Constipation Increases Disability and Decreases Dopamine Levels in the Nigrostriatal System through Gastric Inflammatory Factors in Parkinson’s Disease

Author(s): Yongtao Zhou, Yusheng Su, Weihua Xu*, Wei Wang, Shukun Yao.

Journal Name: Current Neurovascular Research

Volume 16 , Issue 3 , 2019

Become EABM
Become Reviewer

Abstract:

Objective: Recent studies suggest that not only is constipation a clinical marker of premotor phase in Parkinson’s Disease (PD), but is also correlated with the duration and severity. Some reports indicated that inflammatory from gut dysbiosis might be involved in the pathogenesis of PD, but the correlation between them remains poorly understood. This study aims to investigate how the presence of constipation affects the dopamine level of nigrostriatal system and whether gastrointestinal (GI) inflammation is involved in the brain-gut axis.

Methods: Clinical materials, serum inflammatory factors, and datum of dopamine level including 84 cases and 83 controls, were collected consecutively and randomly from November 1, 2017 to October 31, 2018. Dopamine levels of nigrostriatal system were detected by [18F]-DTBZ radiotracer (18F-AV-133). Data analysis was conducted by variance, covariance analysis, bicorrelation, partial correlation, chi-square analysis and logistic regression.

Results: The mean age of cases was older than that of controls, and male predominance was also observed (P<0.05). The mean scores of Hoehn-Yahr and unified Parkinson’s disease rating scale Ⅲ (UPDRS-Ⅲ) were of significantly different duration between two groups (P<0.05). The total dose of levodopa was not different between two groups (P>0.05). The dopamine levels of putamen and caudate nucleus, especially in the dorsal part of putamen, were significantly decreased in cases than that in controls (P<0.05). There were significant differences of complement 3 (C3) and complement 4 (C4) between cases and controls (P<0.05). Dopamine levels in putamen and caudate nucleus were negatively correlated with serum concentrations of immunoglobulin A (IgA), immunoglobulin G (IgG) and C3 in cases (P<0.05). But we did not observe similar negative correlations in controls (P>0.05).

Conclusion: The presence of constipation may increase the severity of motor symptoms and decrease dopamine levels of nigrostriatal system in PD. Inflammatory factors may be involved in the brain-gut axis of PD.

Keywords: Constipation, Parkinson's disease, inflammation, dopamine, immunoglobulin, nigrostriatal system.

