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Camacho M, Greenland JC, Daruwalla C, Scott KM, Patel B, Apostolopoulos D, Ribeiro J, O'Reilly M, Hu MT, Williams-Gray CH. The profile of gastrointestinal dysfunction in prodromal to late-stage Parkinson's disease. NPJ Parkinsons Dis 2025; 11:123. [PMID: 40348767 PMCID: PMC12065915 DOI: 10.1038/s41531-025-00900-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 02/18/2025] [Indexed: 05/14/2025] Open
Abstract
Gastrointestinal dysfunction (GID) may play a key role in Parkinson's disease (PD) but its relationship with disease progression remains unclear. We recruited 404 PD cases, 37 iRBD (isolated REM Sleep Behaviour Disorder) and 105 controls. Participants completed the Gastrointestinal Dysfunction Scale for PD (GIDS-PD) and standardised disease severity assessments. Whole gut transit time (WGTT) was measured by ingestion of blue dye and recorded time to blue stools appearance ('Blue Poop Challenge') in a subset of PD cases. Gastrointestinal symptoms were more common and prevalent in iRBD and PD versus controls, and WGTT was significantly higher in PD versus controls. After adjustment for confounding factors, disease stage was not a significant predictor of GIDS-PD Constipation or Bowel Irritability scores. Longitudinal assessment of GIDS-PD scores and WGTT confirmed stability over a 4 year period. Bowel dysfunction may be a phenotypic feature in a subset of Parkinson's with implications for patient stratification and management.
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Affiliation(s)
- Marta Camacho
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
| | - Julia C Greenland
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Cyrus Daruwalla
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Kirsten M Scott
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Bina Patel
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | | | - Joana Ribeiro
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Molly O'Reilly
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Michele T Hu
- Nuffield Department Clinical Neurosciences, University of Oxford, Oxford, UK
| | - Caroline H Williams-Gray
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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Yuan XY, Chen YS, Liu Z. Relationship among Parkinson's disease, constipation, microbes, and microbiological therapy. World J Gastroenterol 2024; 30:225-237. [PMID: 38314132 PMCID: PMC10835526 DOI: 10.3748/wjg.v30.i3.225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 11/16/2023] [Accepted: 12/26/2023] [Indexed: 01/18/2024] Open
Abstract
This comprehensive review elucidates the complex interplay between gut microbiota and constipation in Parkinson's disease (PD), a prevalent non-motor symptom contributing significantly to patients' morbidity. A marked alteration in the gut microbiota, predominantly an increase in the abundance of Proteobacteria and Bacteroidetes, is observed in PD-related constipation. Conventional treatments, although safe, have failed to effectively alleviate symptoms, thereby necessitating the development of novel therapeutic strategies. Microbiological interventions such as prebiotics, probiotics, and fecal microbiota transplantation (FMT) hold therapeutic potential. While prebiotics improve bowel movements, probiotics are effective in enhancing stool consistency and alleviating abdominal discomfort. FMT shows potential for significantly alleviating constipation symptoms by restoring gut microbiota balance in patients with PD. Despite promising developments, the causal relationship between changes in gut microbiota and PD-related constipation remains elusive, highlighting the need for further research in this expanding field.
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Affiliation(s)
- Xin-Yang Yuan
- Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, Guangdong Province, China
- Institute of Neurology, Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Zhanjiang 524000, Guangdong Province, China
| | - Yu-Sen Chen
- Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, Guangdong Province, China
- Institute of Neurology, Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Zhanjiang 524000, Guangdong Province, China
| | - Zhou Liu
- Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, Guangdong Province, China
- Institute of Neurology, Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Zhanjiang 524000, Guangdong Province, China
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Seo MH, Kim SH, Yeo S. Serping1 associated with α-synuclein increase in colonic smooth muscles of MPTP-induced Parkinson's disease mice. Sci Rep 2024; 14:1140. [PMID: 38212417 PMCID: PMC10784473 DOI: 10.1038/s41598-024-51770-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 01/09/2024] [Indexed: 01/13/2024] Open
Abstract
Patients with Parkinson's disease (PD) have gastrointestinal motility disorders, which are common non-motor symptoms. However, the reasons for these motility disorders remain unclear. Increased alpha-synuclein (α-syn) is considered an important factor in peristalsis dysfunction in colonic smooth muscles in patients with PD. In this study, the morphological changes and association between serping1 and α-syn were investigated in the colon of the 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine-induced chronic PD model. Increased serping1 and α-syn were noted in the colon of the PD model, and decreased serping1 also induced a decrease in α-syn in C2C12 cells. Serping1 is a major regulator of physiological processes in the kallikrein-kinin system, controlling processes including inflammation and vasodilation. The kinin system also comprises bradykinin and bradykinin receptor 1. The factors related to the kallikrein-kinin system, bradykinin, and bradykinin receptor 1 were regulated by serping1 in C2C12 cells. The expression levels of bradykinin and bradykinin receptor 1, modulated by serping1 also increased in the colon of the PD model. These results suggest that the regulation of increased serping1 could alleviate Lewy-type α-synucleinopathy, a characteristic of PD. Furthermore, this study could have a positive effect on the early stages of PD progression because of the perception that α-syn in colonic tissues is present prior to the development of PD motor symptoms.
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Affiliation(s)
- Min Hyung Seo
- Department of Meridian and Acupoint, College of Korean Medicine, Sang Ji University, Wonju, 26339, Republic of Korea
- Division of Biological Science and Technology, Yonsei University, Yonseidae 1 Gil, Wonju, 26493, Republic of Korea
| | - Soo-Hwan Kim
- Division of Biological Science and Technology, Yonsei University, Yonseidae 1 Gil, Wonju, 26493, Republic of Korea.
| | - Sujung Yeo
- Research Institute of Korean Medicine, College of Korean Medicine, Sangji University, Wonju, 26339, Republic of Korea.
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Holtz AV, Fink A, Tamgüney G, Doblhammer G. Colonoscopy and Subsequent Risk of Parkinson's Disease. JOURNAL OF PARKINSON'S DISEASE 2024; 14:747-760. [PMID: 38669559 PMCID: PMC11191466 DOI: 10.3233/jpd-240017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 03/26/2024] [Indexed: 04/28/2024]
Abstract
Background Parkinson's disease (PD) is caused by the misfolding and aggregation of α-synuclein in neurons into toxic oligomers and fibrils that have prion-like properties allowing them to infect healthy neurons and to be transmitted to animal models of PD by injection or oral exposure. Given α-synuclein fibrils' potential transmission on the gut-brain axis, α-synuclein may be transmitted through colonoscopy procedures. Objective This study examines a possible association between colonoscopy and PD. Methods Longitudinal health insurance data of 250,000 individuals aged 50+ from 2004-2019 was analyzed. Cox proportional hazard and competing risk models with death as a competing event were estimated to calculate the risk of PD. Colonoscopy was categorized as never receiving colonoscopy, colorectal cancer (CRC) screening without or with biopsy, destruction or excision (BDE), and diagnostic colonoscopy without or with BDE. Results We identified 6,422 new cases of PD among 221,582 individuals. The Cox model revealed a significantly increased risk of PD for patients who ever had a diagnostic colonoscopy without or with BDE (HR = 1.31; 95% CI: [1.23-1.40]; HR = 1.32 [1.22-1.42]) after adjustment for age and sex. After controlling for covariates and death, persons who ever underwent CRC screening had a 40% reduced risk of PD (CRHR = 0.60 [0.54-0.67]), while persons who underwent diagnostic colonoscopy had a 20% reduced risk of PD (CRHR = 0.81 [0.75-0.88]). Conclusions Colonoscopy does not increase the risk of PD, after adjusting for death and covariates. Individuals who underwent only CRC screening had the lowest risk of PD, which may be a result of a more health-conscious lifestyle.
