The Non-Motor Prodromal Symptoms of Parkinson's Disease: A Review

(Amjad Mhanna , Subhia Maya , Ali Ghassa , Abdallah Aladna and Zuheir Alshehabi )

---

Abstract

Parkinson's disease is a common progressive neurodegenerative disorder with both motor and non-motor symptoms. There is no clear etiology, and it has no cure. The non-motor features often precede the motor symptoms by many years, so they are considered prodromal symptoms of the disease. These symptoms include olfactory dysfunction, constipation, sleep problems, and depression. The purpose of this study is to review the literature on Parkinson's disease non-motor prodromal symptoms and their role from the early stages throughout the disease's development. The review discusses several aspects related to the prodromal features of Parkinson's disease: their prevalence in Parkinson's disease patients, the pathophysiology, the treatment, if it is possible, and the prodromal symptoms' effect on the diagnosis, prognosis, and management of the disease, in addition to their impact on patients' quality of life. More studies are required to precisely pinpoint the timing of non-motor prodromal symptoms onset and modify the diagnostic criteria for Parkinson's disease accordingly.
KEYWORDS
constipation, depression, gastrointestinal dysfunctions, hyposmia, olfactory dysfunction, sleep disturbances

PDF

References

Almikhlafi, M.A. (2023). The role of exercise in Parkinson’s Disease. Neurosciences (Riyadh, Saudi Arabia), 28(1), 4–12. DOI: 10.17712/nsj.2023.1.20220105
Armstrong, M.J. and Okun, M.S. (2020). Diagnosis and Treatment of Parkinson Disease: A Review. JAMA - Journal of the American Medical Association, 323(6), 548–60. DOI: 10.1001/jama.2019.22360
Balestrino, R. and Schapira, A.H.V. (2020). Parkinson disease. European Journal of Neurology, 27(1), 27–42. DOI: 10.1111/ene.14108
Bang, Y., Lim, J. and Choi, H.J. (2021). 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. Archives of Pharmacal Research, 44(6), 588–604. DOI: 10.1007/s12272-021-01337-3
Basellini, M.J., Kothuis, J.M., Comincini, A., Pezzoli, G., Cappelletti, G. and Mazzetti, S. (2023). Pathological pathways and Alpha-synuclein in parkinson’s disease: A view from the periphery. Frontiers in Bioscience (Landmark Edition), 28(2), 33. DOI: 0.31083/j.fbl2802033
Bohnen, N.I. and Hu, M.T.M. (2019). Sleep disturbance as potential risk and progression factor for parkinson’s disease. Journal of Parkinson’s Disease, 9(3), 603–14. DOI: 10.3233/JPD-191627
Calabresi, P., Mechelli, A., Natale, G., Volpicelli-Daley, L., Di Lazzaro, G. and Ghiglieri, V. (2023). Alpha-synuclein in Parkinson’s disease and other synucleinopathies: From overt neurodegeneration back to early synaptic dysfunction. Cell Death and Disease, 14(3), 176. DOI: 10.1038/s41419-023-05672-9
Camilleri, M. (2021). Gastrointestinal motility disorders in neurologic disease. The Journal of Clinical Investigation, 131(4), e143771. DOI: 10.1172/JCI143771
Chase, B.A. and Markopoulou, K. (2020). Olfactory dysfunction in familial and sporadic Parkinson’s disease. Frontiers in Neurology, 11(n/a), 1–11. DOI: 10.3389/fneur.2020.00447
Chen, H., Wang, K., Scheperjans, F. and Killinger, B. (2022). Environmental triggers of Parkinson’s disease – Implications of the Braak and dual-hit hypotheses. Neurobiology of Disease, 163(n/a), 105601. DOI: 10.1016/j.nbd.2021.105601
Chen, X.Y., Liu, C., Xue, Y. and Chen, L. (2023). Changed firing activity of nigra dopaminergic neurons in Parkinson’s disease. Neurochemistry International, 162(n/a), 105465. DOI: 10.1016/j.neuint.2022.105465
Chen, Z., Li, G. and Liu, J. (2020). Autonomic dysfunction in Parkinson’s disease: Implications for pathophysiology, diagnosis, and treatment. Neurobiology of Disease, 134(n/a), 104700. DOI: 10.1016/j.nbd.2019.104700

