Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Parkinson disease therapy: current strategies and future research priorities

Nature Reviews Neurology volume 20, pages 695–707 (2024) Cite this article

Save article
View saved research

Subjects

Abstract

Parkinson disease (PD) is the fastest growing neurological disorder globally and poses substantial management challenges owing to progressive disability, emergence of levodopa-resistant symptoms, and treatment-related complications. In this Review, we examine the current state of research into PD therapies and outline future priorities for advancing our understanding and treatment of the disease. We identify two main research priorities for the coming years: first, slowing the progression of the disease through the integration of sensitive biomarkers and targeted biological therapies, and second, enhancing existing symptomatic treatments, encompassing surgical and infusion therapies, with the goal of postponing complications and improving long-term patient management. The path towards disease modification is impeded by the multifaceted pathophysiology and diverse mechanisms underlying PD. Ongoing studies are directed at α-synuclein aggregation, complemented by efforts to address specific pathways associated with the less common genetic forms of the disease. The success of these efforts relies on establishing robust end points, incorporating technology, and identifying reliable biomarkers for early diagnosis and continuous monitoring of disease progression. In the context of symptomatic treatment, the focus should shift towards refining existing approaches and fostering the development of novel therapeutic strategies that target levodopa-resistant symptoms and clinical manifestations that substantially impair quality of life.

Key points

  • Parkinson disease (PD) is the fastest growing neurological disorder globally but, currently, no therapeutic intervention can modify disease progression and treatment is still based on levodopa (either alone or in combination with dopamine agonists or monoamine oxidase B or catechol-O-methyltransferase inhibitors) and device-aided therapies.

  • Disease-modifying therapies targeting α-synuclein that are under investigation include active and passive immunization and small molecules that can inhibit protein aggregation.

  • Studies of compounds that can enhance glucocerebrosidase activity, reduce leucine-rich repeat kinase 2 activity or prevent inflammation are ongoing or starting.

  • Medications that can alleviate symptomatic manifestations, including new levodopa formulations, dopamine agonists with different dopamine receptor stimulation profiles or modes of administration, and gene and cell transplantation therapies, are under investigation.

  • Early detection of PD is crucial, and educational programmes aimed at the general population could aid this effort by increasing awareness of the early symptoms.

  • Biomarker discovery and validation initially require considerable financial and human resources, but the development of safe, easy-to-perform biomarker assays — for example, using blood samples or skin biopsies — would allow screening of large cohorts in a cost-effective manner.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Pathophysiological mechanisms underlying Parkinson disease and possible disease-modifying therapies.
Image

Similar content being viewed by others

References

  1. GBD 2015 Neurological Disorders Collaborator Group. Global, regional, and national burden of neurological disorders during 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Neurol. 16, 877–897 (2017).

    Article  Google Scholar 

  2. Dorsey, E. R., Sherer, T., Okun, M. S. & Bloem, B. R. The emerging evidence of the Parkinson pandemic. J. Parkinsons Dis. 8, S3–S8 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Uebelacker, L. A., Epstein-Lubow, G., Lewis, T., Broughton, M. K. & Friedman, J. H. A survey of Parkinson’s disease patients: most bothersome symptoms and coping preferences. J. Parkinsons Dis. 4, 717–723 (2014).

    Article  PubMed  Google Scholar 

  4. Antonini, A., Emmi, A. & Campagnolo, M. Beyond the dopaminergic system: lessons learned from levodopa resistant symptoms in Parkinson’s disease. Mov. Disord. Clin. Pract. 10, S50–S55 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Vijayakumar, D. & Jankovic, J. Drug-induced dyskinesia, part 1: treatment of levodopa-induced dyskinesia. Drugs 76, 759–777 (2016).

    Article  CAS  PubMed  Google Scholar 

  6. Aquino, C. C. & Fox, S. H. Clinical spectrum of levodopa-induced complications. Mov. Disord. 30, 80–89 (2015).

    Article  CAS  PubMed  Google Scholar 

  7. Antonini, A., Moro, E., Godeiro, C. & Reichmann, H. Medical and surgical management of advanced Parkinson’s disease. Mov. Disord. 33, 900–908 (2018).

    Article  PubMed  Google Scholar 

  8. Ayers, J. I. et al. Different α-synuclein prion strains cause dementia with Lewy bodies and multiple system atrophy. Proc. Natl Acad. Sci. USA 119, e2113489119 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. So, R. W. L. & Watts, J. C. α-Synuclein conformational strains as drivers of phenotypic heterogeneity in neurodegenerative diseases. J. Mol. Biol. 435, 168011 (2023).