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Affiliation(s)
- Anna-Victoria Holtz
- German Center for Neurodegenerative Diseases(DZNE), Demographic Studies, Bonn, Germany
- University of Rostock, Institute for Sociology and Demography, Rostock, Germany
| | - Anne Fink
- German Center for Neurodegenerative Diseases(DZNE), Demographic Studies, Bonn, Germany
| | - Gültekin Tamgüney
- Forschungszentrum Jülich, Institute of Biological Information Processing – Structural Biochemistry (IBI-7), Jülich, Germany
- Mathematisch-Naturwissenschaftliche Fakultät, Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
| | - Gabriele Doblhammer
- German Center for Neurodegenerative Diseases(DZNE), Demographic Studies, Bonn, Germany
- University of Rostock, Institute for Sociology and Demography, Rostock, Germany
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Seo MH, Kwon D, Kim SH, Yeo S. Association between Decreased SGK1 and Increased Intestinal α-Synuclein in an MPTP Mouse Model of Parkinson's Disease. Int J Mol Sci 2023; 24:16408. [PMID: 38003598 PMCID: PMC10671719 DOI: 10.3390/ijms242216408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 11/13/2023] [Accepted: 11/14/2023] [Indexed: 11/26/2023] Open
Abstract
Parkinson's disease (PD) is a globally common progressive neurodegenerative disease resulting from the loss of dopaminergic neurons in the brain. Increased α-synuclein (α-syn) is associated with the degeneration of dopaminergic neurons and non-motor symptoms like gastrointestinal disorders. In this study, we investigated the association between serum/glucocorticoid-related kinase 1 (SGK1) and α-syn in the colon of a PD mouse model. SGK1 and α-syn expression patterns were opposite in the surrounding colon tissue, with decreased SGK1 expression and increased α-syn expression in the PD group. Immunofluorescence analyses revealed the colocation of SGK1 and α-syn; the PD group demonstrated weaker SGK1 expression and stronger α-syn expression than the control group. Immunoblotting analysis showed that Na+/K+ pump ATPase α1 expression levels were significantly increased in the PD group. In SW480 cells with SGK1 knockdown using SGK1 siRNA, decreasing SGK1 levels corresponded with significant increases in the expression levels of α-syn and ATPase α1. These results suggest that SGK1 significantly regulates Na+/K+ pump ATPase, influencing the relationship between electrolyte balance and fecal formation in the PD mouse model. Gastrointestinal disorders are some of the major prodromal symptoms of PD. Therefore, modulating SGK1 expression could be an important strategy for controlling PD.
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Affiliation(s)
- Min Hyung Seo
- Department of Meridian and Acupoint, College of Korean Medicine, Sang Ji University, Wonju 26339, Republic of Korea; (M.H.S.); (D.K.)
| | - Dasom Kwon
- Department of Meridian and Acupoint, College of Korean Medicine, Sang Ji University, Wonju 26339, Republic of Korea; (M.H.S.); (D.K.)
| | - Soo-Hwan Kim
- Division of Biological Science and Technology, Yonsei University, 1 Yonseidae-gil, Wonju 26493, Republic of Korea
| | - Sujung Yeo
- Research Institute of Korean Medicine, Sangji University, Wonju 26339, Republic of Korea
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Krasko MN, Szot J, Lungova K, Rowe LM, Leverson G, Kelm-Nelson CA, Ciucci MR. Pink1-/- Rats Demonstrate Swallowing and Gastrointestinal Dysfunction in a Model of Prodromal Parkinson Disease. Dysphagia 2023; 38:1382-1397. [PMID: 36949296 PMCID: PMC10514238 DOI: 10.1007/s00455-023-10567-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 02/27/2023] [Indexed: 03/24/2023]
Abstract
Early motor and non-motor signs of Parkinson disease (PD) include dysphagia, gastrointestinal dysmotility, and constipation. However, because these often manifest prior to formal diagnosis, the study of PD-related swallow and GI dysfunction in early stages is difficult. To overcome this limitation, we used the Pink1-/- rat, a well-established early-onset genetic rat model of PD to assay swallowing and GI motility deficits. Thirty male rats were tested at 4 months (Pink1-/- = 15, wildtype (WT) control = 15) and 6 months (Pink1-/- = 7, WT = 6) of age; analogous to early-stage PD in humans. Videofluoroscopy of rats ingesting a peanut-butter-barium mixture was used to measure mastication rate and oropharyngeal and pharyngoesophageal bolus speeds. Abnormal swallowing behaviors were also quantified. A second experiment tracked barium contents through the stomach, small intestine, caecum, and colon at hours 0-6 post-barium gavage. Number and weight of fecal emissions over 24 h were also collected. Compared to WTs, Pink1-/- rats showed slower mastication rates, slower pharyngoesophageal bolus speeds, and more abnormal swallowing behaviors. Pink1-/- rats demonstrated significantly delayed motility through the caecum and colon. Pink1-/- rats also had significantly lower fecal pellet count and higher fecal pellet weight after 24 h at 6 months of age. Results demonstrate that swallowing dysfunction occurs early in Pink1-/- rats. Delayed transit to the colon and constipation-like signs are also evident in this model. The presence of these early swallowing and GI deficits in Pink1-/- rats are analogous to those observed in human PD.
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Affiliation(s)
- Maryann N Krasko
- Department of Surgery, Division of Otolaryngology-Head & Neck Surgery, University of Wisconsin-Madison, 1300 University Ave, Madison, WI, 53706, USA.
- Department of Communication Sciences and Disorders, University of Wisconsin-Madison, 1975 Willow Drive, Madison, WI, 53706, USA.
| | - John Szot
- Department of Surgery, Division of Otolaryngology-Head & Neck Surgery, University of Wisconsin-Madison, 1300 University Ave, Madison, WI, 53706, USA
| | - Karolina Lungova
- Department of Surgery, Division of Otolaryngology-Head & Neck Surgery, University of Wisconsin-Madison, 1300 University Ave, Madison, WI, 53706, USA
- Department of Neuroscience, University of Wisconsin-Madison, 1111 Highland Ave, Madison, WI, 53705, USA
| | - Linda M Rowe
- Department of Surgery, Division of Otolaryngology-Head & Neck Surgery, University of Wisconsin-Madison, 1300 University Ave, Madison, WI, 53706, USA
- Department of Communication Sciences and Disorders, University of Wisconsin-Madison, 1975 Willow Drive, Madison, WI, 53706, USA
| | - Glen Leverson
- Department of Surgery, Division of Otolaryngology-Head & Neck Surgery, University of Wisconsin-Madison, 1300 University Ave, Madison, WI, 53706, USA
| | - Cynthia A Kelm-Nelson
- Department of Surgery, Division of Otolaryngology-Head & Neck Surgery, University of Wisconsin-Madison, 1300 University Ave, Madison, WI, 53706, USA
| | - Michelle R Ciucci
- Department of Surgery, Division of Otolaryngology-Head & Neck Surgery, University of Wisconsin-Madison, 1300 University Ave, Madison, WI, 53706, USA
- Department of Communication Sciences and Disorders, University of Wisconsin-Madison, 1975 Willow Drive, Madison, WI, 53706, USA
- Neuroscience Training Program, University of Wisconsin-Madison, 1111 Highland Ave, Madison, WI, 53705, USA
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7
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Seo MH, Yeo S. The Effects of Serping1 siRNA in α-Synuclein Regulation in MPTP-Induced Parkinson's Disease. Biomedicines 2023; 11:1952. [PMID: 37509591 PMCID: PMC10377285 DOI: 10.3390/biomedicines11071952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 07/06/2023] [Accepted: 07/07/2023] [Indexed: 07/30/2023] Open
Abstract
Our understanding of the gastrointestinal system in the pathophysiology of Parkinson's disease (PD) has grown considerably over the last two decades. Patients with PD experience notable gastrointestinal symptoms, including constipation. In this study, the effects of knocked-down serping1, associated with the contraction and relaxation of smooth muscle and inflammation responses, by applying the serping1 siRNA were investigated in 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine-induced PD mice in an α-syn change aspect. In the result, serping1 expression was knocked down by the treatment of serping1 siRNA, and decreased serping1 induced the decrease α-syn in the colon. Furthermore, the changes in α-syn aggregation were also examined in the brain, and alleviated α-syn aggregation was also observed in an serping1 siRNA treatment group. The results indicated that serping1 siRNA could ease synucleinopathy related to the gastrointestinal system in PD. This study also raises the possibility that serping1 siRNA could alleviate α-syn aggregation in striatum and substantia nigra regions of the brain.