Church, F.C. (2021). Review treatment options for motor and non‐motor symptoms of Parkinson’s disease. Biomolecules, 11(4), 612. DOI: 10.3390/biom11040612
Cong, S., Xiang, C., Zhang, S., Zhang, T., Wang, H. and Cong, S. (2022). Prevalence and clinical aspects of depression in Parkinson’s disease: A systematic review and meta analysis of 129 studies. Neuroscience and Biobehavioral Reviews, 141(n/a), 104749. DOI: 10.1016/j.neubiorev.2022.104749
De Rui, M., Inelmen, E.M., Trevisan, C., Pigozzo, S., Manzato, E. and Sergi, G. (2020). Parkinson’s disease and the non-motor symptoms: hyposmia, weight loss, osteosarcopenia. Aging Clinical and Experimental Research, 32(7), 1211–8. DOI: 10.1007/s40520-020-01470-x
Dong-Chen, X., Yong, C., Yang, X., Chen-Yu, S.T. and Li-Hua, P. (2023). Signaling pathways in Parkinson’s disease: Molecular mechanisms and therapeutic interventions. Signal Transduction and Targeted Therapy, 8(1), n/a. DOI: 10.1038/s41392-023-01353-3
Fullard, M.E., Morley, J.F. and Duda, J.E. (2017). Olfactory dysfunction as an early biomarker in Parkinson’s disease. Neuroscience Bulletin, 33(5), 515–25. DOI: 10.1007/s12264-017-0170-x
Gan-Or, Z., Alcalay, R.N., Rouleau, G.A. and Postuma, R.B. (2018). Sleep disorders and Parkinson disease; lessons from genetics. Sleep Medicine Reviews, 41(n/a),  101–12. DOI: 10.1016/j.smrv.2018.01.006
Gros, P. and Videnovic, A. (2020). Overview of sleep and circadian rhythm disorders in Parkinson disease. Clinics in Geriatric Medicine, 36(1), 119–30. DOI: 10.1016/j.cger.2019.09.005
Horsager, J., Knudsen, K. and Sommerauer, M. (2022). Clinical and imaging evidence of brain-first and body-first Parkinson's disease. Neurobiology of Disease, 164(n/a), 105626. DOI: 10.1016/j.nbd.2022.105626
Hu, X., Li, J., Wang, X., Liu, H., Wang, T., Lin, Z. and Xiong, N. (2023). Neuroprotective Effect of melatonin on sleep disorders associated with Parkinson’s disease. Antioxidants, 12(2), 1–23. DOI: 10.3390/antiox12020396
Hustad, E. and Aasly, J.O. (2020). Clinical and imaging markers of prodromal Parkinson’s disease. Frontiers in Neurology, 11(n/a), 1–11. DOI: 10.3389/fneur.2020.00395
Jellinger, K.A. (2022). The pathobiological basis of depression in Parkinson disease: Challenges and outlooks. Journal of Neural Transmission, 129(12), 1397–418. DOI: 10.1007/s00702-022-02559-5
Lesenskyj, A.M., Samples, M.P., Farmer, J.M. and Maxwell, C.R. (2018). Treating refractory depression in Parkinson’s disease: A meta-analysis of transcranial magnetic stimulation. Translational Neurodegeneration, 7(1), 4–9. DOI: 10.1186/s40035-018-0113-0
Lim, J., Bang, Y. and Choi, H.J. (2018). Abnormal hippocampal neurogenesis in Parkinson’s disease: relevance to a new therapeutic target for depression with Parkinson’s disease. Archives of Pharmacal Research, 41(10), 943–54. DOI: 10.1007/s12272-018-1063-x
Lintel, H., Corpuz, T., Paracha, S.U.R. and Grossberg, G.T. (2021). Mood Disorders and Anxiety in Parkinson’s Disease: Current Concepts. Journal of Geriatric Psychiatry and Neurology, 34(4), 280–8. DOI: 10.1177/08919887211018267
