical therapy on quality-of-life function and balance in Parkinson's disease patients: A randomized controlled trial. Journal of Health and Rehabilitation Research, 3(2), 623–628. https://doi.org/10.61919/jhrr.v3i2.206
AndersenJ.MoJ.HomD.LeeF.HarnishP.HamillR.McNeillT. (1996). Effect of buthionine sulfoximine, a synthesis inhibitor of the antioxidant glutathione, on the murine nigrostriatal neurons. Journal of Neurochemistry, 67(5), 2164–2171. https://doi.org/10.1046/j.1471-4159.1996.67052164.x
7.
AngeliniL.PaparellaG.BolognaM. (2024). Distinguishing essential tremor from Parkinson’s disease: Clinical and experimental tools. Expert Review of Neurotherapeutics, 24(8), 799–814. https://doi.org/10.1080/14737175.2024.2372339
8.
AngiusF.MocciI.ErcoliT.LoyF.FaddaL.PalmasM. F.CannasG.ManzinA.DefazioG.CartaA. R. (2023). Combined measure of salivary alpha-synuclein species as diagnostic biomarker for Parkinson’s disease. Journal of Neurology, 270(11), 5613–5621. https://doi.org/10.1007/s00415-023-11893-x
9.
Arboleda-MontealegreG. Y.Cano-de-la-CuerdaR.Fernández-de-Las-PeñasC.Sanchez-CamareroC.Ortega-SantiagoR. (2021). Drooling, swallowing difficulties and health related quality of life in Parkinson’s disease patients. International Journal of Environmental Research and Public Health, 18(15), 8138. https://doi.org/10.3390/ijerph18158138
Bastías-CandiaS.Di BenedettoM.D'AddarioC.CandelettiS.RomualdiP. (2015). Combined exposure to agriculture pesticides, paraquat and maneb, induces alterations in the N/OFQ—NOPr and PDYN/KOPr systems in rats: Relevance to sporadic Parkinson's disease. Environmental Toxicology, 30(6), 656–663. https://doi.org/10.1002/tox.21943
12.
BekticM.SmithB. E.RidgelA.KimK. (2024). Virtual reality game with haptic feedback for upper limb rehabilitation in Parkinson’s disease. 2024 46th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC).
13.
BhidayasiriR.IshidaT.KameiT.HusniR. E.SuzukiI.WuS. L.ChoJ. W. (2023). Safinamide as an adjunct to Levodopa in Asian and Caucasian patients with Parkinson’s disease and motor fluctuations: A post hoc analysis of the SETTLE study. Journal of Movement Disorders, 16(2), 180. https://doi.org/10.14802/jmd.22196
14.
BreasailMÓSmithM. D.TenisonE.HendersonE. J.LithanderF. E. (2022). Parkinson's disease: The nutrition perspective. Proceedings of the Nutrition Society, 81(1), 12–26. https://doi.org/10.1017/S0029665121003645
Campo-PrietoP.Cancela-CarralJ. M.Rodríguez-FuentesG. (2022). Wearable immersive virtual reality device for promoting physical activity in Parkinson’s disease patients. Sensors, 22(9), 3302. https://doi.org/10.3390/s22093302
17.
CanningC. G.AllenN. E.NackaertsE.PaulS. S.NieuwboerA.GilatM. (2020). Virtual reality in research and rehabilitation of gait and balance in Parkinson disease. Nature Reviews Neurology, 16(8), 409–425. https://doi.org/10.1038/s41582-020-0370-2
18.
CeylanM.GültekinM.ÇelikN. D.SamanciB.ÇakmakliG. Y.YilmazR. (2022). Intermittent subcutaneous injections of Apomorphine in Parkinson’s disease. The Eurasian Journal of Medicine, 54(Suppl 1), S71. https://doi.org/10.5152/eurasianjmed.2022.22134
19.
ChauB.HumbertS.ShouA. (2021). Systemic literature review of the use of virtual reality for rehabilitation in Parkinson disease. Federal Practitioner, 38(Suppl 1), S20. https://doi.org/10.12788/FP.0112
20.
CikajloI.Peterlin PotiskK. (2019). Advantages of using 3D virtual reality based training in persons with Parkinson’s disease: A parallel study. Journal of Neuroengineering and Rehabilitation, 16(1), 1–14.https://doi.org/10.1186/s12984-019-0601-1
21.
CostaG.FrauL.WardasJ.PinnaA.PlumitalloA.MorelliM. (2013). MPTP-Induced dopamine neuron degeneration and glia activation is potentiated in MDMA-pretreated mice. Movement Disorders, 28(14), 1957–1965. https://doi.org/10.1002/mds.25646
22.