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Affiliation(s)
- Min Hyung Seo
- Department of Meridian and Acupoint, College of Korean Medicine, Sang Ji University, Wonju 26339, Republic of Korea
| | - Sujung Yeo
- Research Institute of Korean Medicine, Sang Ji University, #83 Sangjidae-Gil, Wonju 26339, Republic of Korea
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8
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Warnecke T, Schäfer KH, Claus I, Del Tredici K, Jost WH. Gastrointestinal involvement in Parkinson's disease: pathophysiology, diagnosis, and management. NPJ Parkinsons Dis 2022; 8:31. [PMID: 35332158 PMCID: PMC8948218 DOI: 10.1038/s41531-022-00295-x] [Citation(s) in RCA: 79] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 02/23/2022] [Indexed: 12/12/2022] Open
Abstract
Growing evidence suggests an increasing significance for the extent of gastrointestinal tract (GIT) dysfunction in Parkinson's disease (PD). Most patients suffer from GIT symptoms, including dysphagia, sialorrhea, bloating, nausea, vomiting, gastroparesis, and constipation during the disease course. The underlying pathomechanisms of this α-synucleinopathy play an important role in disease development and progression, i.e., early accumulation of Lewy pathology in the enteric and central nervous systems is implicated in pharyngeal discoordination, esophageal and gastric motility/peristalsis impairment, chronic pain, altered intestinal permeability and autonomic dysfunction of the colon, with subsequent constipation. Severe complications, including malnutrition, dehydration, insufficient drug effects, aspiration pneumonia, intestinal obstruction, and megacolon, frequently result in hospitalization. Sophisticated diagnostic tools are now available that permit more detailed examination of specific GIT impairment patterns. Furthermore, novel treatment approaches have been evaluated, although high-level evidence trials are often missing. Finally, the burgeoning literature devoted to the GIT microbiome reveals its importance for neurologists. We review current knowledge about GIT pathoanatomy, pathophysiology, diagnosis, and treatment in PD and provide recommendations for management in daily practice.
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Affiliation(s)
- T Warnecke
- Department of Neurology with Institute of Translational Neurology, University Hospital of Münster, 48149, Münster, Germany
| | - K-H Schäfer
- Research and Transfer Working Group Enteric Nervous System (AGENS), University of Applied Sciences Kaiserslautern, Campus Zweibrücken, 66482, Zweibrücken, Germany
| | - I Claus
- Department of Neurology with Institute of Translational Neurology, University Hospital of Münster, 48149, Münster, Germany
| | - K Del Tredici
- Clinical Neuroanatomy, Department of Neurology, Center for Biomedical Research, University of Ulm, 89081, Ulm, Germany
| | - W H Jost
- Parkinson-Klinik Ortenau, 77709, Wolfach, Germany.
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Madla CM, Gavins FKH, Trenfield SJ, Basit AW. Special Populations. BIOPHARMACEUTICS 2022:205-237. [DOI: 10.1002/9781119678366.ch13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Han MN, Finkelstein DI, McQuade RM, Diwakarla S. Gastrointestinal Dysfunction in Parkinson’s Disease: Current and Potential Therapeutics. J Pers Med 2022; 12:jpm12020144. [PMID: 35207632 PMCID: PMC8875119 DOI: 10.3390/jpm12020144] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 01/17/2022] [Accepted: 01/18/2022] [Indexed: 02/04/2023] Open
Abstract
Abnormalities in the gastrointestinal (GI) tract of Parkinson’s disease (PD) sufferers were first reported over 200 years ago; however, the extent and role of GI dysfunction in PD disease progression is still unknown. GI dysfunctions, including dysphagia, gastroparesis, and constipation, are amongst the most prevalent non-motor symptoms in PD. These symptoms not only impact patient quality of life, but also complicate disease management. Conventional treatment pathways for GI dysfunctions (i.e., constipation), such as increasing fibre and fluid intake, and the use of over-the-counter laxatives, are generally ineffective in PD patients, and approved compounds such as guanylate cyclase C agonists and selective 5-hyroxytryptamine 4 receptor agonists have demonstrated limited efficacy. Thus, identification of potential targets for novel therapies to alleviate PD-induced GI dysfunctions are essential to improve clinical outcomes and quality of life in people with PD. Unlike the central nervous system (CNS), where PD pathology and the mechanisms involved in CNS damage are relatively well characterised, the effect of PD at the cellular and tissue level in the enteric nervous system (ENS) remains unclear, making it difficult to alleviate or reverse GI symptoms. However, the resurgence of interest in understanding how the GI tract is involved in various disease states, such as PD, has resulted in the identification of novel therapeutic avenues. This review focuses on common PD-related GI symptoms, and summarizes the current treatments available and their limitations. We propose that by targeting the intestinal barrier, ENS, and/or the gut microbiome, may prove successful in alleviating PD-related GI symptoms, and discuss emerging therapies and potential drugs that could be repurposed to target these areas.
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Affiliation(s)
- Myat Noe Han
- Gut-Axis Injury and Repair Laboratory, Department of Medicine Western Health, University of Melbourne, Melbourne, VIC 3021, Australia; (M.N.H.); (S.D.)
- The Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3010, Australia
- Australian Institute of Musculoskeletal Science (AIMSS), Melbourne, VIC 3021, Australia
| | - David I. Finkelstein
- Parkinson’s Disease Laboratory, The Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3010, Australia;
| | - Rachel M. McQuade
- Gut-Axis Injury and Repair Laboratory, Department of Medicine Western Health, University of Melbourne, Melbourne, VIC 3021, Australia; (M.N.H.); (S.D.)
- The Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3010, Australia
- Australian Institute of Musculoskeletal Science (AIMSS), Melbourne, VIC 3021, Australia
- Correspondence: ; Tel.: +61-3-8395-8114
| | - Shanti Diwakarla
- Gut-Axis Injury and Repair Laboratory, Department of Medicine Western Health, University of Melbourne, Melbourne, VIC 3021, Australia; (M.N.H.); (S.D.)