Mantovani, S., Smith, S.S., Gordon, R. and O’Sullivan, J.D. (2018). An overview of sleep and circadian dysfunction in Parkinson’s disease. Journal of Sleep Research, 27(3), n/a. DOI: 10.1111/jsr.12673
Mantri, B.S. and Morley, J.F. (2018). Prodromal and early Parkinson ’ s disease diagnosis. Practical Neurology, 2(n/a), 28–32.
Marin, C., Vilas, D., Langdon, C., Alobid, I., López-Chacón, M., Haehner, A., Hummel, T. and Mullol, J. (2018). Olfactory dysfunction in neurodegenerative diseases. Current Allergy and Asthma Reports, 18(8), n/a. DOI: 10.1007/s11882-018-0796-4
Marinus, J., Zhu, K., Marras, C., Aarsland, D. and van Hilten, J.J. (2018). Risk factors for non-motor symptoms in Parkinson’s disease. The Lancet Neurology, 17(6), 559–68. DOI: 10.1016/S1474-4422(18)30127-3
Matsumoto, S. and Tsunematsu, T. (2021). Association between sleep, alzheimer’s, and parkinson’s disease. Biology, 10(11), n/a. DOI: 10.3390/biology10111127
Metta, V., Leta, V., Mrudula, K.R., Prashanth, L.K., Goyal, V., Borgohain, R. and Chaudhuri, K.R. (2022a). Gastrointestinal dysfunction in Parkinson’s disease: Molecular pathology and implications of gut microbiome, probiotics, and fecal microbiota transplantation. Journal of neurology, 269(3), 1154–63. DOI: 10.1007/s00415-021-10567-w
Metta, V., Leta, V., Mrudula, K.R., Prashanth, L.K., Goyal, V., Borgohain, R., Chung-Faye, G., Chaudhuri, K.R., Camilleri, M., Chen, Z., Li, G., Liu, J., Quigley, E.M.M., Xu, J., Wang, L., Chen, X., Le, W., Sun, X., Xue, L. and Kaufmann, H. (2022b). Update to the treatment of parkinson’s disease based on the gut-brain axis mechanism. Neurobiology of Disease, 16(3), 243–9. DOI: 10.1002/mds.27344
Murakami, H., Shiraishi, T., Umehara, T., Omoto, S. and Iguchi, Y. (2023). Recent advances in drug therapy for Parkinson’s disease. Internal Medicine, 62(1), 33–42. DOI: 10.2169/internalmedicine.8940-21
Palma, J.A. and Kaufmann, H. (2018). Treatment of autonomic dysfunction in Parkinson disease and other synucleinopathies. Movement Disorders, 33(3), 372–90. DOI: 10.1002/mds.27344
Poewe, W., Seppi, K., Tanner, C.M., Halliday, G.M., Brundin, P., Volkmann, J., Schrag, A.E. and Lang, A.E. (2017). Parkinson disease. Nature Reviews Disease Primers, 3(n/a), 1–21. DOI: 10.1038/nrdp.2017.13
Prell, T., Witte, O.W. and Grosskreutz, J. (2019). Biomarkers for dementia, fatigue, and depression in Parkinson’s disease. Frontiers in Neurology, 10(n/a), 1–13. DOI: 10.3389/fneur.2019.00195
Zuzuárregui, J.R.P. and During, E.H. (2020). Sleep issues in Parkinson’s disease and their management. Neurotherapeutics, 17(4), 1480–94. DOI: 10.1007/s13311-020-00938-y
Ray, S. and Agarwal, P. (2020). Depression and anxiety in Parkinson disease. Clinics in Geriatric Medicine, 36(1), 93–104. DOI: 10.1016/j.cger.2019.09.012