Crosby, N. J., Deane, K. H., & Clarke, C. E. (2003). Amantadine in Parkinson's disease. Cochrane Database of Systematic Reviews, 2010(1), 695. https://doi.org/10.1002/14651858
de LeeuwS. M.DavazS.WannerD.MilleretV.EhrbarM.GietlA.TackenbergC. (2021). Increased maturation of iPSC-derived neurons in a hydrogel-based 3D culture. Journal of Neuroscience Methods, 360, 109254. https://doi.org/10.1016/j.jneumeth.2021.109254
25.
DelenclosM.JonesD. R.McLeanP. J.UittiR. J. (2016). Biomarkers in Parkinson's disease: Advances and strategies. Parkinsonism & Related Disorders, 22(Supplement 1 (S1)), S106–S110.https://doi.org/10.1016/j.parkreldis.2015.09.048
26.
DodetP.HouotM.Leu-SemenescuS.CorvolJ.-C.LehéricyS.MangoneG.VidailhetM.RozeE.ArnulfI. (2024). Sleep disorders in Parkinson’s disease, an early and multiple problem. npj Parkinson's Disease, 10(1), 46. https://doi.org/10.1038/s41531-024-00642-0
27.
Dusonchet, J., Kochubey, O., Stafa, K., Young, S. M., Jr, Zufferey, R., Moore, D. J., Schneider, B. L., & Aebischer, P. (2011). A rat model of progressive nigral neurodegeneration induced by the Parkinson's disease-associated G2019S mutation in LRRK2. The Journal of neuroscience, 31(3), 907–912.
28.
EbrahimG.HutchinsonH.GonzalezM.DagraA. (2025). Central and peripheral immunity responses in Parkinson’s disease: An overview and update. Neuroglia, 6(2), 17. https://doi.org/10.3390/neuroglia6020017
29.
ElkurdM. T.BahrooL. B.PahwaR. (2018). The role of extended-release amantadine for the treatment of dyskinesia in Parkinson’s disease patients. Neurodegenerative Disease Management, 8(2), 73–80. https://doi.org/10.2217/nmt-2018-0001
30.
EmigM.GeorgeT.ZhangJ. K.Soudagar-TurkeyM. (2021). The role of exercise in Parkinson’s disease. Journal of Geriatric Psychiatry and Neurology, 34(4), 321–330. https://doi.org/10.1177/08919887211018273
31.
FantiniV.BordoniM.ScocozzaF.ContiM.ScarianE.CarelliS.Di GiulioA. M.MarconiS.PansarasaO.AuricchioF. (2019). Bioink composition and printing parameters for 3D modeling neural tissue. Cells, 8(8), 830. https://doi.org/10.3390/cells8080830
32.
FassinaH. M.MujahedG. B. U.MinnitiG. (2023). 3D Bioprinting: From the functional restitution of organs and tissues to the modeling of chronic degenerative diseases. Peer Review, 5(18), 366–393. https://doi.org/10.53660/883.prw2509
33.
FerreiraJ. J.PoeweW.RascolO.StocchiF.AntoniniA.MoreiraJ.PereiraA.RochaJ.-F.Soares-da-SilvaP. (2022). Opicapone as an add-on to levodopa in patients with Parkinson’s disease without motor fluctuations: Rationale and design of the phase III, double-blind, randomised, placebo-controlled EPSILON trial. Neurology and Therapy, 11(3), 1409–1425. https://doi.org/10.1007/s40120-022-00371-7
34.
FlemingS. M.DavisA.SimonsE. (2022). Targeting alpha-synuclein via the immune system in Parkinson's disease: Current vaccine therapies. Neuropharmacology, 202, 108870. https://doi.org/10.1016/j.neuropharm.2021.108870
35.
FullardM. E.MorleyJ. F.DudaJ. E. (2017). Olfactory dysfunction as an early biomarker in Parkinson’s disease. Neuroscience Bulletin, 33(5), 515–525.https://doi.org/10.1007/s12264-017-0170-x
36.
GispertS.RicciardiF.KurzA.AzizovM.HoepkenH.-H.BeckerD.VoosW.LeunerK.MüllerW. E.KudinA. P. (2009). Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration. PLoS One, 4(6), e5777. https://doi.org/10.1371/journal.pone.0005777
37.
GlajchK. E.FlemingS. M.SurmeierD. J.OstenP. (2012). Sensorimotor assessment of the unilateral 6-hydroxydopamine mouse model of Parkinson's disease. Behavioural Brain Research, 230(2), 309–316. https://doi.org/10.1016/j.bbr.2011.12.007
38.