- The Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3010, Australia
- Australian Institute of Musculoskeletal Science (AIMSS), Melbourne, VIC 3021, Australia
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Katunina E, Shipilova N, Katunin D. Mechanisms of development of constipation in Parkinson’s disease and therapeutic approaches. Zh Nevrol Psikhiatr Im S S Korsakova 2022; 122:21-26. [DOI: 10.17116/jnevro202212208121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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Franco R, Casanovas B, Camps J, Navarro G, Martínez-Pinilla E. Antixoxidant Supplements versus Health Benefits of Brief/Intermittent Exposure to Potentially Toxic Physical or Chemical Agents. Curr Issues Mol Biol 2021; 43:650-664. [PMID: 34287292 PMCID: PMC8929025 DOI: 10.3390/cimb43020047] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 07/04/2021] [Accepted: 07/08/2021] [Indexed: 12/14/2022] Open
Abstract
Although antioxidants can act locally to react with an oxidant, oral administration of "antioxidants" is quite useless in treating oxidative stress in tissues. Furthermore, it does not make sense to consider a vitamin as an antioxidant, but vitamin B3 leads to the in vivo formation of compounds that are essential for reducing this stress. A rigorous treatment of the subject indicates that to deal with oxidative stress, the most direct approach is to enhance the innate antioxidant mechanisms. The question is whether this is possible through daily activities. Diets can contain the necessary components for these mechanisms or may induce the expression of the genes involved in them. Another possibility is that pro-oxidant molecules in food increase the sensitivity and power of the detoxification pathways. This option is based on well-known DNA repair mechanisms after exposure to radiation (even from the Sun), or strong evidence of induction of antioxidant capacity after exposure to powerful pro-oxidants such as H2O2. More experimental work is required to test whether some molecules in food can increase the expression of antioxidant enzymes and/or improve antioxidant mechanisms. Identifying effective molecules to achieve such antioxidant power is critical to the food and nutraceutical industries. The potential of diet-based interventions to combat oxidative stress must be viewed from a new perspective.
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Affiliation(s)
- Rafael Franco
- Department of Biochemistry and Molecular Biomedicine, School of Chemistry, University of Barcelona, 08028 Barcelona, Spain; (B.C.); (J.C.)
- Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CiberNed), Instituto de Salud Carlos III, 28031 Madrid, Spain;
- Correspondence: (R.F.); (E.M.-P.); Tel.: +34-934-021-208 (R.F.)
| | - Berta Casanovas
- Department of Biochemistry and Molecular Biomedicine, School of Chemistry, University of Barcelona, 08028 Barcelona, Spain; (B.C.); (J.C.)
| | - Jordi Camps
- Department of Biochemistry and Molecular Biomedicine, School of Chemistry, University of Barcelona, 08028 Barcelona, Spain; (B.C.); (J.C.)
| | - Gemma Navarro
- Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CiberNed), Instituto de Salud Carlos III, 28031 Madrid, Spain;
- Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Science, University of Barcelona, 02028 Barcelona, Spain
| | - Eva Martínez-Pinilla
- Department of Morphology and Cell Biology, Faculty of Medicine, University of Oviedo, 33006 Oviedo, Spain
- Instituto de Neurociencias del Principado de Asturias (INEUROPA), 33003 Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- Correspondence: (R.F.); (E.M.-P.); Tel.: +34-934-021-208 (R.F.)
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Walker AC, Bhargava R, Vaziriyan-Sani AS, Pourciau C, Donahue ET, Dove AS, Gebhardt MJ, Ellward GL, Romeo T, Czyż DM. Colonization of the Caenorhabditis elegans gut with human enteric bacterial pathogens leads to proteostasis disruption that is rescued by butyrate. PLoS Pathog 2021; 17:e1009510. [PMID: 33956916 PMCID: PMC8101752 DOI: 10.1371/journal.ppat.1009510] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 03/29/2021] [Indexed: 12/12/2022] Open
Abstract
Protein conformational diseases are characterized by misfolding and toxic aggregation of metastable proteins, often culminating in neurodegeneration. Enteric bacteria influence the pathogenesis of neurodegenerative diseases; however, the complexity of the human microbiome hinders our understanding of how individual microbes influence these diseases. Disruption of host protein homeostasis, or proteostasis, affects the onset and progression of these diseases. To investigate the effect of bacteria on host proteostasis, we used Caenorhabditis elegans expressing tissue-specific polyglutamine reporters that detect changes in the protein folding environment. We found that colonization of the C. elegans gut with enteric bacterial pathogens disrupted proteostasis in the intestine, muscle, neurons, and the gonad, while the presence of bacteria that conditionally synthesize butyrate, a molecule previously shown to be beneficial in neurodegenerative disease models, suppressed aggregation and the associated proteotoxicity. Co-colonization with this butyrogenic strain suppressed bacteria-induced protein aggregation, emphasizing the importance of microbial interaction and its impact on host proteostasis. Further experiments demonstrated that the beneficial effect of butyrate depended on the bacteria that colonized the gut and that this protective effect required SKN-1/Nrf2 and DAF-16/FOXO transcription factors. We also found that bacteria-derived protein aggregates contribute to the observed disruption of host proteostasis. Together, these results reveal the significance of enteric infection and gut dysbiosis on the pathogenesis of protein conformational diseases and demonstrate the potential of using butyrate-producing microbes as a preventative and treatment strategy for neurodegenerative disease.
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Affiliation(s)
- Alyssa C. Walker
- Department of Microbiology & Cell Science, University of Florida, Gainesville, Florida, United States of America
| | - Rohan Bhargava
- Department of Microbiology & Cell Science, University of Florida, Gainesville, Florida, United States of America
| | - Alfonso S. Vaziriyan-Sani
- Department of Microbiology & Cell Science, University of Florida, Gainesville, Florida, United States of America
| | - Christine Pourciau
- Department of Microbiology & Cell Science, University of Florida, Gainesville, Florida, United States of America
| | - Emily T. Donahue
- Department of Microbiology & Cell Science, University of Florida, Gainesville, Florida, United States of America
| | - Autumn S. Dove
- Department of Microbiology & Cell Science, University of Florida, Gainesville, Florida, United States of America
| | - Michael J. Gebhardt
- Division of Infectious Diseases, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Garrett L. Ellward
- Department of Microbiology & Cell Science, University of Florida, Gainesville, Florida, United States of America
| | - Tony Romeo
- Department of Microbiology & Cell Science, University of Florida, Gainesville, Florida, United States of America
| | - Daniel M. Czyż
- Department of Microbiology & Cell Science, University of Florida, Gainesville, Florida, United States of America
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14
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Gastrointestinal dysfunction in the synucleinopathies. Clin Auton Res 2020; 31:77-99. [PMID: 33247399 DOI: 10.1007/s10286-020-00745-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 11/04/2020] [Indexed: 12/15/2022]
Abstract
Interest in gastrointestinal dysfunction in Parkinson's disease has blossomed over the past 30 years and has generated a wealth of investigation into this non-motor aspect of the disorder, research that has encompassed its pathophysiology, its clinical features, and its impact on quality of life. The question of gastrointestinal dysfunction in the other synucleinopathies has not received nearly as much attention, but information and knowledge are growing. In this review, the current knowledge, controversies, and gaps in our understanding of the pathophysiology of gastrointestinal dysfunction in Parkinson's disease and the other synucleinopathies will be addressed, and extended focus will be directed toward the clinical problems involving saliva management, swallowing, gastric emptying, small intestinal function, and bowel function that are so problematic in these disorders.