    Article  CAS  PubMed  Google Scholar 

  10. Calabresi, P. et al. Alpha-synuclein in Parkinson’s disease and other synucleinopathies: from overt neurodegeneration back to early synaptic dysfunction. Cell Death Dis. 14, 176 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Pringsheim, T. et al. Dopaminergic therapy for motor symptoms in early Parkinson disease practice guideline summary. Neurology 97, 942–957 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Stathis, P., Konitsiotis, S. & Antonini, A. Dopamine agonists early monotherapy for the delay of development of levodopa-induced dyskinesias. Expert Rev. Neurother. 15, 207–213 (2015).

    Article  CAS  PubMed  Google Scholar 

  13. Clarke, C. et al. 15-Year effects of initiating treatment for Parkinson’s disease with dopamine agonists or monoamine oxidase B inhibitors compared with levodopa: final results of PD MED early disease randomisation [abstract]. Mov. Disord. 38 (Suppl. 1), Abstract 41 (2023).

    Google Scholar 

  14. Olanow, C. W., Poewe, W., Rascol, O. & Stocchi, F. On-demand therapy for OFF episodes in Parkinson’s disease. Mov. Disord. 36, 2244–2253 (2021).

    Article  PubMed  Google Scholar 

  15. Olanow, C. W., Obeso, J. A. & Stocchi, F. Continuous dopamine-receptor treatment of Parkinson’s disease: scientific rationale and clinical implications. Lancet Neurol. 5, 677–687 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Antonini, A. et al. Comparative effectiveness of device-aided therapies on quality of life and off-time in advanced Parkinson’s disease: a systematic review and Bayesian network meta-analysis. CNS Drugs 36, 1269–1283 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Demailly, A., Moreau, C. & Devos, D. Effectiveness of continuous dopaminergic therapies in Parkinson’s disease: a review of L-DOPA pharmacokinetics/pharmacodynamics. J. Parkinsons Dis. 14, 925–939 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Leta, V. et al. Gastrointestinal barriers to levodopa transport and absorption in Parkinson’s disease. Eur. J. Neurol. 30, 1465–1480 (2023).

    Article  PubMed  Google Scholar 

  19. Stocchi, F., Jenner, P. & Obeso, J. A. When do levodopa motor fluctuations first appear in Parkinson’s disease? Eur. Neurol. 63, 257–266 (2010).

    Article  CAS  PubMed  Google Scholar 

  20. Cenci, M. A. Presynaptic mechanisms of l-DOPA-induced dyskinesia: the findings, the debate, and the therapeutic implications. Front. Neurol. 5, 242 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Calabresi, P., Filippo, M. D., Ghiglieri, V., Tambasco, N. & Picconi, B. Levodopa-induced dyskinesias in patients with Parkinson’s disease: filling the bench-to-bedside gap. Lancet Neurol. 9, 1106–1117 (2010).

    Article  CAS  PubMed  Google Scholar 

  22. Abbruzzese, G., Barone, P., Lopiano, L. & Stocchi, F. The current evidence for the use of safinamide for the treatment of Parkinson’s disease. Drug Des. Devel. Ther. 15, 2507–2517 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Ferreira, J. J. et al. Effect of opicapone on levodopa pharmacokinetics in patients with fluctuating Parkinson’s disease. Mov. Disord. 37, 2272–2283 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Rocha, J. F. et al. The safety/tolerability of opicapone when used early in Parkinson’s disease patients with levodopa-induced motor fluctuations: a post-hoc analysis of BIPARK-I and II. Front. Neurol. 13, 994114 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Schuepbach, W. M. M. et al. Neurostimulation for Parkinson’s disease with early motor complications. N. Engl. J. Med. 368, 610–622 (2013).

    Article  CAS  PubMed  Google Scholar 

  26. Ko, T. H. et al. Magnetic resonance-guided focused ultrasound surgery for Parkinson’s disease: a mini-review and comparison between deep brain stimulation. Parkinsonism Relat. Disord. 111, 105431 (2023).

    Article  PubMed  Google Scholar 

  27. Coelho, M. & Ferreira, J. In: Movement Disorders Curricula (eds Falup-Pecurariu, C., Ferreira, J., Martinez-Martin, P. & Chaudhuri, K. R.) 129–137 (Springer, 2017).

