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Health Review

Vol. 3 No. 1 (2025): January/December - 2025

Prodromal Parkinson's Disease: What We Know and What We do Not Know

DOI
https://doi.org/10.52600/2965-0968.bjcmr.2025.3.1.bjcmr13
Submitted
August 8, 2024
Published
2024-09-03

Abstract

Prodromal Parkinson's Disease (PD) represents a critical phase preceding the clinical onset of the disease, characterized by subtle and often non-motor symptoms that precede the classic motor manifestations. Understanding this prodromal phase is essential for early diagnosis, intervention, and potentially altering the disease course. This narrative review aims to elucidate the current knowledge on the prodromal phase of PD, highlighting known biomarkers, genetic predispositions, and environmental factors that contribute to early detection. Furthermore, it examines the limitations and gaps in our understanding, including the variability in prodromal symptoms, challenges in identifying definitive biomarkers, and the need for longitudinal studies. By synthesizing the existing literature, this review provides a comprehensive overview of what we know about prodromal PD and underscores the areas that require further research to enhance early diagnostic accuracy and develop preventative strategies.

References

  1. Ben-Shlomo Y, Darweesh S, Llibre-Guerra J, Marras C, San Luciano M, Tanner C. The epidemiology of Parkinson's disease. Lancet. 2024;403(10423):283-292. doi:10.1016/S0140-6736(23)01419-8.
  2. Morris HR, Spillantini MG, Sue CM, Williams-Gray CH. The pathogenesis of Parkinson's disease. Lancet. 2024;403(10423):293-304. doi:10.1016/S0140-6736(23)01478-2.
  3. Hayes MT. Parkinson's Disease and Parkinsonism. Am J Med. 2019;132(7):802-807. doi:10.1016/j.amjmed.2019.03.001.
  4. Reich SG, Savitt JM. Parkinson's Disease. Med Clin North Am. 2019;103(2):337-350. doi:10.1016/j.mcna.2018.10.014.
  5. Cabreira V, Massano J. Doença de Parkinson: Revisão Clínica e Atualização [Parkinson's Disease: Clinical Review and Update]. Acta Med Port. 2019;32(10):661-670. doi:10.20344/amp.11978.
  6. Ding XS, Gao L, Han Z, Eleuteri S, Shi W, Shen Y, et al. Ferroptosis in Parkinson's disease: Molecular mechanisms and ther-apeutic potential. Ageing Res Rev. 2023;91:102077. doi:10.1016/j.arr.2023.102077.
  7. Romano S, Savva GM, Bedarf JR, Charles IG, Hildebrand F, Narbad A. Meta-analysis of the Parkinson's disease gut microbiome suggests alterations linked to intestinal inflammation. NPJ Parkinsons Dis. 2021;7(1):27. doi:10.1038/s41531-021-00156-z.
  8. Chu Y, Hirst WD, Federoff HJ, Harms AS, Stoessl AJ, Kordower JH. Nigrostriatal tau pathology in parkinsonism and Park-inson's disease. Brain. 2024;147(2):444-457. doi:10.1093/brain/awad388.
  9. Yang Y, Shi Y, Schweighauser M, Zhang X, Kotecha A, Murzin AG, et al. Structures of α-synuclein filaments from human brains with Lewy pathology. Nature. 2022;610(7933):791-795. doi:10.1038/s41586-022-05319-3.
  10. Berg D, Borghammer P, Fereshtehnejad SM, Heinzel S, Horsager J, Schaeffer E, et al. Prodromal Parkinson disease subtypes - key to understanding heterogeneity. Nat Rev Neurol. 2021;17(6):349-361. doi:10.1038/s41582-021-00486-9.
  11. Joza S, Hu MT, Jung KY, Kunz D, Stefani A, Dušek P, et al. Progression of clinical markers in prodromal Parkinson's disease and dementia with Lewy bodies: a multicentre study. Brain. 2023;146(8):3258-3272. doi:10.1093/brain/awad072.