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15
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Sesaminol prevents Parkinson's disease by activating the Nrf2-ARE signaling pathway. Heliyon 2020; 6:e05342. [PMID: 33163674 PMCID: PMC7609457 DOI: 10.1016/j.heliyon.2020.e05342] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 09/11/2020] [Accepted: 10/21/2020] [Indexed: 12/17/2022] Open
Abstract
Parkinson's disease (PD) is a neurodegenerative disease caused by the degeneration of substantia nigra neurons due to oxidative stress. Sesaminol has strong antioxidant and anti-cancer effects. We investigated the preventive effect on PD as a new physiological action of sesaminol produced from sesaminol glycoside using in vitro and in vivo PD models. To prepare an in vitro PD model, 6-hydroxydopamine (6-OHDA) was added to human neuroblastoma (SH-SY5Y cells). The viability of SH-SY5Y cells decreased dose-dependently following 6-OHDA treatment, but the addition of sesaminol restored viability to the control level. 6-OHDA increased intracellular reactive oxygen species production, and the addition of sesaminol significantly suppressed this increase. No Nrf2 expression in the nucleus was observed in the control group, but a slight increase was observed in the 6-OHDA group. The sesaminol group showed strong expression of Nrf2 in the cytoplasm and nucleus. NAD(P)H: quinone oxidoreductase (NQO1) activity was enhanced in the 6-OHDA group and further enhanced in the sesaminol group. Furthermore, the neurotoxine rotenone was orally administrated to mice to prepare an in vivo PD model. The motor function of rotenone-treated mice was shorter than that of the control group, but a small amount of sesaminol restored it to the control level. The intestinal motility in the rotenone group was significantly lower than that in the control group, but it remained at the control level in the sesaminol group. The expression of α-synuclein in the substantia nigra increased in the rotenone group but decreased in the sesaminol group. The rotenone group exhibited shortening and damage to the colonic mucosa, but these abnormalities of the colonic mucosa were scarcely observed in the sesaminol group. These results suggest that sesaminol has a preventative effect on PD.
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16
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Abstract
Recognition of the importance of nonmotor dysfunction as a component of Parkinson's disease has exploded over the past three decades. Autonomic dysfunction is a frequent and particularly important nonmotor feature because of the broad clinical spectrum it covers. Cardiovascular, gastrointestinal, urinary, sexual, and thermoregulatory abnormalities all can appear in the setting of Parkinson's disease. Cardiovascular dysfunction is characterized most prominently by orthostatic hypotension. Gastrointestinal dysfunction can involve virtually all levels of the gastrointestinal tract. Urinary dysfunction can entail either too frequent voiding or difficulty voiding. Sexual dysfunction is frequent and frustrating for both patient and partner. Alterations in sweating and body temperature are not widely recognized but often are present. Autonomic dysfunction can significantly and deleteriously impact quality of life for individuals with Parkinson's disease. Because effective treatment for many aspects of autonomic dysfunction is available, it is vitally important that assessment of autonomic dysfunction be a regular component of the neurologic history and exam and that appropriate treatment be initiated and maintained.
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Affiliation(s)
- Ronald F Pfeiffer
- Department of Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239-3098, USA.
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17
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Crowley EK, Nolan YM, Sullivan AM. Exercise as a therapeutic intervention for motor and non-motor symptoms in Parkinson's disease: Evidence from rodent models. Prog Neurobiol 2018; 172:2-22. [PMID: 30481560 DOI: 10.1016/j.pneurobio.2018.11.003] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 10/25/2018] [Accepted: 11/23/2018] [Indexed: 12/11/2022]
Abstract
Parkinson's disease (PD) is characterised by degeneration of dopaminergic neurons of the nigrostriatal pathway, which leads to the cardinal motor symptoms of the disease - tremor, rigidity and postural instability. A number of non-motor symptoms are also associated with PD, including cognitive impairment, mood disturbances and dysfunction of gastrointestinal and autonomic systems. Current therapies provide symptomatic relief but do not halt the disease process, so there is an urgent need for preventative strategies. Lifestyle interventions such as aerobic exercise have shown potential to lower the risk of developing PD and to alleviate both motor and non-motor symptoms. However, there is a lack of large-scale randomised clinical trials that have employed exercise in PD patients. This review will focus on the evidence from studies on rodent models of PD, for employing exercise as an intervention for both motor and non-motor symptoms.
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Affiliation(s)
- E K Crowley
- Department of Anatomy and Neuroscience, University College Cork, Ireland
| | - Y M Nolan
- Department of Anatomy and Neuroscience, University College Cork, Ireland; APC Microbiome Institute, University College Cork, Ireland
| | - A M Sullivan
- Department of Anatomy and Neuroscience, University College Cork, Ireland; APC Microbiome Institute, University College Cork, Ireland.
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18
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Hatton GB, Madla CM, Rabbie SC, Basit AW. Gut reaction: impact of systemic diseases on gastrointestinal physiology and drug absorption. Drug Discov Today 2018; 24:417-427. [PMID: 30453059 DOI: 10.1016/j.drudis.2018.11.009] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 10/25/2018] [Accepted: 11/13/2018] [Indexed: 12/17/2022]
Abstract
It was in 400 BC that Hippocrates reportedly stated that "death sits in the colon". The growth in our knowledge of the intestinal microbiome, the gut-brain axis and their function and imbalance has distinctly uncovered the complex relationship between the gut to disease predisposition and development, heralding the problem and the solution to disease pathology. Human studies of new drug molecules are typically performed in healthy volunteers and their specific disease indication. Approved drugs, however, are used by patients with diverse disease backgrounds. Here, we review the current literature of the gastrointestinal tract reacting to systemic disease pathology that elicits physiological and functional changes that consequently affect oral drug product performance.
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Affiliation(s)
- Grace B Hatton
- UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK
| | - Christine M Madla
- UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK
| | - Sarit C Rabbie
- UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK
| | - Abdul W Basit
- UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK.
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19
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Abstract
PURPOSE OF REVIEW During the past 25 years, there has been an explosion of information regarding the occurrence of gastrointestinal dysfunction in Parkinson's disease. In this review, the clinical features of gastrointestinal dysfunction in Parkinson's disease will be described and information regarding the potential role of the enteric nervous system and the gut microbiome in the genesis of Parkinson's disease will be addressed. RECENT FINDINGS Recognition is growing regarding the role that gastroparesis and small intestinal dysfunction may play in Parkinson's disease, especially with regard to erratic responses to anti-Parkinson medication. The presence of enteric nervous system involvement in Parkinson's disease is now well established, but whether the enteric nervous system is the starting point for Parkinson's disease pathology remains a source of debate. The potential role of the gut microbiome also is beginning to emerge. Gastrointestinal dysfunction is a prominent nonmotor feature of Parkinson's disease and dysfunction can be found along the entire length of the gastrointestinal tract. The enteric nervous system is clearly involved in Parkinson's disease. Whether it is the initial source of pathology is still a source of controversy. There also is growing recognition of the role that the gut microbiome may play in Parkinson's disease, but much more research is needed to fully assess this aspect of the disorder.
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Affiliation(s)
- Ronald F Pfeiffer
- Department of Neurology, Oregon Health and Science University, Portland, OR, USA.