Rietdijk, C.D., Perez-Pardo, P., Garssen, J., van Wezel, R.J.A. and Kraneveld, A.D. (2017). Exploring braak’s hypothesis of parkinson’s disease. Frontiers in Neurology, 8(n/a), n/a. DOI: 10.3389/fneur.2017.00037
Roos, D.S., Klein, M., Deeg, D.J.H., Doty, R.L. and Berendse, H.W. (2022). Prevalence of prodromal symptoms of Parkinson’s disease in the late middle-aged population. Journal of Parkinson’s Disease, 12(3), 967–74. DOI: 10.3233/JPD-213007
Ryan, M., Eatmon, C.V. and Slevin, J.T. (2019). Drug treatment strategies for depression in Parkinson disease. Expert Opinion on Pharmacotherapy, 20(11), 1351–63. DOI: 10.1080/14656566.2019.1612877
Sandeep, Sahu, M.R., Rani, L., Kharat, A.S. and Mondal, A.C. (2023). Could vitamins have a positive impact on the treatment of Parkinson’s disease? Brain Sciences, 13(2), n/a. DOI: 10.3390/brainsci13020272
Schapira, A.H.V., Chaudhuri, K.R. and Jenner, P. (2017). Non-motor features of Parkinson disease. Nature Reviews Neuroscience, 18(7), 435–50. DOI: 10.1038/nrn.2017.62
Seppi, K., Ray Chaudhuri, K., Coelho, M., Fox, S.H., Katzenschlager, R., Perez Lloret, S., Weintraub, D., Sampaio, C., Chahine, L., Hametner, E.M., Heim, B., Lim, S.Y., Poewe, W. and Djamshidian-Tehrani, A. (2019). Update on treatments for nonmotor symptoms of Parkinson’s disease—an evidence-based medicine review. Movement Disorders, 34(2), 180–98. DOI: 10.1002/mds.27602
Shen, Y., Lv, Q. kun, Xie, W. ye, Gong, S. yi, Zhuang, S., Liu, J. yi, Mao, C. jie and Liu, C. feng. (2023). Circadian disruption and sleep disorders in neurodegeneration. Translational Neurodegeneration, 12(1), 1–25. DOI: 10.1186/s40035-023-00340-6
Smith, J.K., Mellick, G.D. and Sykes, A.M. (2023). The role of the endolysosomal pathway in α-synuclein pathogenesis in Parkinson’s disease. Frontiers in Cellular Neuroscience, 16(n/a), 1–19. DOI: 10.3389/fncel.2022.1081426
Stefani, A. and Högl, B. (2020). Sleep in Parkinson’s disease. Neuropsychopharmacology, 45(1),  121–8. DOI: 10.1038/s41386-019-0448-y
Taguchi, T., Ikuno, M., Yamakado, H. and Takahashi, R. (2020). Animal model for prodromal Parkinson’s disease. International Journal of Molecular Sciences, 21(6), n/a. DOI: 10.3390/ijms21061961
Takamiya, A., Seki, M., Kudo, S., Yoshizaki, T., Nakahara, J., Mimura, M. and Kishimoto, T. (2021). Electroconvulsive therapy for Parkinson’s disease: A systematic review and meta-analysis. Movement Disorders, 36(1), 50–8. DOI: 10.1002/mds.28335
Tizabi, Y., Getachew, B., Csoka, A.B., Manaye, K.F. and Copeland, R.L. (2019). Novel targets for parkinsonism-depression comorbidity. Progress in Molecular Biology and Translational Science, 167(n/a), 1–24. DOI: 10.1016/bs.pmbts.2019.06.004
Tysnes, O.B. and Storstein, A. (2017). Epidemiology of Parkinson’s disease. Journal of Neural Transmission, 124(8), 901–5. DOI: 10.1007/s00702-017-1686-y
Xu, J., Wang, L., Chen, X. and Le, W. (2022). New understanding on the pathophysiology and treatment of constipation in Parkinson’s disease. Frontiers in Aging Neuroscience, 14(n/a), 1–9. DOI: 10.3389/fnagi.2022.917499