GöksuA. Y. (2024). A review article on the development of dopaminergic neurons and establishment of dopaminergic neuron–based in vitro models by using immortal cell lines or stem cells to study and treat Parkinson's disease. International Journal of Developmental Neuroscience, 84(8), 817–842. https://doi.org/10.1002/jdn.10383
39.
GongX.HuangM.ChenL. (2024). NRF1 Mitigates motor dysfunction and dopamine neuron degeneration in mice with Parkinson's disease by promoting GLRX m6A methylation through upregulation of METTL3 transcription. CNS Neuroscience & Therapeutics, 30(3), e14441. https://doi.org/10.1111/cns.14441
40.
Gonzalez-ReyesL. E.VerbitskyM.BlesaJ.Jackson-LewisV.ParedesD.TillackK.PhaniS.KramerE. R.PrzedborskiS.KottmannA. H. (2012). Sonic hedgehog maintains cellular and neurochemical homeostasis in the adult nigrostriatal circuit. Neuron, 75(2), 306–319. https://doi.org/10.1016/j.neuron.2012.05.018
41.
GoodC. H.HoffmanA. F.HofferB. J.CheferV. I.ShippenbergT. S.BäckmanC. M.LarssonN.-G.OlsonL.GellhaarS.GalterD. (2011). Impaired nigrostriatal function precedes behavioral deficits in a genetic mitochondrial model of Parkinson's disease. The FASEB Journal, 25(4), 1333. https://doi.org/10.1096/fj.10-173625
42.
GouldingS. R.LévesqueM.SullivanA. M.CollinsL. M.O’KeeffeG. W. (2021). Quinacrine and niclosamide promote neurite growth in midbrain dopaminergic neurons through the canonical BMP-smad pathway and protect against neurotoxin and α-Synuclein-Induced neurodegeneration. Molecular Neurobiology, 58(7), 3405–3416. https://doi.org/10.1007/s12035-021-02351-8
HafsteinsdóttirB.FarmanH.LagerströmN.ZetterbergH.AndersenO.NovakovaL.NellgårdB.RosénH.MalmeströmC.RosensteinI. (2024). Neurofilament light chain as a diagnostic and prognostic biomarker in Guillain–Barré syndrome. Journal of Neurology, 271(11), 7282–7293. https://doi.org/10.1007/s00415-024-12679-5
45.
Hargus, G., Cooper, O., Deleidi, M., Levy, A., Lee, K., Marlow, E., Yow, A., Soldner, F., Hockemeyer, D., Hallett, P. J., Osborn, T., Jaenisch, R., & Isacson, O. (2010). Differentiated Parkinson patient-derived induced pluripotent stem cells grow in the adult rodent brain and reduce motor asymmetry in Parkinsonian rats. Proceedings of the National Academy of Sciences, 107(36), 15921–15926. https://doi.org/10.1073/pnas.1010209107
46.
HarizM.BlomstedtP. (2022). Deep brain stimulation for Parkinson's disease. Journal of Internal Medicine, 292(5), 764–778. https://doi.org/10.1111/joim.13541
47.
HauserR. A.GiladiN.PoeweW.BrotchieJ.FriedmanH.OrenS.LitmanP. (2022). P2b001 (extended release pramipexole and rasagiline): A new treatment option in development for Parkinson’s disease. Advances in Therapy, 39(5), 1881–1894. https://doi.org/10.1007/s12325-022-02097-2
48.
HauserR. A.Torres-YaghiY.FisherS.BanisadrG. (2025). How to dose extended-release carbidopa-levodopa capsules (IPX203, CREXONT®) in patients with Parkinson’s disease. Clinical Parkinsonism & Related Disorders, 13, 100357. https://doi.org/10.1016/j.prdoa.2025.100357
49.
HenryE.LaiE. C.Hypokinesia and movement challenges in Parkinson’s disease. Neurology Care Line, 1(1), 1–2.
HsiehF.-Y.HsuS.-h. (2015). 3D Bioprinting: A new insight into the therapeutic strategy of neural tissue regeneration. Organogenesis, 11(4), 153–158. https://doi.org/10.1080/15476278.2015.1123360
52.
HuntJ.CoulsonE. J.RajnarayananR.OsterH.VidenovicA.RawashdehO. (2022). Sleep and circadian rhythms in Parkinson’s disease and preclinical models. Molecular Neurodegeneration, 17, 1–21. https://doi.org/10.1186/s13024-021-00504-w
53.
InvestigatorsP. S. G. Q. (2014). A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease no evidence of benefit. JAMA Neurology, 75(1), 543–552. https://doi.org/10.1001/jamaneurol.2014.131
54.