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20
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A practical review of gastrointestinal manifestations in Parkinson's disease. Parkinsonism Relat Disord 2017; 39:17-26. [DOI: 10.1016/j.parkreldis.2017.02.029] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Revised: 02/06/2017] [Accepted: 02/21/2017] [Indexed: 02/06/2023]
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21
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Borghammer P, Knudsen K, Fedorova TD, Brooks DJ. Imaging Parkinson's disease below the neck. NPJ Parkinsons Dis 2017; 3:15. [PMID: 28649615 PMCID: PMC5460119 DOI: 10.1038/s41531-017-0017-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Revised: 12/21/2016] [Accepted: 03/21/2017] [Indexed: 01/18/2023] Open
Abstract
Parkinson's disease is a systemic disorder with widespread and early α-synuclein pathology in the autonomic and enteric nervous systems, which is present throughout the gastrointestinal canal prior to diagnosis. Gastrointestinal and genitourinary autonomic symptoms often predate clinical diagnosis by several years. It has been hypothesized that progressive α-synuclein aggregation is initiated in hyperbranched, non-myelinated neuron terminals, and may subsequently spread via retrograde axonal transport. This would explain why autonomic nerves are so prone to formation of α-synuclein pathology. However, the hypothesis remains unproven and in vivo imaging methods of peripheral organs may be essential to study this important research field. The loss of sympathetic and parasympathetic nerve terminal function in Parkinson's disease has been demonstrated using radiotracers such as 123I-meta-iodobenzylguanidin, 18F-dopamine, and 11C-donepezil. Other radiotracer and radiological imaging methods have shown highly prevalent dysfunction of pharyngeal and esophageal motility, gastric emptying, colonic transit time, and anorectal function. Here, we summarize the methodology and main findings of radio-isotope and radiological modalities for imaging peripheral pathology in Parkinson's disease.
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Affiliation(s)
- Per Borghammer
- Department of Nuclear Medicine & PET Centre, Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Karoline Knudsen
- Department of Nuclear Medicine & PET Centre, Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Tatyana D. Fedorova
- Department of Nuclear Medicine & PET Centre, Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - David J. Brooks
- Department of Nuclear Medicine & PET Centre, Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Division of Neuroscience, Department of Medicine, Imperial College London, London, UK
- Division of Neuroscience, Newcastle University, Newcastle upon Tyne, UK
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Knudsen K, Krogh K, Østergaard K, Borghammer P. Constipation in parkinson's disease: Subjective symptoms, objective markers, and new perspectives. Mov Disord 2016; 32:94-105. [PMID: 27873359 DOI: 10.1002/mds.26866] [Citation(s) in RCA: 106] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Revised: 09/30/2016] [Accepted: 10/05/2016] [Indexed: 12/16/2022] Open
Abstract
Constipation is among the first nonmotor symptoms to develop in the prodromal phase of PD. Pathological alpha-synuclein deposition is present throughout the gastrointestinal tract up to 20 years preceding diagnosis. Nevertheless, constipation in the context of PD remains ill defined and poorly understood. In this review, we summarize current knowledge of subjective symptoms and objective measures of constipation in PD. More than 10 different definitions of constipation have been used in the PD literature, making generalizations difficult. When pooling results from the most homogeneous studies in PD, a median constipation prevalence of 40% to 50% emerges, but with large variation across individual studies. Also, constipation prevalence tends to increase with disease progression. A similar prevalence is observed among patients with idiopathic rapid eye movement sleep behavior disorder. Interestingly, we detected a correlation between constipation prevalence in PD patients and healthy control groups in individual studies, raising concerns about how various constipation questionnaires are implemented across study populations. More than 80% of PD patients exhibit prolonged colonic transit time, and the same is probably true for de novo PD patients. Thus, the prevalence of objective colonic dysfunction exceeds the prevalence of subjective constipation. Colonic transit time measures are simple, widely available, and hold promise as a useful biomarker in manifest PD. More research is needed to elucidate the role of gastrointestinal dysfunction in disease progression of PD. Moreover, colonic transit measures may have utility as a more accurate risk factor for predicting PD in the prodromal phase. © 2016 International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Karoline Knudsen
- Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark
| | - Klaus Krogh
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Karen Østergaard
- Department of Neurology, Aarhus University Hospital, Aarhus, Denmark
| | - Per Borghammer
- Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark
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23
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Borghammer P, Knudsen K, Brooks DJ. Imaging Systemic Dysfunction in Parkinson’s Disease. Curr Neurol Neurosci Rep 2016; 16:51. [DOI: 10.1007/s11910-016-0655-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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Ali SA, Yin N, Rehman A, Justilien V. Parkinson Disease-Mediated Gastrointestinal Disorders and Rational for Combinatorial Therapies. Med Sci (Basel) 2016; 4:medsci4010001. [PMID: 29083365 PMCID: PMC5635767 DOI: 10.3390/medsci4010001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Revised: 12/24/2015] [Accepted: 01/13/2016] [Indexed: 12/29/2022] Open
Abstract
A gradual loss of dopamine-producing nerve cells gives rise to a common neurodegenerative Parkinson’s disease (PD). This disease causes a neurotransmitter imbalance in the brain and initiates a cascade of complications in the rest of the body that appears as distressing symptoms which include gait problems, tremor, gastrointestinal (GI) disorders and cognitive decline. To aid dopamine deficiency, treatment in PD patients includes oral medications, in addition to other methods such as deep brain stimulation and surgical lesioning. Scientists are extensively studying molecular and signaling mechanisms, particularly those involving phenotypic transcription factors and their co-regulatory proteins that are associated with neuronal stem cell (SC) fate determination, maintenance and disease state, and their role in the pathogenesis of PD. Advancement in scientific research and “personalized medicine” to augment current therapeutic intervention and minimize the side effects of chemotherapy may lead to the development of more effective therapeutic strategies in the near future. This review focuses on PD and associated GI complications and summarizes the current therapeutic modalities that include stem cell studies and combinatorial drug treatment.
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Affiliation(s)
- Syed A Ali
- Department of Cancer Biology, Mayo Clinic Cancer Center, Jacksonville, FL 32224, USA.
| | - Ning Yin
- Department of Cancer Biology, Mayo Clinic Cancer Center, Jacksonville, FL 32224, USA.
| | - Arkam Rehman
- Department of Pain Medicine, Baptist Medical Center, Jacksonville, FL 32258, USA.
| | - Verline Justilien
- Department of Cancer Biology, Mayo Clinic Cancer Center, Jacksonville, FL 32224, USA.
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25
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Essa H, Hamdy S. Evaluating the Scope of Gastrointestinal Symptoms of Parkinson's Disease: A Review of the Evidence. ACTA ACUST UNITED AC 2016. [DOI: 10.4303/ne/235955] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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27
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Kim JS, Sung HY. Gastrointestinal Autonomic Dysfunction in Patients with Parkinson's Disease. J Mov Disord 2015; 8:76-82. [PMID: 26090079 PMCID: PMC4460543 DOI: 10.14802/jmd.15008] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Revised: 04/03/2015] [Accepted: 04/07/2015] [Indexed: 12/20/2022] Open
Abstract
Currently, gastrointestinal dysfunctions in Parkinson’s disease (PD) are well-recognized problems and are known to be an initial symptom in the pathological process that eventually results in PD. Gastrointestinal symptoms may result from the involvement of either the central or enteric nervous systems, or these symptoms may be side effects of antiparkinsonian medications. Weight loss, excessive salivation, dysphagia, nausea/gastroparesis, constipation, and defecation dysfunction all may occur. Increased identification and early detection of these symptoms can result in a significant improvement in the quality of life for PD patients.
