The Impact of Prodromal Stage Non-Motor Symptoms on Clinical Progression in Parkinson’s Disease

Abstract

Objectives: Several non-motor symptoms (NMSs) were described in the prodromal Parkinson’s disease (PD). The aim of this study is to investigate the impact of the presence of prodromal NMSs on clinical progression of PD. Materials and Methods: We questioned the presence of NMSs in the prediagnostic stage in patients with PD. Group 1 reported at least one prodromal NMS and Group 2 reported no prodromal NMSs. As recommended by the Movement Disorder Society Task Force, the total likelihood ratios (LRs) of NMSs were calculated and correlated with disease progression. Clinical progression was determined by dividing the Unified Parkinson’s Disease Rating Scale Part III total score by the duration of the disease. Generalized linear model (GzLM) was used to determine associations between clinical progression rate and the predictor variables. Results: Group 1 had 48 patients (24 male, 24 female), and Group 2 had 46 patients (32 male, 14 female). Both groups were similar in terms of demographic and disease characteristics. Depression and constipation (for each symptom, 18 patients and 37.5%) were common in Group 1. The rate of clinical progression was higher in Group 1 than in Group 2 (p=0.037). There was no significant correlation between clinical progression rate and LRs of NMSs in Group 1 (rs=0.10, p=0.49). However, age of the diagnosis was the only significant factor associated with the clinical progression (p=0.69). Conclusion: Prodromal NMSs do not seem to impact the rate of disease progression, which may be explained by the non-dopaminergic and extra nigro-striatal pathway that cause NMSs.

Keywords

• Parkinson’s Disease
• Prodromal Stage
• Constipation
• Depression

Parkinson Hastalığında Prodromal Dönem Non-Motor Semptomların Hastalık Klinik Progresyonu Üzerine Etkisi

Abstract

Objectives: Several non-motor symptoms (NMSs) were described in the prodromal Parkinson’s disease (PD). The aim of this study is to investigate the impact of the presence of prodromal NMSs on clinical progression of PD. Materials and Methods: We questioned the presence of NMSs in the prediagnostic stage in patients with PD. Group 1 reported at least one prodromal NMS and Group 2 reported no prodromal NMSs. As recommended by the Movement Disorder Society Task Force, the total likelihood ratios (LRs) of NMSs were calculated and correlated with disease progression. Clinical progression was determined by dividing the Unified Parkinson’s Disease Rating Scale Part III total score by the duration of the disease. Generalized linear model (GzLM) was used to determine associations between clinical progression rate and the predictor variables. Results: Group 1 had 48 patients (24 male, 24 female), and Group 2 had 46 patients (32 male, 14 female). Both groups were similar in terms of demographic and disease characteristics. Depression and constipation (for each symptom, 18 patients and 37.5%) were common in Group 1. The rate of clinical progression was higher in Group 1 than in Group 2 (p=0.037). There was no significant correlation between clinical progression rate and LRs of NMSs in Group 1 (rs=0.10, p=0.49). However, age of the diagnosis was the only significant factor associated with the clinical progression (p=0.69). Conclusion: Prodromal NMSs do not seem to impact the rate of disease progression, which may be explained by the non-dopaminergic and extra nigro-striatal pathway that cause NMSs.

Keywords

• Parkinson’s Disease
• Prodromal Stage
• Constipation
• Depression

References

1. 1. Parkinson J. An Essay on the Shaking Palsy. London: Sherwood, Neely and Jones (1817). J Neuropsychiarty Clin Neurosci. 2002;14:223-236. https:// neuro.psychiatryonline.org/doi/pdf/10.1176/jnp.14.2.223
2. 2. Stern MB, Lang A, Poewe W. Toward a redefinition of Parkinson’s disease. Mov Disord. 2012;27:54-60.
3. 3. Berg D, Postuma RB, Bloem B, et al. Time to redefine PD? Introductory statement of the MDS Task Force on the definition of Parkinson’s disease. Mov Disord. 2014;29:454-462.
4. 4. Antonini A, Barone P, Marconi R, et al. The progression of non-motor symptoms in Parkinson’s disease and their contribution to motor disability, and quality of life. J Neurol. 2012;259:2621-2631.
5. 5. Kadastik-Eerme L, Muldmaa M, Lilles S, et al. Nonmotor Features in Parkinson’s Disease: What Are the Most Important Associated Factors? Parkinsons Dis. 2016;2016:4370674.
6. 6. Martinez-Martin P, Rodriguez-Blazquez C, Kurtis MM, et al. The impact of non-motor symptoms on health-related quality of life of patients with Parkinson’s disease. Mov Disord. 2011;26:399-406.
7. 7. Lyons KE, Pahwa R. The impact and management of nonmotor symptoms of Parkinson’s disease. Am J Manag Care. 2011;17(Suppl 12):S308-S314.
8. 8. Berg D, Postuma RB, Adler CH, et al. MDS research criteria for prodromal Parkinson’s disease. Mov Disord. 2015;30:1600-1611.