[1]
Todorova A, Jenner P, Ray Chaudhuri K. Non-motor Parkinson’s: Integral to motor Parkinson’s, yet often neglected. Pract Neurol 2014; 14(5): 310-22.
[2]
Pfeiffer RF. Gastrointestinal dysfunction in Parkinson’s disease. Curr Treat Options Neurol 2018; 20(12): 54.
[3]
Marrinan S, Emmanuel AV, Burn DJ. Delayed gastric emptying in Parkinson’s disease. Mov Disord 2014; 29(1): 23-32.
[4]
Mukherjee A, Biswas A, Das SK. Gut dysfunction in Parkinson’s disease. World J Gastroenterol 2016; 22(25): 5742-52.
[5]
Cersosimo MG, Raina GB, Pecci C, et al. Gastrointestinal manifestations in Parkinson’s disease: Prevalence and occurrence before motor symptoms. J Neurol 2013; 260(5): 1332-8.
[6]
Lin CH, Lin JW, Liu YC, Chang CH, Wu RM. Risk of Parkinson’s disease following severe constipation: A nationwide population-based cohort study. Parkinsonism Relat Disord 2014; 20(12): 1371-5.
[7]
Yu QJ, Yu SY, Zuo LJ, et al. Parkinson disease with constipation: Clinical features and relevant factors. Sci Rep 2018; 8(1): 567.
[8]
Krogh K, Ostergaard K, Sabroe S, Laurberg S. Clinical aspects of bowel symptoms in Parkinson’s disease. Acta Neurol Scand 2008; 117(1): 60-4.
[9]
Braak H, Del Tredici K. Neuropathological staging of brain pathology in sporadic Parkinson’s disease: Separating the wheat from the chaff. J Parkinsons Dis 2017; 7(s1): S71-85.
[10]
Williams-Gray CH, Wijeyekoon R, Yarnall AJ, et al. ICICLE-PD study group Serum immune markers and disease progression in an incident Parkinson’s disease cohort (ICICLE-PD). Mov Disord 2016; 31(7): 995-1003.
[11]
Bodea LG, Wang Y, Linnartz-Gerlach B, et al. Neurodegeneration by activation of the microglial complement-phagosome pathway. J Neurosci 2014; 34(25): 8546-56.
[12]
Liang Y, Li S, Guo Q, et al. Complement 3-deficient mice are not protected against MPTP-induced dopaminergic neurotoxicity. Brain Res 2007; 1178: 132-40.
[13]
Carpanini SM, Torvell M, Morgan BP. Therapeutic inhibition of the complement system in diseases of the central nervous system. Front Immunol 2019; 10: 362.
[14]
Loeffler DA, Camp DM, Conant SB. Complement activation in the Parkinson’s disease substantia nigra: An immunocytochemical study. J Neuroinflammation 2006; 3: 29.
[15]
Wang XJ, Yan ZQ, Lu GQ, Stuart S, Chen SD. Parkinson disease IgG and C5a-induced synergistic dopaminergic neurotoxicity: Role of microglia. Neurochem Int 2007; 50(1): 39-50.
[16]
Skorvanek M, Ladomirjakova Z, Han V, et al. Prevalence of prodromal Parkinson’s disease as defined by MDS research criteria among elderly patients undergoing colonoscopy. J Parkinsons Dis 2017; 7(3): 481-9.
[17]
Lebouvier T, Neunlist M, des Varannes SB, et al. Colonic biopsies to assess the neuropathology of Parkinson’s disease and its relationship with symptoms. PLoS One 2010; 5(9): e12728.
[18]
Unger MM, Belke M, Menzler K, et al. Diffusion tensor imaging in idiopathic REM sleep behavior disorder reveals microstructural changes in the brainstem, substantia nigra, olfactory region, and other brain regions. Sleep 2010; 33(6): 767-73.
[19]
Gao R, Zhang G, Chen X, et al. CSF Biomarkers and its associations with 18F-AV133 cerebral VMAT2 binding in Parkinson’s disease-a preliminary report. PLoS One 2016; 11(10): e0164762.
[20]
Matthews DC, Lerman H, Lukic A, et al. FDG PET Parkinson’s disease-related pattern as a biomarker for clinical trials in early stage disease. Neuroimage Clin 2018; 20: 572-9.
[21]
Knudsen K, Szwebs M, Hansen AK, Borghammer P. Gastric emptying in Parkinson’s disease- A mini-review. Parkinsonism Relat Disord 2018; 55: 18-25.
[22]
Savica R, Bradley BF, Mielke MM. When do α-synucleinopathies start? An epidemiological timeline: A review. JAMA Neurol 2018; 75(4): 503-9.
[23]
Zhou YT, Yang JF, Zhang YL, Wang XY, Chan P. Protective role of interlekin-1 alpha gene polymorphism in Chinese Han population with sporadic Parkinson’s disease. Neurosci Lett 2008; 445(1): 23-5.
[24]
Zhang H, Gu Z, An J, Wang C, Chan P. Non-motor symptoms in treated and untreated Chinese patients with early Parkinson’s disease. Tohoku J Exp Med 2014; 232(2): 129-36.
[25]
Rome F. Guidelines--Rome III diagnostic criteria for functional gastrointestinal disorders. J Gastrointestin Liver Dis 2006; 15(3): 307-12.