  28. Garon, M. et al. Quantification of brain β-amyloid load in Parkinson’s disease with mild cognitive impairment: a PET/MRI study. Front. Neurol. 12, 760518 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  29. McFarthing, K. et al. Parkinson’s disease drug therapies in the clinical trial pipeline: 2023 update. J. Parkinsons Dis. 13, 427–439 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hauser, R. A. et al. IPX203 vs immediate-release carbidopa-levodopa for the treatment of motor fluctuations in Parkinson disease: the RISE-PD randomized clinical trial. JAMA Neurol. 80, 1062–1069 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Soileau, M. J. et al. Safety and efficacy of continuous subcutaneous foslevodopa-foscarbidopa in patients with advanced Parkinson’s disease: a randomised, double-blind, active-controlled, phase 3 trial. Lancet Neurol. 21, 1099–1109 (2022).

    Article  CAS  PubMed  Google Scholar 

  32. Espay, A. J. et al. Safety and efficacy of continuous subcutaneous levodopa-carbidopa infusion (ND0612) for Parkinson’s disease with motor fluctuations (BouNDless): a phase 3, randomised, double-blind, double-dummy, multicentre trial. Lancet Neurol. 23, 465–476 (2024).

    Article  CAS  PubMed  Google Scholar 

  33. Olanow, C. W. et al. Continuous versus intermittent oral administration of levodopa in Parkinson’s disease patients with motor fluctuations: a pharmacokinetics, safety, and efficacy study. Mov. Disord. 34, 425–429 (2019).

    Article  Google Scholar 

  34. Olanow, C. W. et al. Continuous levodopa delivery with an intraoral micropump system: an open-label pharmacokinetics and clinical study. Mov. Disord. 39, 945–954 (2024).

    Article  CAS  PubMed  Google Scholar 

  35. Olanow, C. W., Standaert, D. G., Kieburtz, K., Viegas, T. X. & Moreadith, R. Once‐weekly subcutaneous delivery of polymer‐linked rotigotine (SER‐214) provides continuous plasma levels in Parkinson’s disease patients. Mov. Disord. 35, 1055–1061 (2020).

    Article  CAS  PubMed  Google Scholar 

  36. Riesenberg, R., Werth, J., Zhang, Y., Duvvuri, S. & Gray, D. PF-06649751 efficacy and safety in early Parkinson’s disease: a randomized, placebo-controlled trial. Ther. Adv. Neurol. Disord. 13, 175628642091129 (2020).

    Article  Google Scholar 

  37. Antonini, A. et al. Results from IRL790C005 — a randomized, double-blind, placebo-controlled phase IIb study evaluating the efficacy of mesdopetam on daily on-time without troublesome dyskinesia in patients with Parkinson’s disease [abstract]. Mov. Disord. 38 (Suppl. 1), Abstract 22 (2023).

    Google Scholar 

  38. Heiss, J. D. et al. Trial of magnetic resonance-guided putaminal gene therapy for advanced Parkinson’s disease. Mov. Disord. 34, 1073–1078 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bayer Global. AskBio phase Ib trial of AB-1005 gene therapy in patients with Parkinson’s disease meets primary endpoint. https://www.bayer.com/en/ca/askbio-phase-ib-trial-of-ab-1005-gene-therapy-in-patients-with-parkinsons-disease-meets-primary (2024).

  40. Henchcliffe, C. et al. Motor and non-motor outcomes of bemdaneprocel in people with Parkinson’s disease: results up to 24 months from a phase 1 study [abstract]. Mov. Disord. 39 (Suppl. 1), Abstract 960 (2024).

    Google Scholar 

  41. Kaufmann, H. et al. Safety and efficacy of ampreloxetine in symptomatic neurogenic orthostatic hypotension: a phase 2 trial. Clin. Auton. Res. 31, 699–711 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Hoxhaj, P. et al. Ampreloxetine versus droxidopa in neurogenic orthostatic hypotension: a comparative review. Cureus 15, e38907 (2023).

    PubMed  PubMed Central  Google Scholar 

  43. Stocchi, F. et al. Early DEtection of wEaring off in Parkinson disease: the DEEP study. Parkinsonism Relat. Disord. 20, 204–211 (2014).

    Article  CAS  PubMed  Google Scholar 

  44. Santos García, D. et al. Vortioxetine improves depressive symptoms and cognition in Parkinson’s disease patients with major depression: an open-label prospective study. Brain Sci. 12, 1466 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  45. BioSpace. CuraSen Therapeutics to present phase 2 data showing rapid-onset cognition and mood benefit with CST-103/CST-107 (clenbuterol/nadolol) in Parkinson’s Disease at the Alzheimer’s Disease and Parkinson’s Disease (AD/PD’23) Conference. https://www.biospace.com/article/releases/curasen-therapeutics-to-present-phase-2-data-showing-rapid-onset-cognition-and-mood-benefit-with-cst-103-cst-107-clenbuterol-nadolol-in-parkinson-s-disease-at-the-alzheimer-s-disease-and-parkinson-s-disease-ad-pd-23-conference/ (2023).