  12. Mahlknecht P, Seppi K, Poewe W. The Concept of Prodromal Parkinson's Disease. J Parkinsons Dis. 2015;5(4):681-697. doi:10.3233/JPD-150685.
  13. Elsworth JD. Parkinson's disease treatment: past, present, and future. J Neural Transm (Vienna). 2020;127(5):785-791. doi:10.1007/s00702-020-02167-1.
  14. Pajares M, Rojo AI, Manda G, Boscá L, Cuadrado A. Inflammation in Parkinson's Disease: Mechanisms and Therapeutic Implications. Cells. 2020;9(7):1687. doi:10.3390/cells9071687.
  15. Vijiaratnam N, Simuni T, Bandmann O, Morris HR, Foltynie T. Progress towards therapies for disease modification in Parkinson's disease. Lancet Neurol. 2021;20(7):559-572. doi:10.1016/S1474-4422(21)00061-2.
  16. Horsager J, Knudsen K, Sommerauer M. Clinical and imaging evidence of brain-first and body-first Parkinson's disease. Neurobiol Dis. 2022;164:105626. doi:10.1016/j.nbd.2022.105626.
  17. Weintraub D, Aarsland D, Chaudhuri KR, Dobkin RD, Leentjens AF, Rodriguez-Violante M, Schrag A. The neuropsychiatry of Parkinson's disease: advances and challenges. Lancet Neurol. 2022;21(1):89-102. doi:10.1016/S1474-4422(21)00330-6.
  18. Abeliovich A, Hefti F, Sevigny J. Gene Therapy for Parkinson's Disease Associated with GBA1 Mutations. J Parkinsons Dis. 2021;11(s2). doi:10.3233/JPD-212739.
  19. Tolosa E, Garrido A, Scholz SW, Poewe W. Challenges in the diagnosis of Parkinson's disease. Lancet Neurol. 2021;20(5):385-397. doi:10.1016/S1474-4422(21)00030-2.
  20. Church FC. Treatment Options for Motor and Non-Motor Symptoms of Parkinson's Disease. Biomolecules. 2021;11(4):612. doi:10.3390/biom11040612.
  21. Bang Y, Lim J, Choi HJ. Recent advances in the pathology of prodromal non-motor symptoms olfactory deficit and depression in Parkinson's disease: clues to early diagnosis and effective treatment. Arch Pharm Res. 2021;44(6):588-604. doi:10.1007/s12272-021-01337-3.
  22. Mestre TA, Fereshtehnejad SM, Berg D, Bohnen NI, Dujardin K, Erro R, et al. Parkinson's Disease Subtypes: Critical Appraisal and Recommendations. J Parkinsons Dis. 2021;11(2):395-404. doi:10.3233/JPD-202472.
  23. Trist BG, Hare DJ, Double KL. Oxidative stress in the aging substantia nigra and the etiology of Parkinson's disease. Aging Cell. 2019;18(6). doi:10.1111/acel.13031.
  24. Exner N, Lutz AK, Haass C, Winklhofer KF. Mitochondrial dysfunction in Parkinson's disease: molecular mechanisms and pathophysiological consequences. EMBO J. 2012;31(14):3038-3062. doi:10.1038/emboj.2012.170.
  25. Haider A, Elghazawy NH, Dawoud A, et al. Translational molecular imaging and drug development in Parkinson's disease. Mol Neurodegener. 2023;18(1):11. doi:10.1186/s13024-023-00600-z.
  26. Gan-Or Z, Liong C, Alcalay RN. GBA-Associated Parkinson's Disease and Other Synucleinopathies. Curr Neurol Neurosci Rep. 2018;18(8):44. doi:10.1007/s11910-018-0860-4.
  27. Borghammer P, Van Den Berge N. Brain-First versus Gut-First Parkinson's Disease: A Hypothesis. J Parkinsons Dis. 2019;9(s2). doi:10.3233/JPD-191721.
  28. Zhu L, Ploessl K, Kung HF. PET/SPECT imaging agents for neurodegenerative diseases. Chem Soc Rev. 2014;43(19):6683-6691. doi:10.1039/c3cs60430f.
  29. Chen Z, Li G, Liu J. Autonomic dysfunction in Parkinson's disease: Implications for pathophysiology, diagnosis, and treat-ment. Neurobiol Dis. 2020;134:104700. doi:10.1016/j.nbd.2019.104700.
  30. Kim JS, Park HE, Park IS, et al. Normal 'heart' in Parkinson's disease: is this a distinct clinical phenotype?. Eur J Neurol. 2017;24(2):349-356. doi:10.1111/ene.13206.