IsaacsonS. H.EspayA. J.PahwaR.AgarwalP.ShillH. A.HuiJ.DashtipourK.LewM.QinP.FormellaA. E. (2025). Continuous, subcutaneous apomorphine infusion for Parkinson disease motor fluctuations: Results from the phase 3, long-term, open-label United States InfusON study. Journal of Parkinson’s Disease, 15(2), 1877718X241310727. https://doi.org/10.1177/1877718X241310727
55.
JacksonA.ForsythC. B.ShaikhM.VoigtR. M.EngenP. A.RamirezV.KeshavarzianA. (2019). Diet in Parkinson's disease: Critical role for the microbiome. Frontiers in Neurology, 10, 1245. https://doi.org/10.3389/fneur.2019.01245
56.
Jimenez-ShahedJ. (2021). Device profile of the Percept PC deep brain stimulation system for the treatment of Parkinson’s disease and related disorders. Expert Review of Medical Devices, 18(4), 319–332. https://doi.org/10.1080/17434440.2021.1909471
KitadaT.PisaniA.KarouaniM.HaburcakM.MartellaG.TscherterA.PlataniaP.WuB.PothosE. N.ShenJ. (2009). Impaired dopamine release and synaptic plasticity in the striatum of Parkin−/− mice. Journal of Neurochemistry, 110(2), 613–621. https://doi.org/10.1111/j.1471-4159.2009.06152.x
60.
KitamuraY.KakimuraJ.-i.TaniguchiT. (2002). Antiparkinsonian drugs and their neuroprotective effects. Biological and Pharmaceutical Bulletin, 25(3), 284–290. https://doi.org/10.1248/bpb.25.284
61.
LeeD. J.DallapiazzaR. F.De VlooP.LozanoA. M. (2018). Current surgical treatments for Parkinson's disease and potential therapeutic targets. Neural Regeneration Research, 13(8), 1342–1345. https://doi.org/10.4103/1673-5374.235220
62.
LeeJ.-Y.Martin-BastidaA.Murueta-GoyenaA.GabilondoI.CuencaN.PicciniP.JeonB. (2022). Multimodal brain and retinal imaging of dopaminergic degeneration in Parkinson disease. Nature Reviews Neurology, 18(4), 203–220. https://doi.org/10.1038/s41582-022-00618-9
63.
LiS.LiuY.LuS.XuJ.LiuX.YangD.YangY.HouL.LiN. (2025). A crazy trio in Parkinson's disease: Metabolism alteration, α-synuclein aggregation, and oxidative stress. Molecular and Cellular Biochemistry, 480(1), 139–157. https://doi.org/10.1007/s11010-024-04985-3
64.
LozanoR.StevensL.ThompsonB. C.GilmoreK. J.GorkinR.,IIIStewartE. M.in het PanhuisM.Romero-OrtegaM.WallaceG. G. (2015). 3D Printing of layered brain-like structures using peptide modified gellan gum substrates. Biomaterials, 67, 264–273. https://doi.org/10.1016/j.biomaterials.2015.07.022
65.
MaJ.TangZ.WuY.ZhangJ.WuZ.HuangL.LiuS.WangY. (2024). Differences in blood and cerebrospinal fluid between Parkinson’s disease and related diseases. Cellular and Molecular Neurobiology, 45(1), 9. https://doi.org/10.1007/s10571-024-01523-z
66.
MahajanU. V.RavikumarV. K.KumarK. K.KuS.OjukwuD. I.KilbaneC.GhanouniP.RosenowJ. M.SteinS. C.HalpernC. H. (2021). Bilateral deep brain stimulation is the procedure to beat for advanced Parkinson disease: A meta-analytic, cost-effective threshold analysis for focused ultrasound. Neurosurgery, 88(3), 487–496. https://doi.org/10.1093/neuros/nyaa485
67.
MaitiP.MannaJ.DunbarG. L. (2017). Current understanding of the molecular mechanisms in Parkinson's disease: Targets for potential treatments. Translational Neurodegeneration, 6, 1–35. https://doi.org/10.1186/s40035-017-0099-z
68.
Martínez-MoralesP. L.ListeI. (2012). Stem cells as in vitro model of Parkinson′ s disease. Stem Cells International, 2012(1), 980941. https://doi.org/10.1155/2012/980941
McDonnellM. N.RischbiethB.SchammerT. T.SeaforthC.ShawA. J.PhillipsA. C. (2018). Lee Silverman voice treatment (LSVT)-BIG to improve motor function in people with Parkinson’s disease: A systematic review and meta-analysis. Clinical Rehabilitation, 32(5), 607–618.https://doi.org/10.1177/0269215517734385
71.