  46. Mullin, S. et al. Ambroxol for the treatment of patients with Parkinson disease with and without glucocerebrosidase gene mutations. JAMA Neurol. 77, 427–434 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Abdel-Magid, A. F. LRRK2 kinase inhibitors as possible therapy for Parkinson’s disease and other neurodegenerative disorders. ACS Med. Chem. Lett. 10, 846–847 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Del Tredici, K. & Braak, H. Review: sporadic Parkinson’s disease: development and distribution of α-synuclein pathology. Neuropathol. Appl. Neurobiol. 42, 33–50 (2016).

    Article  PubMed  Google Scholar 

  49. Wang, W. et al. A soluble α-synuclein construct forms a dynamic tetramer. Proc. Natl Acad. Sci. USA 108, 17797–17802 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Bartels, T., Choi, J. G. & Selkoe, D. J. α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature 477, 107–110 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Gould, N. et al. Evidence of native α-synuclein conformers in the human Brain. J. Biol. Chem. 289, 7929–7934 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Espay, A. J. & McFarthing, K. Alpha-synuclein and the Parkinson’s disease drug pipeline. Parkinsonism Relat. Disord. 111, 105432 (2023).

    Article  PubMed  Google Scholar 

  53. Bergström, A. L., Kallunki, P. & Fog, K. Development of passive immunotherapies for synucleinopathies. Mov. Disord. 31, 203–213 (2016).

    Article  PubMed  Google Scholar 

  54. Pagano, G. et al. Trial of prasinezumab in early-stage Parkinson’s disease. N. Engl. J. Med. 387, 421–432 (2022).

    Article  CAS  PubMed  Google Scholar 

  55. Lang, A. E. et al. Trial of cinpanemab in early Parkinson’s disease. N. Engl. J. Med. 387, 408–420 (2022).

    Article  CAS  PubMed  Google Scholar 

  56. Pagano, G. et al. Prasinezumab slows motor progression in rapidly progressing early-stage Parkinson’s disease. Nat. Med. 30, 1096–1103 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Price, D. L. et al. The small molecule alpha-synuclein misfolding inhibitor, NPT200-11, produces multiple benefits in an animal model of Parkinson’s disease. Sci. Rep. 8, 16165 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Wrasidlo, W. et al. A de novo compound targeting α-synuclein improves deficits in models of Parkinson’s disease. Brain 139, 3217–3236 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Smit, J. W. et al. Phase 1/1b studies of UCB0599, an oral inhibitor of α‐synuclein misfolding, including a randomized study in Parkinson’s disease. Mov. Disord. 37, 2045–2056 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Fang, C. et al. Buntanetap, a novel translational inhibitor of multiple neurotoxic proteins, proves to be safe and promising in both Alzheimer’s and Parkinson’s patients. J. Prev. Alzheimers Dis. 10, 25–33 (2023).

    CAS  PubMed  Google Scholar 

  61. Walsh, R. R. et al. Plasma and cerebrospinal fluid pharmacokinetics of vodobatinib, a neuroprotective c-Abl tyrosine kinase inhibitor for the treatment of Parkinson’s disease. Parkinsonism Relat. Disord. 108, 105281 (2023).

    Article  CAS  PubMed  Google Scholar 

  62. Dzamko, N. et al. Toll-like receptor 2 is increased in neurons in Parkinson’s disease brain and may contribute to alpha-synuclein pathology. Acta Neuropathol. 133, 303–319 (2017).

    Article  CAS  PubMed  Google Scholar 

  63. Cheng, Y. et al. α-Synuclein induces prodromal symptoms of Parkinson’s disease via activating TLR2/MyD88/NF-κB pathway in Schwann cells of vagus nerve in a rat model. J. Neuroinflammation 20, 36 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Reilly, M. et al. Randomized, double-blind, placebo-controlled, dose-escalating phase I, healthy subjects study of intravenous OPN-305, a humanized anti-TLR2 antibody. Clin. Pharmacol. Ther. 94, 593–600 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Wagner, J. et al. Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson’s disease. Acta Neuropathol. 125, 795–813 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Matthes, D., Gapsys, V., Griesinger, C. & de Groot, B. L. Resolving the atomistic modes of anle138b inhibitory action on peptide oligomer formation. ACS Chem. Neurosci. 8, 2791–2808 (2017).

    Article  CAS  PubMed  Google Scholar 

  67. Jewell, S., Herath, A. M. & Gordon, R. Inflammasome activation in Parkinson’s disease. J. Parkinsons Dis. 12, S113–S128 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. El Otmani, H., Daghi, M., Tahiri Jouti, N. & Lesage, S. An overview of the worldwide distribution of LRRK2 mutations in Parkinson’s disease. Neurodegener. Dis. Manag. 13, 335–350 (2023).