  31. Sung HY, Park HE, Kim HW. The Frequency and Severity of Gastrointestinal Symptoms in Patients with Early Parkinson’s Disease. J Mov Disord. 2014;7(1):7-12.
  32. Malek N, Lawton MA, Grosset KA, Bajaj N, Barker RA, Burn DJ, et al.; PRoBaND Clinical Consortium. Autonomic Dysfunction in Early Parkinson's Disease: Results from the United Kingdom Tracking Parkinson's Study. Mov Disord Clin Pract. 2017;4(4):509-516. doi:10.1002/mdc3.12454.
  33. Takizawa C, Gemmell E, Kenworthy J, Speyer R. A Systematic Review of the Prevalence of Oropharyngeal Dysphagia in Stroke, Parkinson’s Disease, Alzheimer’s Disease, Head Injury, and Pneumonia. Dysphagia. 2016;31(3):434-441. doi:10.1007/s00455-016-9695-9.
  34. McDonald C, Winge K, Burn DJ. Lower urinary tract symptoms in Parkinson's disease: Prevalence, aetiology and manage-ment. Parkinsonism Relat Disord. 2017;35:8-16. doi:10.1016/j.parkreldis.2016.10.024.
  35. Joza S, Hu MT, Jung KY, Kunz D, Arnaldi D, Lee JY, et al.; International REM Sleep Behavior Disorder Study Group. Prodromal dementia with Lewy bodies in REM sleep behavior disorder: A multicenter study. Alzheimers Dement. 2024;20(1):91-102. doi:10.1002/alz.13386.
  36. Hu MT. REM sleep behavior disorder (RBD). Neurobiol Dis. 2020;143:104996. doi:10.1016/j.nbd.2020.104996.
  37. van Wamelen DJ, Leta V, Podlewska AM, et al. Exploring hyperhidrosis and related thermoregulatory symptoms as a possible clinical identifier for the dysautonomic subtype of Parkinson’s disease. J Neurol. 2019;266(8):1736-1742. doi:10.1007/s00415-019-09325-w.
  38. Siderowf A, Concha-Marambio L, Lafontant DE, et al.; Parkinson's Progression Markers Initiative. Assessment of heteroge-neity among participants in the Parkinson's Progression Markers Initiative cohort using α-synuclein seed amplification: a cross-sectional study. Lancet Neurol. 2023;22(5):407-417. doi:10.1016/S1474-4422(23)00109-6.
  39. Rutledge J, Lehallier B, Zarifkar P, et al. Comprehensive proteomics of CSF, plasma, and urine identify DDC and other biomarkers of early Parkinson's disease. Acta Neuropathol. 2024;147(1):52. doi:10.1007/s00401-024-02706-0.
  40. Jia F, Fellner A, Kumar KR. Monogenic Parkinson's Disease: Genotype, Phenotype, Pathophysiology, and Genetic Testing. Genes (Basel). 2022;13(3):471. doi:10.3390/genes13030471.
  41. Blesa J, Trigo-Damas I, Quiroga-Varela A, Jackson-Lewis VR. Oxidative stress and Parkinson's disease. Front Neuroanat. 2015;9:91. doi:10.3389/fnana.2015.00091.
  42. Gegg ME, Schapira AH. Mitochondrial dysfunction associated with glucocerebrosidase deficiency. Neurobiol Dis. 2016;90:43-50. doi:10.1016/j.nbd.2015.09.006.
  43. Ye H, Robak LA, Yu M, Cykowski M, Shulman JM. Genetics and Pathogenesis of Parkinson's Syndrome. Annu Rev Pathol. 2023;18:95-121. doi:10.1146/annurev-pathmechdis-031521-034145.
  44. Domenicale C, Magnabosco S, Morari M. Modeling Parkinson's disease in LRRK2 rodents. Neuronal Signal. 2023;7(3). doi:10.1042/NS20220040.
  45. Lesage S, Lunati A, Houot M, et al.; French Parkinson Disease Genetics Study Group. Characterization of Recessive Parkinson Disease in a Large Multicenter Study. Ann Neurol. 2020;88(4):843-850. doi:10.1002/ana.25787.
  46. Liu H, Koros C, Strohäker T, et al. A Novel SNCA A30G Mutation Causes Familial Parkinson's Disease. Mov Disord. 2021;36(7):1624-1633. doi:10.1002/mds.28534.