MeredithG. E.TotterdellS.PotashkinJ. A.SurmeierD. J. (2008). Modeling PD pathogenesis in mice: Advantages of a chronic MPTP protocol. Parkinsonism & Related Disorders, 14(Supplement 2 (S2)), S112–S115.https://doi.org/10.1016/j.parkreldis.2008.04.012
MischleyL. K.LauR. C.BennettR. D. (2017). Role of diet and nutritional supplements in Parkinson’s disease progression. Oxidative Medicine and Cellular Longevity, 2017(1), 6405278. https://doi.org/10.1155/2017/6405278
74.
MitturA.GuptaS.ModiN. B. (2017). Pharmacokinetics of Rytary®, an extended-release capsule formulation of carbidopa–levodopa. Clinical Pharmacokinetics, 56(9), 999–1014. https://doi.org/10.1007/s40262-017-0511-y
75.
Muleiro AlvarezM.Cano-HerreraG.Osorio MartínezM. F.Vega Gonzales-PortilloJ.MonroyG. R.Murguiondo PérezR.Torres-RíosJ. A.van TienhovenX. A.Garibaldi BernotE. M.Esparza SalazarF. (2024). A comprehensive approach to Parkinson’s disease: Addressing its molecular, clinical, and therapeutic aspects. International Journal of Molecular Sciences, 25(13), 7183. https://doi.org/10.3390/ijms25137183
76.
NaiaC. V.de Souza FariaG.de Lima FilhoF.DionísioA. C.OliveiraL. P.GuizardiM. P. P.de Castro AguiarM. F.dos SantosJ. C. C.StangherlinL. (2025). Sleep disturbances in Parkinson's disease: A scoping review. Brazilian Journal of Clinical Medicine Review, 3(1), bjcmr22. https://doi.org/10.52600/2965-0968.bjcmr.2025.3.1.bjcmr22
77.
NemadeD.SubramanianT.ShivkumarV. (2021). An update on medical and surgical treatments of Parkinson’s disease. Aging and Disease, 12(4), 1021. https://doi.org/10.14336/AD.2020.1225
78.
OlegárioR. L.FobbsJ. B.LopesB. S.StriniP. J. S. A.StriniP. J. S. A.de MeloL. M. A. B. (2018). Parkinson disease and its clinical manifestations. Revista de Medicina e Saúde de Brasília, 7(3), 11–403. https://doi.org/10.5216/revufg.v19.59178
79.
PaffM.LohA.SaricaC.LozanoA. M.FasanoA. (2020). Journal of movement disorders. Journal of Movement Disorders, 13(3), 185–198. https://doi.org/10.14802/jmd.20052
80.
PaganoG.BoessF. G.TaylorK. I.RicciB.MollenhauerB.PoeweW.BoulayA.Anzures-CabreraJ.VogtA.MarchesiM. (2021). A phase II study to evaluate the safety and efficacy of prasinezumab in early Parkinson's disease (PASADENA): Rationale, design, and baseline data. Frontiers in Neurology, 12, 705407. https://doi.org/10.14802/jmd.20052
Pan-MontojoF.AnichtchikO.DeningY.KnellsL.PurscheS.JungR.JacksonS.GilleG.SpillantiniM. G.ReichmannH. (2010). Progression of Parkinson’s disease pathology is reproduced by intragastric administration of rotenone in mice. Nature Precedings, 1–1. https://doi.org/10.1007/s40265-020-01307-x
83.
PanunggalB.YehT.-H.TsaoS.-P.PanC.-H.ShihW.-T.LinY.-T.FaradinaA.FangC.-L.HuangH.-Y.HuangS.-Y. (2025). Treadmill intervention attenuates motor deficit with 6-OHDA-induced Parkinson’s disease rat via changes in lipid profiles in brain and muscle. Aging (Albany NY), 17(1), 232. https://doi.org/10.18632/aging.206181
84.
Peña-ZelayetaL.Delgado-MinjaresK. M.Villegas-RojasM. M.León-ArciaK.Santiago-BalmasedaA.Andrade-GuerreroJ.Pérez-SeguraI.Ortega-RoblesE.Soto-RojasL. O.Arias-CarriónO. (2025). Redefining non-motor symptoms in Parkinson’s disease. Journal of Personalized Medicine, 15(5), 172. https://doi.org/10.18632/aging.206181
85.
PengS.LiuP.WangX.LiK. (2025). Global, regional and national burden of Parkinson’s disease in people over 55 years of age: A systematic analysis of the global burden of disease study, 1991–2021. BMC Neurology, 25(1), 178. https://doi.org/10.3390/jpm15050172
86.