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Affiliation(s)
- Joong-Seok Kim
- Department of Neurology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hye-Young Sung
- Department of Gastroenterology, The Neighborhood Christian Clinic, AZ, USA
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29
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Rossi M, Merello M, Perez-Lloret S. Management of constipation in Parkinson's disease. Expert Opin Pharmacother 2014; 16:547-57. [PMID: 25539892 DOI: 10.1517/14656566.2015.997211] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Constipation is a frequent non-motor feature of Parkinson's disease (PD). It is the most common gastrointestinal symptom of the disease and it can precede motor symptoms by as much as 20 years. Constipation can produce discomfort and affect activities of daily living, productivity and quality of life, thus warranting early diagnosis and treatment. AREAS COVERED In this review, the safety and efficacy of traditional and novel strategies for constipation management will be discussed. A treatment algorithm for constipation in PD will be presented. EXPERT OPINION Polyethylene glycol and lubiprostone are first-line compounds recommended by evidence-based medicine guidelines for the treatment of constipation due to slow colonic transit in PD. Management of constipation secondary to defecatory dysfunction due to pelvic floor dyssynergia can be done by levodopa or apomorphine injections, botulinum toxin type A injection into the puborectalis muscle, and nonpharmacological interventions, like biofeedback therapy or functional magnetic stimulation, which showed some benefit in PD patients with constipation, but in general more extensive studies are warranted.
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Affiliation(s)
- Malco Rossi
- Raul Carrea Institute for Neurological Research (FLENI), Neuroscience Department, Movement Disorders Section , Buenos Aires , Argentina
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30
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Gjerløff T, Fedorova T, Knudsen K, Munk OL, Nahimi A, Jacobsen S, Danielsen EH, Terkelsen AJ, Hansen J, Pavese N, Brooks DJ, Borghammer P. Imaging acetylcholinesterase density in peripheral organs in Parkinson's disease with 11C-donepezil PET. ACTA ACUST UNITED AC 2014; 138:653-63. [PMID: 25539902 DOI: 10.1093/brain/awu369] [Citation(s) in RCA: 110] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Parkinson's disease is associated with early parasympathetic dysfunction leading to constipation and gastroparesis. It has been suggested that pathological α-synuclein aggregations originate in the gut and ascend to the brainstem via the vagus. Our understanding of the pathogenesis and time course of parasympathetic denervation in Parkinson's disease is limited and would benefit from a validated imaging technique to visualize the integrity of parasympathetic function. The positron emission tomography tracer 5-[(11)C]-methoxy-donepezil was recently validated for imaging acetylcholinesterase density in the brain and peripheral organs. Donepezil is a high-affinity ligand for acetylcholinesterase-the enzyme that catabolizes acetylcholine in cholinergic synapses. Acetylcholinesterase histology has been used for many years for visualizing cholinergic neurons. Using 5-[(11)C]-methoxy-donepezil positron emission tomography, we studied 12 patients with early-to-moderate Parkinson's disease (three female; age 64 ± 9 years) and 12 age-matched control subjects (three female; age 62 ± 8 years). We collected clinical information about motor severity, constipation, gastroparesis, and other parameters. Heart rate variability measurements and gastric emptying scintigraphies were performed in all subjects to obtain objective measures of parasympathetic function. We detected significantly decreased (11)C-donepezil binding in the small intestine (-35%; P = 0.003) and pancreas (-22%; P = 0.001) of the patients. No correlations were found between the (11)C-donepezil signal and disease duration, severity of constipation, gastric emptying time, and heart rate variability. In Parkinson's disease, the dorsal motor nucleus of the vagus undergoes severe degeneration and pathological α-synuclein aggregations are also seen in nerve fibres innervating the gastro-intestinal tract. In contrast, the enteric nervous system displays little or no loss of cholinergic neurons. Decreases in (11)C-donepezil binding may, therefore, represent a marker of parasympathetic denervation of internal organs, but further validation studies are needed.
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Affiliation(s)
- Trine Gjerløff
- 1 Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark
| | - Tatyana Fedorova
- 1 Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark
| | - Karoline Knudsen
- 1 Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark
| | - Ole L Munk
- 1 Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark
| | - Adjmal Nahimi
- 1 Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark
| | - Steen Jacobsen
- 1 Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark
| | | | | | - John Hansen
- 3 Department of Health Science and Technology, Aalborg University, Denmark
| | - Nicola Pavese
- 1 Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark 4 Division of Brain Sciences, Imperial College, London, UK
| | - David J Brooks
- 1 Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark 4 Division of Brain Sciences, Imperial College, London, UK
| | - Per Borghammer
- 1 Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark
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Abstract
Nonmotor symptoms occur commonly in Parkinson's disease (PD) patients and are frequently under-recognized and undertreated. Symptoms include sleep abnormalities, fatigue, autonomic disturbances, mood disorders and cognitive dysfunction. Early recognition and treatment of nonmotor symptoms in PD is critical to providing optimal management. A new screening questionnaire and the revised Unified PD Rating Scale should assist healthcare providers to better identify and evaluate these symptoms. This article reviews the identification and treatment of nonmotor symptoms in PD.
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Affiliation(s)
- Theresa A Zesiewicz
- Parkinson's Disease and Movement Disorders Center and Department of Neurology, University of South Florida,12901 Bruce B. Downs Blvd, MDC Box 55, Tampa, FL 33612, USA.
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32
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Berg D, Lang AE, Postuma RB, Maetzler W, Deuschl G, Gasser T, Siderowf A, Schapira AH, Oertel W, Obeso JA, Olanow CW, Poewe W, Stern M. Changing the research criteria for the diagnosis of Parkinson's disease: obstacles and opportunities. Lancet Neurol 2013; 12:514-24. [DOI: 10.1016/s1474-4422(13)70047-4] [Citation(s) in RCA: 94] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Abstract
Growing recognition of the non-motor features of Parkinson's disease (PD) has led to increased awareness of autonomic dysfunction as part of the disease process, not only in advanced disease but also early in its course, sometimes even preceding the development of the classic motor features of PD. Virtually all aspects of autonomic function can become impaired in PD, including cardiovascular, gastrointestinal, urological, sexual and thermoregulatory function. Recognition of the various autonomic abnormalities of PD is important because effective treatment may be available and may measurably improve quality of life for individuals with PD.
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Affiliation(s)
- Ronald F Pfeiffer
- Department of Neurology, University of Tennessee Health Science Center, 855 Monroe Avenue, Memphis, TN 38163, USA.
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Toebosch S, Tudyka V, Masclee A, Koek G. Treatment of recurrent sigmoid volvulus in Parkinson's disease by percutaneous endoscopic colostomy. World J Gastroenterol 2012; 18:5812-5. [PMID: 23155325 PMCID: PMC3484353 DOI: 10.3748/wjg.v18.i40.5812] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2012] [Revised: 06/13/2012] [Accepted: 06/28/2012] [Indexed: 02/06/2023] Open
Abstract
The exact aetiology of sigmoid volvulus in Parkinson's disease (PD) remains unclear. A multiplicity of factors may give rise to decreased gastrointestinal function in PD patients. Early recognition and treatment of constipation in PD patients may alter complications like sigmoid volvulus. Treatment of sigmoid volvulus in PD patients does not differ from other patients and involves endoscopic detorsion. If feasible, secondary sigmoidal resection should be performed. However, if the expected surgical morbidity and mortality is unacceptably high or if the patient refuses surgery, percutaneous endoscopic colostomy (PEC) should be considered. We describe an elderly PD patient who presented with sigmoid volvulus. She was treated conservatively with endoscopic detorsion. Surgery was consistently refused by the patient. After recurrence of the sigmoid volvulus a PEC was placed.