    Article  CAS  PubMed  Google Scholar 

  69. Smith, W. W. et al. Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nat. Neurosci. 9, 1231–1233 (2006).

    Article  CAS  PubMed  Google Scholar 

  70. Jennings, D. et al. Preclinical and clinical evaluation of the LRRK2 inhibitor DNL201 for Parkinson’s disease. Sci. Transl. Med. 14, eabj2658 (2022).

    Article  CAS  PubMed  Google Scholar 

  71. Walton, R. L. et al. Role of GBA variants in Lewy body disease neuropathology. Acta Neuropathol. 147, 54 (2024).

    Article  CAS  PubMed  Google Scholar 

  72. Chen, S. D., Chuang, Y. C., Lin, T. K. & Yang, J. L. Alternative role of glucagon-like peptide-1 receptor agonists in neurodegenerative diseases. Eur. J. Pharmacol. 938, 175439 (2023).

    Article  CAS  PubMed  Google Scholar 

  73. Olanow, C. W. et al. Factors predictive of the development of Levodopa-induced dyskinesia and wearing-off in Parkinson’s disease. Mov. Disord. 28, 1064–1071 (2013).

    Article  CAS  Google Scholar 

  74. Hauser, R. A. et al. Ten-year follow-up of Parkinson’s disease patients randomized to initial therapy with ropinirole or levodopa. Mov. Disord. 22, 2409–2417 (2007).

    Article  PubMed  Google Scholar 

  75. Olanow, C. W. The role of dopamine agonists in the treatment of early Parkinson’s disease. Neurology 58, S33–S41 (2002).

    Article  CAS  PubMed  Google Scholar 

  76. Stocchi, F., Fossati, B. & Torti, M. Safety considerations when using non-ergot dopamine agonists to treat Parkinson’s disease. Expert Opin. Drug Saf. 19, 1155–1172 (2020).

    Article  CAS  PubMed  Google Scholar 

  77. Bezard, E. et al. Rationale and development of tavapadon, a D1/D5-selective partial dopamine agonist for the treatment of Parkinson’s disease. CNS Neurol. Disord. Drug Targets 23, 476–487 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Stocchi, F. et al. Initiating levodopa/carbidopa therapy with and without entacapone in early Parkinson disease: the STRIDE-PD study. Ann. Neurol. 68, 18–27 (2010).

    Article  CAS  PubMed  Google Scholar 

  79. Rascol, O., Fabbri, M. & Poewe, W. Amantadine in the treatment of Parkinson’s disease and other movement disorders. Lancet Neurol. 20, 1048–1056 (2021).

    Article  CAS  PubMed  Google Scholar 

  80. Wu, W., Lu, X., Zhang, L. & Hong, D. Effectiveness and safety of different catechol-o-methyl transferase inhibitors for patients with Parkinson’s disease: systematic review and network meta-analysis. Clin. Neurol. Neurosurg. 239, 108189 (2024).

    Article  PubMed  Google Scholar 

  81. Hauser, R. A. et al. Efficacy of istradefylline, an adenosine A2A receptor antagonist, as adjunctive therapy to levodopa in Parkinson’s disease: a pooled analysis of 8 phase 2b/3 trials. J. Parkinsons Dis. 11, 1663–1675 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Lees, A. et al. Optimizing levodopa therapy, when and how? Perspectives on the importance of delivery and the potential for an early combination approach. Expert Rev. Neurother. 23, 15–24 (2023).

    Article  CAS  PubMed  Google Scholar 

  83. Gonzalez-Latapi, P., Bhowmick, S. S., Saranza, G. & Fox, S. H. Non-dopaminergic treatments for motor control in Parkinson’s disease: an update. CNS Drugs 34, 1025–1044 (2020).

    Article  CAS  PubMed  Google Scholar 

  84. Marceglia, S. et al. Deep brain stimulation: is it time to change gears by closing the loop? J. Neural Eng. 18, 061001 (2021).

    Article  Google Scholar 

  85. Schnitzler, A. et al. Directional deep brain stimulation for Parkinson’s disease: results of an international crossover study with randomized, double-blind primary endpoint. Neuromodulation 25, 817–828 (2022).

    Article  PubMed  Google Scholar 

  86. Neumann, W., Gilron, R., Little, S. & Tinkhauser, G. Adaptive deep brain stimulation: from experimental evidence toward practical implementation. Mov. Disord. 38, 937–948 (2023).