PermadiN. G. A.MeidiaryA.LaksmidewiA. P.The low serum vitamin D levels as a risk factor for cognitive impairment in Parkinson’s disease: A literature review. https://doi.org/10.1186/s12883-025-04191-8
PoojaN.PahujaS.VeerK. (2021). Significance of MRI guided focused ultrasound thalamotomy for Parkinson’s disease: A review. Current Medical Imaging, 17(6), 714–719. https://doi.org/10.1111/j.1468-1331.2008.02056.x
90.
PorrasG.LiQ.BezardE. (2012). Modeling Parkinson’s disease in primates: The MPTP model. Cold Spring Harbor Perspectives in Medicine, 2(3), a009308. https://doi.org/10.2174/1573405616666201223142505
91.
PotjewydG.MoxonS.WangT.DomingosM.HooperN. M. (2018). Tissue engineering 3D neurovascular units: A biomaterials and bioprinting perspective. Trends in Biotechnology, 36(4), 457–472. https://doi.org/10.1101/cshperspect.a009308
QiuB.BesslerN.FiglerK.BuchholzM. B.RiosA. C.MaldaJ.LevatoR.CaiazzoM. (2020). Bioprinting neural systems to model Central Nervous System diseases. Advanced Functional Materials, 30(44), 1910250. https://doi.org/10.3390/antiox9101007
94.
RadderD. L.SturkenboomI. H.van NimwegenM.KeusS. H.BloemB. R.de VriesN. M. (2017). Physical therapy and occupational therapy in Parkinson's disease. International Journal of Neuroscience, 127(10), 930–943. https://doi.org/10.1002/adfm.201910250
95.
RajmohanR.WenA.HenchcliffeC. (2025). Recent advances in fluid and tissue-based biomarkers for use in Parkinson’s disease. Expert Review of Neurotherapeutics, 25(7), 951–958. https://doi.org/10.1080/00207454.2016.1275617
96.
RansmayrG. (2011). Physical, occupational, speech and swallowing therapies and physical exercise in Parkinson’s disease. Journal of Neural Transmission, 118(5), 773–781.https://doi.org/10.1080/14737175.2025.2515068
97.
RätyV.KuusimäkiT.MajuriJ.VahlbergT.GardbergM.NoponenT.SeppänenM.TolppanenA.-M.KaasinenV. (2025). Stability and accuracy of a diagnosis of Parkinson disease over 10 years. Neurology, 104(9), e213499. https://doi.org/10.1007/s00702-011-0622-9
98.
RecasensA.DehayB.BovéJ.Carballo-CarbajalI.DoveroS.Pérez-VillalbaA.FernagutP. O.BlesaJ.ParentA.PerierC. (2014). Lewy body extracts from Parkinson disease brains trigger α-synuclein pathology and neurodegeneration in mice and monkeys. Annals of Neurology, 75(3), 351–362. https://doi.org/10.1212/WNL.0000000000213499
99.
ReynosoA.TorricelliR.JacobsB. M.ShiJ.AslibekyanS.Norcliffe-KaufmannL.NoyceA. J.HeilbronK. (2024). Gene–environment interactions for Parkinson's disease. Annals of Neurology, 95(4), 677–687. https://doi.org/10.1002/ana.24066
100.
RidgelA. L.VitekJ. L.AlbertsJ. L. (2009). Forced, not voluntary, exercise improves motor function in Parkinson's disease patients. Neurorehabilitation and Neural Repair, 23(6), 600–608. https://doi.org/10.1002/ana.26852
101.
RissardoJ. P.Fornari CapraraA. L. (2025). Alpha-Synuclein seed amplification assays in Parkinson’s disease: A systematic review and network meta-analysis. Clinics and Practice, 15(6), 107. https://doi.org/10.1177/1545968308328726
102.
RuschC.FlanaganR.SuhH.SubramanianI. (2023). To restrict or not to restrict? Practical considerations for optimizing dietary protein interactions on Levodopa absorption in Parkinson’s disease. npj Parkinson’s Disease, 9(1), 98. https://doi.org/10.3390/clinpract15060107
103.
Rydning, S. L., Backe, P. H., Sousa, M. M. L., Iqbal, Z., Øye, A. M., Sheng, Y., Yang, M., Lin, X., Slupphaug, G., Nordenmark, T. H., Vigeland, M. D., Bjørås, M., Tallaksen, C. M., & Selmer, K. K. (2016). Novel UCHL1 mutations reveal new insights into ubiquitin processing. Human Molecular Genetics, ddw391. https://doi.org/10.1093/hmg/ddw391
104.