9. 9. Yilmaz R, Hopfner F, van Eimeren T, et al. Biomarkers of Parkinson’s disease: 20 years later. J Neural Transm (Vienna). 2019;126:803-813.
10. 10. Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord. 2015;30:1591-1601.
11. 11. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189-198.
12. 12. Goetz CG, Tilley BC, Shaftman SR, et al. Movement Disorder Societysponsored revision of the Unified Parkinson’s Disease Rating Scale (MDSUPDRS): scale presentation and clinimetric testing results. Mov Disord. 2008;23:2129-2170.
13. 13. Akbostanci MC, Bayram E, Yilmaz V, et al. Turkish Standardization of Movement Disorders Society Unified Parkinson’s Disease Rating Scale and Unified Dyskinesia Rating Scale. Mov Disord Clin Pract. 2017;5:54-59.
14. 14. Ramaker C, Marinus J, Stiggelbout AM, et al. Systematic evaluation of rating scales for impairment and disability in Parkinson’s disease. Mov Disord. 2002;17:867-876.
15. 15. Gan-Or Z, Alcalay RN, Rouleau GA, et al. Sleep disorders and Parkinson disease; lessons from genetics. Sleep Med Rev. 2018;41:101-112.
16. 16. Plouvier AO, Hameleers RJ, van den Heuvel EA, et al. Prodromal symptoms and early detection of Parkinson’s disease in general practice: a nested case-control study. Fam Pract. 2014;31:373-378.
17. 17. Postuma RB, Aarsland D, Barone P, et al. Identifying prodromal Parkinson’s disease: pre-motor disorders in Parkinson’s disease. Mov Disord. 2012;27:617-626.
18. 18. Stiasny-Kolster K, Mayer G, Schäfer S, et al. The REM sleep behavior disorder screening questionnaire--a new diagnostic instrument. Mov Disord. 2007;22:2386-2393.
19. 19. Heinzel S, Berg D, Gasser T, et al. Update of the MDS research criteria for prodromal Parkinson’s disease. Mov Disord. 2019;34:1464-1470.
20. 20. Jankovic J, Kapadia AS. Functional decline in Parkinson disease. Arch Neurol. 2001;58:1611-1615.
21. 21. Schrag A, Sampaio C, Counsell N, et al. Minimal clinically important change on the unified Parkinson’s disease rating scale. Mov Disord. 2006;21:1200-1207.
22. 22. Olanow CW. Levodopa: effect on cell death and the natural history of Parkinson’s disease. Mov Disord. 2015;30:37-44.
23. 23. Poewe W, Mahlknecht P. The clinical progression of Parkinson’s disease. Parkinsonism Relat Disord. 2009;15 Suppl 4:S28-S32.
24. 24. Holden SK, Finseth T, Sillau SH, et al. Progression of MDS-UPDRS Scores Over Five Years in De Novo Parkinson Disease from the Parkinson’s Progression Markers Initiative Cohort. Mov Disord Clin Pract. 2018;5:47-53.
25. 25. Harrison MB, Wylie SA, Frysinger RC, et al. UPDRS activity of daily living score as a marker of Parkinson’s disease progression. Mov Disord. 2009;24:224-230.
26. 26. Regnault A, Boroojerdi B, Meunier J, et al. Does the MDS-UPDRS provide the precision to assess progression in early Parkinson’s disease? Learnings from the Parkinson’s progression marker initiative cohort. J Neurol. 2019;266:1927-1936.
27. 27. Kotagal V, Albin RL, Müller ML, et al. Diabetes is associated with postural instability and gait difficulty in Parkinson disease. Parkinsonism Relat Disord. 2013;19:522-526.
28. 28. Kotagal V, Albin RL, Müller ML, et al. Modifiable cardiovascular risk factors and axial motor impairments in Parkinson disease. Neurology. 2014;82:1514-1520.
29. 29. Swallow DM, Lawton MA, Grosset KA, et al. Variation in Recent Onset Parkinson’s Disease: Implications for Prodromal Detection. J Parkinsons Dis. 2016;6:289-300.
30. 30. Walter U, Kleinschmidt S, Rimmele F, et al. Potential impact of self-perceived prodromal symptoms on the early diagnosis of Parkinson’s disease. J Neurol. 2013;260:3077-3085.
31. 31. Gaenslen A, Swid I, Liepelt-Scarfone I, et al. The patients’ perception of prodromal symptoms before the initial diagnosis of Parkinson’s disease. Mov Disord. 2011;26:653-658.
32. 32. Durcan R, Wiblin L, Lawson RA, et al. Prevalence and duration of non-motor symptoms in prodromal Parkinson’s disease. Eur J Neurol. 2019;26:979-985.
33. 33. Schrag A, Zhelev SS, Hotham S, et al. Heterogeneity in progression of prodromal features in Parkinson’s disease. Parkinsonism Relat Disord. 2019;64:275-279.
34. 34. Chen H, Zhao EJ, Zhang W, et al. Meta-analyses on prevalence of selected Parkinson’s nonmotor symptoms before and after diagnosis. Transl Neurodegener. 2015;4:1.
35. 35. Savica R, Carlin JM, Grossardt BR, et al. Medical records documentation of constipation preceding Parkinson disease: A case-control study. Neurology. 2009;73:1752-1758.
36. 36. Elbaz A. Prodromal symptoms of Parkinson’s disease: Implications for epidemiological studies of disease etiology. Rev Neurol (Paris). 2016;172:503-511.
37. 37. Tolosa E, Pont-Sunyer C. Progress in defining the premotor phase of Parkinson’s disease. J Neurol Sci. 2011;310:4-8.
38. 38. Adler CH, Beach TG. Neuropathological basis of nonmotor manifestations of Parkinson’s disease. Mov Disord. 2016;31:1114-1119.