    Article  PubMed  Google Scholar 

  87. Pozzi, N. G. et al. Distinctive neuronal firing patterns in subterritories of the subthalamic nucleus. Clin. Neurophysiol. 127, 3387–3393 (2016).

    Article  PubMed  Google Scholar 

  88. Daniels, C. et al. Combined subthalamic and nucleus basalis of Meynert deep brain stimulation for Parkinson’s disease with dementia (DEMPARK-DBS): protocol of a randomized, sham-controlled trial. Neurol. Res. Pract. 2, 41 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Bega, D. et al. Clinical utility of DaTscan in patients with suspected Parkinsonian syndrome: a systematic review and meta-analysis. NPJ Parkinsons Dis. 7, 43 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Torti, M. et al. Effect of family history, occupation and diet on the risk of Parkinson disease: a case-control study. PLoS One 15, e0243612 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Gibbons, C. H. et al. Skin biopsy detection of phosphorylated α-synuclein in patients with synucleinopathies. JAMA 331, 1298 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Iranzo, A. et al. Misfolded α-synuclein assessment in skin and CSF by RT-QuIC in isolated REM sleep behavior disorder. Neurology 100, e1944–e1954 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Siderowf, A. et al. Assessment of heterogeneity among participants in the Parkinson’s Progression Markers Initiative cohort using α-synuclein seed amplification: a cross-sectional study. Lancet Neurol. 22, 407–417 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Eusebi, P. et al. Diagnostic utility of cerebrospinal fluid α-synuclein in Parkinson’s disease: a systematic review and meta-analysis. Mov. Disord. 32, 1389–1400 (2017).

    Article  CAS  PubMed  Google Scholar 

  95. Li, T. & Le, W. Biomarkers for Parkinson’s disease: how good are they? Neurosci. Bull. 36, 183–194 (2020).

    Article  CAS  PubMed  Google Scholar 

  96. Majbour, N. K. et al. Cerebrospinal α-synuclein oligomers reflect disease motor severity in DeNoPa longitudinal cohort. Mov. Disord. 36, 2048–2056 (2021).

    Article  CAS  PubMed  Google Scholar 

  97. Majbour, N. K. et al. Oligomeric and phosphorylated alpha-synuclein as potential CSF biomarkers for Parkinson’s disease. Mol. Neurodegener. 11, 7 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Majbour, N. K. et al. Longitudinal changes in CSF alpha-synuclein species reflect Parkinson’s disease progression. Mov. Disord. 31, 1535–1542 (2016).

    Article  CAS  PubMed  Google Scholar 

  99. Okuzumi, A. et al. Propagative α-synuclein seeds as serum biomarkers for synucleinopathies. Nat. Med. 29, 1448–1455 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Kluge, A. et al. Detection of neuron-derived pathological α-synuclein in blood. Brain 145, 3058–3071 (2022).

    Article  PubMed  Google Scholar 

  101. Kluge, A. et al. Detecting misfolded α‐synuclein in blood years before the diagnosis of Parkinson’s disease. Mov. Disord. 39, 1289–1299 (2024).

    Article  CAS  PubMed  Google Scholar 

  102. Chelban, V. et al. Neurofilament light levels predict clinical progression and death in multiple system atrophy. Brain 145, 4398–4408 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Lerche, S. et al. The mutation matters: CSF profiles of GCase, sphingolipids, α‐synuclein in PD GBA. Mov. Disord. 36, 1216–1228 (2021).

    Article  CAS  PubMed  Google Scholar 

  104. Si, X. et al. Central nervous system-derived exosomal alpha-synuclein in serum may be a biomarker in Parkinson’s disease. Neuroscience 413, 308–316 (2019).

    Article  CAS  PubMed  Google Scholar 

  105. Reale, M. et al. Peripheral cytokines profile in Parkinson’s disease. Brain Behav. Immun. 23, 55–63 (2009).

    Article  CAS  PubMed  Google Scholar 

  106. Eidson, L. N. et al. Candidate inflammatory biomarkers display unique relationships with alpha-synuclein and correlate with measures of disease severity in subjects with Parkinson’s disease. J. Neuroinflammation 14, 164 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Vallelunga, A. et al. Identification of circulating microRNAs for the differential diagnosis of Parkinson’s disease and multiple system atrophy. Front. Cell. Neurosci. 8, 156 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Patil, K. S. et al. Combinatory microRNA serum signatures as classifiers of Parkinson’s disease. Parkinsonism Relat. Disord. 64, 202–210 (2019).