SalamonA.ZádoriD.SzpisjakL.KlivényiP.VécseiL. (2020). Neuroprotection in Parkinson’s disease: Facts and hopes. Journal of Neural Transmission, 127(5), 821–829.https://doi.org/10.1038/s41531-023-00541-w
105.
SaleemS.MilesA.AllenJ. (2025). Effects of LSVT LOUD and EMST in individuals with Parkinson’s disease: A two arm non-randomized clinical trial. International Journal of Speech-Language Pathology, 28(1), 1–15.https://doi.org/10.1007/s00702-019-02115-8
106.
SantoroM.FaddaP.KlephanK. J.HullC.TeismannP.PlattB.RiedelG. (2023). Neurochemical, histological, and behavioral profiling of the acute, sub-acute, and chronic MPTP mouse model of parkinson's disease. Journal of Neurochemistry, 164(2), 121–142. https://doi.org/10.1080/17549507.2025.2494652
107.
SariD. M.DjuwitaR. (2025). Exploring the lived experiences of hope and uncertainty in patients undergoing stem cell therapy for neurodegenerative diseases. Journal of Regenerative Medicine and Molecular Innovation, 1(11), 476–485. https://doi.org/10.1111/jnc.15699
108.
SeiblerP.GraziottoJ.JeongH.SimunovicF.KleinC.KraincD. (2011). Mitochondrial Parkin recruitment is impaired in neurons derived from mutant PINK1 induced pluripotent stem cells. Journal of Neuroscience, 31(16), 5970–5976. https://doi.org/10.1523/JNEUROSCI.4441-10.2011
SharmaR.BhateL.AgrawalY.AspatwarA. (2025). Advanced nutraceutical approaches to Parkinson's disease: Bridging nutrition and neuroprotection. Nutritional Neuroscience, 28(9), 1–17. https://doi.org/10.1080/1028415x.2025.2469170
112.
SharmaV. D.PatelM.MiocinovicS. (2020). Surgical treatment of Parkinson's disease: Devices and lesion approaches. Neurotherapeutics, 17(4), 1525–1538. https://doi.org/10.1007/s13311-020-00939-x
113.
Shikama DiasE. H.Duarte FerreiraA.Zamberlan FerreiraN.Augusto SiscouttoR. (2024). Parkinsonvr: A realidade virtual como auxiliadora em tratamentos fisioterapêuticos para pacientes com doença de Parkinson. Colloquium Exactarum. https://doi.org/10.1007/s13311-020-00939-x
SohD.LozanoA. M.FasanoA. (2019). Hybrid deep brain stimulation system to manage stimulation-induced side effects in Essential Tremor patients. Parkinsonism & Related Disorders, 58, 85–86. https://doi.org/10.1016/S1471-4914(03)00117-5
116.
Soldner, F., Laganière, J., Cheng, A. W., Hockemeyer, D., Gao, Q., Alagappan, R., Khurana, V., Golbe, L. I., Myers, R. H., Lindquist, S., & Zhang, L. (2011). Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations. Cell, 146(2), 318–331.
117.
Soldner, F., Hockemeyer, D., Beard, C., Gao, Q., Bell, G. W., Cook, E. G., Hargus, G., Blak, A., Cooper, O., Mitalipova, M., Isacson, O., & Jaenisch, R. (2009).Parkinson's disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell, 136(5), 964–977. https://doi.org/10.1016/j.cell.2009.02.013
118.
StokerT. B.GreenlandJ. C. (2018). Parkinson’s disease: pathogenesis and clinical aspects [internet].
119.
TaiM. D. S.Gamiz-ArcoG.MartinezA. (2024). Dopamine synthesis and transport: Current and novel therapeutics for parkinsonisms. Biochemical Society Transactions, 52(3), 1275–1291. https://doi.org/10.1097/CM9.0000000000003745
120.
Taipa, R., Pereira, C., Reis, I., Alonso, I., Bastos-Lima, A., Melo-Pires, M., & Magalhães, M. (2016). DJ-1 linked parkinsonism (PARK7) is associated with Lewy body pathology. Brain, 139(6), 1680–1687.
121.
TallP.QamarM.BatzuL.LetaV.Falup-PecurariuC.Ray ChaudhuriK. (2023). Non-oral continuous drug delivery based therapies and sleep dysfunction in Parkinson’s disease. Journal of Neural Transmission, 130(11), 1443–1449. https://doi.org/10.1042/BST20231061
122.