[26]
Hoehn MM, Yahr MD. Parkinsonism: Onset, progression, and mortality. 1967. Neurology 2006; 15(3): 307-12.
[27]
Fahn S, Elton RL. Members of the UPDRS development committee unified Parkinson’s disease rating scale.Recent developments in Parkinson’s disease. Florham Park: Macmillan Healthcare Information 1987; pp. 153-63.
[28]
Tomlinson CL, Stowe R, Patel S, Rick C, Gray R, Clarke CE. Systematic review of levodopa dose equivalency reporting in Parkinson’s disease. Mov Disord 2010; 25(15): 2649-53.
[29]
Zhou YT, Zhang ZX, Chan P, et al. Genetic association between low-density lipoprotein receptor-related protein gene polymorphisms and Alzheimer’s disease in Chinese Han population. Neurosci Lett 2008; 444(1): 109-11.
[30]
Lundström O, Manjer J, Ohlsson B. Smoking is associated with several functional gastrointestinal symptoms. Scand J Gastroenterol 2016; 51(8): 914-22.
[31]
Pedrosa Carrasco AJ, Timmermann L, Pedrosa DJ. Management of constipation in patients with Parkinson’s disease. NPJ Parkinsons Dis 2018; 4: 6.
[32]
Alexander PK, Lie Y, Jones G, et al. Management impact of imaging brain vesicular monoamine transporter type 2 in clinically uncertain Parkinsonian syndrome with 18F-AV133 and PET. J Nucl Med 2017; 58(11): 1815-20.
[33]
Xu SS, Alexander PK, Lie Y, et al. Diagnostic accuracy of imaging brain vesicular monoamine transporter type 2 (VMAT2) in clinically uncertain parkinsonian syndrome (CUPS): A 3-year follow-up study in community patients. BMJ Open 2018; 8(11): e025533.
[34]
Macpherson AJ, Köller Y, McCoy KD. The bilateral responsiveness between intestinal microbes and IgA. Trends Immunol 2015; 36(8): 460-70.
[35]
Gutzeit C, Magri G, Cerutti A. Intestinal IgA production and its role in host-microbe interaction. Immunol Rev 2014; 260(1): 76-85.
[36]
Wang Y, Hancock AM, Bradner J, et al. Complement 3 and factor h in human cerebrospinal fluid in Parkinson’s disease, Alzheimer’s disease, and multiple-system atrophy. Am J Pathol 2011; 178(4): 1509-16.
[37]
Hou L, Wang K, Zhang C, et al. Complement receptor 3 mediates NADPH oxidase activation and dopaminergic neurodegeneration through a Src-Erk-dependent pathway. Redox Biol 2018; 14: 250-60.
[38]
Fiebich BL, Batista CRA, Saliba SW, Yousif NM, de Oliveira ACP. Role of Microglia TLRs in Neurodegeneration. Front Cell Neurosci 2018; 12: 329.
[39]
Kim JS, Sung HY. Gastrointestinal autonomic dysfunction in patients with Parkinson’s disease. J Mov Disord 2015; 8(2): 76-82.
[40]
Edwards L, Quigley EM, Hofman R, Pfeiffer RF. Gastrointestinal symptoms in Parkinson disease: 18-month follow-up study. Mov Disord 1993; 8(1): 83-6.
[41]
Ashraf W, Pfeiffer RF, Park F, Lof J, Quigley EM. Constipation in Parkinson’s disease: Objective assessment and response to psyllium. Mov Disord 1997; 12(6): 946-51.
[42]
Kuo YM, Nwankwo EI, Nussbaum RL, Rogers J, Maccecchini ML. Translational inhibition of α-synuclein by Posiphen normalizes distal colon motility in transgenic Parkinson mice. Am J Neurodegener Dis 2019; 8(1): 1-15.
[43]
Cassani E, Privitera G, Pezzoli G, et al. Use of probiotics for the treatment of constipation in Parkinson’s disease patients. Minerva Gastroenterol Dietol 2011; 57(2): 117-21.
[44]
Albanese A, Brisinda G, Bentivoglio AR, Maria G. Treatment of outlet obstruction constipation in Parkinson’s disease with botulinum neurotoxin A. Am J Gastroenterol 2003; 98(6): 1439-40.
[45]
Barichella M, Pacchetti C, Bolliri C, et al. Probiotics and prebiotic fiber for constipation associated with Parkinson disease: An RCT. Neurology 2016; 87(12): 1274-80.
[46]
Neiworth-Petshow EM, Baldwin-Sayre C. Naturopathic treatment of gastrointestinal dysfunction in the setting of Parkinson’s disease. Integr Med (Encinitas) 2018; 17(4): 44-50.
[47]
Rota L, Pellegrini C, Benvenuti L, et al. Constipation, deficit in colon contractions and alpha-synuclein inclusions within the colon precede motor abnormalities and neurodegeneration in the central nervous system in a mouse model of alpha-synucleinopathy. Transl Neurodegener 2019; 8: 5.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 16
ISSUE: 3
Year: 2019
Page: [241 - 249]
Pages: 9
DOI: 10.2174/1567202616666190618170103
Price: $58

Article Metrics

PDF: 33
HTML: 2