    Article  PubMed  Google Scholar 

  109. Tolosa, E., Garrido, A., Scholz, S. W. & Poewe, W. Challenges in the diagnosis of Parkinson’s disease. Lancet Neurol. 20, 385–397 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Chahine, L. M. et al. In vivo distribution of α-synuclein in multiple tissues and biofluids in Parkinson disease. Neurology 95, e1267–e1284 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Ma, L. Y. et al. Alpha-synuclein in peripheral tissues in Parkinson’s disease. ACS Chem. Neurosci. 10, 812–823 (2019).

    Article  CAS  PubMed  Google Scholar 

  112. Rossi, M. et al. Ultrasensitive RT-QuIC assay with high sensitivity and specificity for Lewy body-associated synucleinopathies. Acta Neuropathol. 140, 49–62 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Donadio, V. et al. Skin nerve α-synuclein deposits: a biomarker for idiopathic Parkinson disease. Neurology 82, 1362–1369 (2014).

    Article  CAS  PubMed  Google Scholar 

  114. Minguez-Castellanos, A. et al. Do α-synuclein aggregates in autonomic plexuses predate Lewy body disorders? a cohort study. Neurology 68, 2012–2018 (2007).

    Article  CAS  PubMed  Google Scholar 

  115. Emmi, A. et al. Duodenal alpha‐synuclein pathology and enteric gliosis in advanced Parkinson’s disease. Mov. Disord. 38, 885–894 (2023).

    Article  CAS  PubMed  Google Scholar 

  116. Skorvanek, M. et al. α-Synuclein antibody 5G4 identifies manifest and prodromal Parkinson’s disease in colonic mucosa. Mov. Disord. 33, 1366–1368 (2018).

    Article  PubMed  Google Scholar 

  117. Beck, G. et al. Detection of phosphorylated alpha-synuclein in the muscularis propria of the gastrointestinal tract is a sensitive predictor for Parkinson’s disease. Parkinsons Dis. 2020, 4687530 (2020).

    PubMed  PubMed Central  Google Scholar 

  118. Fricova, D., Harsanyiova, J. & Kralova Trancikova, A. Alpha-synuclein in the gastrointestinal tract as a potential biomarker for early detection of Parkinson’s disease. Int. J. Mol. Sci. 21, 8666 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Harapan, B. N. et al. No enhanced (p-) α-synuclein deposition in gastrointestinal tissue of Parkinson’s disease patients. Parkinsonism Relat. Disord. 80, 82–88 (2020).

    Article  PubMed  Google Scholar 

  120. Stokholm, M. G., Danielsen, E. H., Hamilton-Dutoit, S. J. & Borghammer, P. Pathological α-synuclein in gastrointestinal tissues from prodromal Parkinson disease patients. Ann. Neurol. 79, 940–949 (2016).

    Article  CAS  PubMed  Google Scholar 

  121. Borghammer, P. The α-synuclein origin and connectome model (SOC model) of Parkinson’s disease: explaining motor asymmetry, non-motor phenotypes, and cognitive decline. J. Parkinsons Dis. 11, 455–474 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Lu, F. M. & Yuan, Z. PET/SPECT molecular imaging in clinical neuroscience: recent advances in the investigation of CNS diseases. Quant. Imaging Med. Surg. 5, 433–447 (2015).

    PubMed  PubMed Central  Google Scholar 

  123. Li, W. et al. 11C‐PE2I and 18F‐dopa PET for assessing progression rate in Parkinson’s: a longitudinal study. Mov. Disord. 33, 117–127 (2018).

    Article  CAS  PubMed  Google Scholar 

  124. Calloni, S. F. et al. Multiparametric MR imaging of Parkinsonisms at 3 tesla: its role in the differentiation of idiopathic Parkinson’s disease versus atypical Parkinsonian disorders. Eur. J. Radiol. 109, 95–100 (2018).

    Article  CAS  PubMed  Google Scholar 

  125. Smith, R. et al. The α-synuclein PET tracer [18F] ACI-12589 distinguishes multiple system atrophy from other neurodegenerative diseases. Nat. Commun. 14, 6750 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Endo, H. et al. Imaging α-synuclein pathologies in animal models and patients with Parkinson’s and related diseases. Neuron 112, 2540–2557.e8 (2024).

    Article  CAS  PubMed  Google Scholar 

  127. Lehericy, S. et al. The role of high‐field magnetic resonance imaging in parkinsonian disorders: pushing the boundaries forward. Mov. Disord. 32, 510–525 (2017).