Taylor, T. N., Caudle, W. M., & Miller, G. W. (2011). VMAT2-deficient mice display nigral and extranigral pathology and motor and nonmotor symptoms of Parkinson′ s disease. Parkinson’s Disease, 2011(1), 124165. https://doi.org/10.4061/2011/124165
123.
ThrashB.ThiruchelvanK.AhujaM.SuppiramaniamV.DhanasekaranM. (2009). Methamphetamine-induced neurotoxicity: The road to Parkinson’s disease. Pharmacological Reports, 61(6), 966–977. https://doi.org/10.1007/s00702-023-02640-7
124.
TimpkaJ.NituB.DatievaV.OdinP.AntoniniA. (2017). Device-aided treatment strategies in advanced Parkinson's disease. International Review of Neurobiology, 132, 453–474. https://doi.org/10.1016/S1734-1140(09)70158-6
125.
TolosaE.GarridoA.ScholzS. W.PoeweW. (2021). Challenges in the diagnosis of Parkinson's disease. The Lancet Neurology, 20(5), 385–397. https://doi.org/10.1016/bs.irn.2017.03.001
126.
TongS.WangR.LiH.TongZ.GengD.ZhangX.RenC. (2025). Executive dysfunction in Parkinson's disease: From neurochemistry to circuits, genetics and neuroimaging. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 137, 111272. https://doi.org/10.1016/S1474-4422(21)00030-2
127.
TsikaE.KannanM.FooC. S.-Y.DikemanD.GlauserL.GellhaarS.GalterD.KnottG. W.DawsonT. M.DawsonV. L. (2014). Conditional expression of Parkinson's disease-related R1441C LRRK2 in midbrain dopaminergic neurons of mice causes nuclear abnormalities without neurodegeneration. Neurobiology of Disease, 71, 345–358. https://doi.org/10.1016/j.pnpbp.2025.111272
128.
TumpaJ. J.HayderQ. U. A.MaisaN. S.IslamM. N. (2025). Peripheral–central immune interactions in Parkinson’s disease: Insights into innate and adaptive immunity. Frontiers in Molecular Neuroscience, 18, 1682006. https://doi.org/10.1016/j.nbd.2014.08.027
129.
UmemuraA. (2021). Surgical procedure for subthalamic nucleus deep brain stimulation (STN-DBS). No Shinkei Geka. Neurological Surgery, 49(4), 787–798. https://doi.org/10.1042/BCJ20240621
130.
WalA.WalP.VigH.SamadA.KhandaiM.TyagiS. (2024). A systematic review of Various in-vivo screening models as well as the mechanisms involved in Parkinson's disease screening procedures. Current Reviews in Clinical and Experimental Pharmacology Formerly Current Clinical Pharmacology, 19(2), 124–136. https://doi.org/10.2174/2772432817666220707101550
131.
Wu, D., & Wu, D. (2020). Dopamine transporter scan (DaTscan). In Clinical nuclear medicine neuroimaging: An instructional casebook (pp. 203-229). Springer, Cham.https://doi.org/10.1016/j.arr.2024.102544
132.
XicoyH.WieringaB.MartensG. J. (2017). The SH-SY5Y cell line in Parkinson’s disease research: A systematic review. Molecular Neurodegeneration, 12, 1–11. https://doi.org/10.1007/978-3-030-40893-0_6
133.
YuH. J.ThijssenE.van BrummelenE.van Der PlasJ. L.RadanovicI.MoerlandM.HsiehE.GroeneveldG. J.DodartJ. C. (2022). A randomized first-in-human study with UB-312, a UBITh® α-Synuclein peptide vaccine. Movement Disorders, 37(7), 1416–1424. https://doi.org/10.1186/s13024-017-0149-0
134.
ZhangL.HeY.LeiK.FangZ.LiQ.SuJ.NieZ.XuY.JinL. (2021). Gene expression profiling of early Parkinson’s disease patient reveals redox homeostasis. Neuroscience Letters, 753, 135893. https://doi.org/10.1002/mds.29016
135.
ZhangL.LeW.XieW.DaniJ. A. (2012). Age-related changes in dopamine signaling in Nurr1 deficient mice as a model of Parkinson's disease. Neurobiology of Aging, 33(5), 1001.e1007–1001.e1016. https://doi.org/10.1016/j.neulet.2021.135893
ZibettiM.MerolaA.ArtusiC.RizziL.AngrisanoS.ReggioD.De AngelisC.RizzoneM.LopianoL. (2014). Levodopa/carbidopa intestinal gel infusion in advanced Parkinson's disease: A 7-year experience. European Journal of Neurology, 21(2), 312–318. https://doi.org/10.1111/cns.14515