  47. Barbuti PA, Ohnmacht J, Santos BF, et al. Gene-corrected p.A30P SNCA patient-derived isogenic neurons rescue neuronal branching and function. Sci Rep. 2021;11(1):21946. doi:10.1038/s41598-021-01505-x.
  48. Armstrong MJ, Okun MS. Diagnosis and Treatment of Parkinson Disease: A Review. JAMA. 2020;323(6):548-560. doi:10.1001/jama.2019.22360.
  49. Cattaneo C, Jost WH. Pain in Parkinson's Disease: Pathophysiology, Classification and Treatment. J Integr Neurosci. 2023;22(5):132. doi:10.31083/j.jin2205132.
  50. Jang Y, Koo JH, Kwon I, et al. Neuroprotective effects of endurance exercise against neuroinflammation in MPTP-induced Parkinson's disease mice. Brain Res. 2017;1655:186-193. doi:10.1016/j.brainres.2016.10.029.
  51. Johansson H, Freidle M, Ekman U, et al. Feasibility Aspects of Exploring Exercise-Induced Neuroplasticity in Parkinson's Disease: A Pilot Randomized Controlled Trial. Parkinsons Dis. 2020;2020:2410863. doi:10.1155/2020/2410863.
  52. Paillard T, Rolland Y, de Souto Barreto P. Protective Effects of Physical Exercise in Alzheimer's Disease and Parkinson's Disease: A Narrative Review. J Clin Neurol. 2015;11(3):212-219. doi:10.3988/jcn.2015.11.3.212.
  53. Church FC. Treatment Options for Motor and Non-Motor Symptoms of Parkinson's Disease. Biomolecules. 2021;11(4):612. doi:10.3390/biom11040612.
  54. Carbone F, Djamshidian A, Seppi K, Poewe W. Apomorphine for Parkinson's Disease: Efficacy and Safety of Current and New Formulations. CNS Drugs. 2019;33(9):905-918. doi:10.1007/s40263-019-00661-z.
  55. Perez-Lloret S, Rascol O. Efficacy and safety of amantadine for the treatment of L-DOPA-induced dyskinesia. J Neural Transm (Vienna). 2018;125(8):1237-1250. doi:10.1007/s00702-018-1869-1.
  56. Ernst M, Folkerts AK, Gollan R, et al. Physical exercise for people with Parkinson's disease: a systematic review and network meta-analysis. Cochrane Database Syst Rev. 2023;1(1). doi:10.1002/14651858.CD013856.pub2.
  57. Ellis TD, Colón-Semenza C, DeAngelis TR, et al. Evidence for Early and Regular Physical Therapy and Exercise in Parkinson's Disease. Semin Neurol. 2021;41(2):189-205. doi:10.1055/s-0041-1725133.
  58. Ashburn A, Pickering R, McIntosh E, et al. Exercise- and strategy-based physiotherapy-delivered intervention for preventing repeat falls in people with Parkinson's: the PDSAFE RCT. Health Technol Assess. 2019;23(36):1-150. doi:10.3310/hta23360.
  59. Jang Y, Koo JH, Kwon I, et al. Neuroprotective effects of endurance exercise against neuroinflammation in MPTP-induced Parkinson's disease mice. Brain Res. 2017;1655:186-193. doi:10.1016/j.brainres.2016.10.029.
  60. Ding H, Dhima K, Lockhart KC, et al. Unrecognized vitamin D3 deficiency is common in Parkinson disease: Harvard Bi-omarker Study. Neurology. 2013;81(17):1531-1537. doi:10.1212/WNL.0b013e3182a95818.
  61. Peterson AL, Murchison C, Zabetian C, et al. Memory, mood, and vitamin D in persons with Parkinson's disease. J Parkinsons Dis. 2013;3(4):547-555. doi:10.3233/JPD-130206.
  62. Cernera S, Eisinger RS, Wong JK, et al. Long-term Parkinson's disease quality of life after staged DBS: STN vs GPi and first vs second lead. NPJ Parkinsons Dis. 2020;6:13. doi:10.1038/s41531-020-0115-3.
  63. Sharma VD, Patel M, Miocinovic S. Surgical Treatment of Parkinson's Disease: Devices and Lesion Approaches. Neurother-apeutics. 2020;17(4):1525-1538. doi:10.1007/s13311-020-00939-x.

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