    Article  PubMed  Google Scholar 

  128. Espay, A. J. et al. A roadmap for implementation of patient‐centered digital outcome measures in Parkinson’s disease obtained using mobile health technologies. Mov. Disord. 34, 657–663 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Luis-Martínez, R., Monje, M. H. G., Antonini, A., Sánchez-Ferro, Á. & Mestre, T. A. Technology-enabled care: integrating multidisciplinary care in Parkinson’s disease through digital technology. Front. Neurol. 11, 575975 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Samhouri, Y. et al. The trend of combined modality treatment and its outcomes in elderly patients with primary CNS lymphoma: a 12-year population-based analysis using propensity score. Anticancer. Res. 42, 1867–1877 (2022).

    Article  PubMed  Google Scholar 

  131. Mendoza, P. et al. Combination therapy with anti-HIV-1 antibodies maintains viral suppression. Nature 561, 479–484 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Herskovic, A. et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N. Engl. J. Med. 326, 1593–1598 (1992).

    Article  CAS  PubMed  Google Scholar 

  133. Meissner, W. G. et al. Trial of lixisenatide in early Parkinson’s disease. N. Engl. J. Med. 390, 1176–1185 (2024).

    Article  CAS  PubMed  Google Scholar 

  134. Athauda, D. et al. Exenatide once weekly versus placebo in Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet 390, 1664–1675 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. del Giudice, K. P. et al. Anti-alpha synuclein and anti-tau immunotherapies: can a cocktail approach work? Parkinsonism Relat. Disord. 122, 106080 (2024).

    Article  PubMed  Google Scholar 

  136. Antonini, A., Bravi, D., Sandre, M. & Bubacco, L. Immunization therapies for Parkinson’s disease: state of the art and considerations for future clinical trials. Expert Opin. Investig. Drugs 29, 685–695 (2020).

    Article  CAS  PubMed  Google Scholar 

  137. Tsukita, K., Sakamaki-Tsukita, H. & Takahashi, R. Long-term effect of regular physical activity and exercise habits in patients with early Parkinson disease. Neurology 98, e859–e871 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Rotondo, R. et al. Physical activity and neurotrophic factors as potential drivers of neuroplasticity in Parkinson’s Disease: A systematic review and meta-analysis. Ageing Res. Rev. 92, 102089 (2023).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, University San Raffaele, Rome, Italy

    Fabrizio Stocchi

  2. Deptartment of Neurology, Institute for Research and Medical Care, IRCCS San Raffaele, Rome, Italy

    Fabrizio Stocchi & Daniele Bravi

  3. Center for Neurodegenerative Diseases (CESNE), Department of Neuroscience, University of Padova, Padova, Italy

    Aron Emmi & Angelo Antonini

  4. Institute of Human Anatomy, Department of Neuroscience, University of Padova, Padova, Italy

    Aron Emmi

  5. Parkinson and Movement Disorders Unit, Centre for Rare Neurological Diseases (ERN-RND), Department of Neuroscience, Padua Neuroscience Center (PNC), University of Padova, Padova, Italy

    Angelo Antonini

Authors
  1. Fabrizio Stocchi
    View author publications

    Search author on:PubMed Google Scholar

  2. Daniele Bravi
    View author publications

    Search author on:PubMed Google Scholar

  3. Aron Emmi
    View author publications

    Search author on:PubMed Google Scholar

  4. Angelo Antonini
    View author publications

    Search author on:PubMed Google Scholar

Contributions

All authors researched data for the article and wrote the article. F.S., D.B. and A.A. contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Fabrizio Stocchi.

Ethics declarations

Competing interests

F.S. has received compensation for consultancy and speaker-related activities from UCB, Britannia, AbbVie, Zambon, Bial, Ever Pharma, Synegile, Biogen, Roche, Blue Rock, Chiesi Pharmaceuticals, Lundbeck, Sunovion and Kiowa. D.B. is a business partner of SixDegrees HealthCare and has received fees from Clexio, Herantis, Theravance, Novartis and PPD. A.A. has received compensation for consultancy and speaker-related activities from UCB, Britannia, AbbVie, Zambon, Bial, Ever Pharma, Ferrer, Theravance Biopharma, Bayer, TreeFrog Therapeutics, Oligy and Medscape. He receives research support from Lundbeck, Bial, Movement Disorders Society, Horizon2020 Grant 825785, Horizon2020 Grant 101016902, Ministry of Education University and Research (MIUR) Grant ARS01_01081 and Fondazione Grigioni per la Malattia di Parkinson. A.E. declares no competing interests.

Peer review

Peer review information

Nature Reviews Neurology thanks D. Nyholm, who co-reviewed with M. Öthman; A. Cenci; N. Hattori; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Stocchi, F., Bravi, D., Emmi, A. et al. Parkinson disease therapy: current strategies and future research priorities. Nat Rev Neurol 20, 695–707 (2024). https://doi.org/10.1038/s41582-024-01034-x

Download citation

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41582-024-01034-x

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research