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Gastrointestinale Störungen beim idiopathischen Parkinson-Syndrom. DER NERVENARZT 2012; 83:1282-91. [DOI: 10.1007/s00115-012-3575-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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Abstract
Gastrointestinal (GI) symptoms are among the most common nonmotor manifestations of Parkinson's disease (PD), and they have many important ramifications for patients. The purpose of this review is to raise awareness of the full spectrum of GI symptoms in PD which include weight loss, sialorrhea, dysphagia, nausea, constipation, and defecatory dysfunction. We will discuss their practical significance, and outline a clear approach to their evaluation and management. A brief discussion about the impacts of commonly used medical and surgical PD therapies on GI symptom manifestation is also included.
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Sakakibara R, Kishi M, Ogawa E, Tateno F, Uchiyama T, Yamamoto T, Yamanishi T. Bladder, bowel, and sexual dysfunction in Parkinson's disease. PARKINSONS DISEASE 2011; 2011:924605. [PMID: 21918729 PMCID: PMC3171780 DOI: 10.4061/2011/924605] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/17/2010] [Revised: 05/06/2011] [Accepted: 05/30/2011] [Indexed: 12/14/2022]
Abstract
Bladder dysfunction (urinary urgency/frequency), bowel dysfunction (constipation), and sexual dysfunction (erectile dysfunction) (also called “pelvic organ” dysfunctions) are common nonmotor disorders in Parkinson's disease (PD). In contrast to motor disorders, pelvic organ autonomic dysfunctions are often nonresponsive to levodopa treatment. The brain pathology causing the bladder dysfunction (appearance of overactivity) involves an altered dopamine-basal ganglia circuit, which normally suppresses the micturition reflex. By contrast, peripheral myenteric pathology causing slowed colonic transit (loss of rectal contractions) and central pathology causing weak strain and paradoxical anal sphincter contraction on defecation (PSD, also called as anismus) are responsible for the bowel dysfunction. In addition, hypothalamic dysfunction is mostly responsible for the sexual dysfunction (decrease in libido and erection) in PD, via altered dopamine-oxytocin pathways, which normally promote libido and erection. The pathophysiology of the pelvic organ dysfunction in PD differs from that in multiple system atrophy; therefore, it might aid in differential diagnosis. Anticholinergic agents are used to treat bladder dysfunction in PD, although these drugs should be used with caution particularly in elderly patients who have cognitive decline. Dietary fibers, laxatives, and “prokinetic” drugs such as serotonergic agonists are used to treat bowel dysfunction in PD. Phosphodiesterase inhibitors are used to treat sexual dysfunction in PD. These treatments might be beneficial in maximizing the patients' quality of life.
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Affiliation(s)
- Ryuji Sakakibara
- Neurology Division, Department of Internal Medicine, Sakura Medical Center, Toho University, 564-1 Shimoshizu, Sakura 285-8741, Japan
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Gastrointestinal dysfunction in a Parkinson's disease rat model and the changes of dopaminergic, nitric oxidergic, and cholinergic neurotransmitters in myenteric plexus. J Mol Neurosci 2011. [PMID: 21647710 PMCID: PMC3462904 DOI: 10.1007/s12031-012-9723-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Zhu HC, Zhao J, Luo CY, Li QQ. Gastrointestinal dysfunction in a Parkinson's disease rat model and the changes of dopaminergic, nitric oxidergic, and cholinergic neurotransmitters in myenteric plexus. J Mol Neurosci 2011; 47:15-25. [PMID: 21647710 PMCID: PMC3338324 DOI: 10.1007/s12031-011-9560-0] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2010] [Accepted: 05/16/2011] [Indexed: 01/30/2023]
Abstract
This study aims to explore the gastrointestinal dysfunction and the changes of dopaminergic, nitric oxidergic, and cholinergic neurons in the myenteric plexus of a Parkinson’s disease (PD) rat model. A PD rat model was induced through unilateral substantia nigra administration of 6-hydroxydopamine. Four weeks later, the feces in 1 h and residual solid food in stomach at 2 h after feeding were measured. Changes in tyrosine hydroxylase (TH) in substantial nigra, TH, choline acetyltransferase (ChAT), and neuronal nitric oxide synthase (nNOS) in gastric antrum and colon tissue were examined by immunohistochemistry. Reverse transcription (RT) polymerase chain reaction (PCR) and Western blot were used to evaluate and compare the levels of messenger RNA (mRNA) and protein expression of TH, ChAT, and nNOS in the GI tract between normal and 6-hydroxydopamine-lesioned rats. Compared with control samples, the number of TH+ cells in the damaged side of substantia nigra of 6-hydroxydopamine-lesioned rats decreased significantly (P < 0.01). The weight and water content of the fecal matter decreased (P < 0.01), and the percentage of residual solid food increased (P < 0.01). The average integrated optical densities of TH-positive areas in the gastric antrum and colon tissue increased significantly (P < 0.01), nNOS decreased significantly (P < 0.01), and there were no significant changes in ChAT (P > 0.05). TH and nNOS mRNA levels in the gastric antrum and proximal colon decreased (P < 0.01), there were no significant changes in ChAT mRNA levels (P > 0.05). The protein levels of TH in the GI tract were significantly increased (P < 0.01), nNOS significantly decreased (P < 0.01), and ChAT had no significant changes (P > 0.05). 6-Hydroxydopamine-lesioned rats had delayed gastric emptying and constipation that might be related to the gastrointestinal TH increase and nNOS decrease. These symptoms were not related to changes in cholinergic transmitters.
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Affiliation(s)
- Hong Can Zhu
- Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
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40
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Pfeiffer RF. Gastrointestinal dysfunction in Parkinson's disease. Parkinsonism Relat Disord 2010; 17:10-5. [PMID: 20829091 DOI: 10.1016/j.parkreldis.2010.08.003] [Citation(s) in RCA: 185] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2010] [Accepted: 08/04/2010] [Indexed: 02/06/2023]
Abstract
In recent years, an increasingly detailed picture of gastrointestinal dysfunction in the setting of Parkinson's disease has emerged. Abnormalities of function may occur at virtually all levels of the gastrointestinal tract. Weight loss, dental deterioration, salivary excess, dysphagia, gastroparesis, decreased bowel movement frequency, and anorectal dysfunction all may occur. The pathophysiologic basis for this dysfunction entails both central and enteric nervous system involvement.
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Affiliation(s)
- Ronald F Pfeiffer
- Department of Neurology, University of Tennessee Health Science Center, 855 Monroe Avenue, Memphis, TN 38163, USA.
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Fernandez N, Garcia JJ, Diez MJ, Sahagun AM, Díez R, Sierra M. Effects of dietary factors on levodopa pharmacokinetics. Expert Opin Drug Metab Toxicol 2010; 6:633-42. [DOI: 10.1517/17425251003674364] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Pfeiffer RF. Gastrointestinal, urological, and sexual dysfunction in Parkinson's disease. Mov Disord 2010; 25 Suppl 1:S94-7. [DOI: 10.1002/mds.22715] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
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Abstract
Gastrointestinal (GI) motility is very frequently disturbed in Parkinson's disease (PD), manifesting chiefly as dysphagia, impaired gastric emptying and constipation. All these symptoms - constipation in particular - may precede the clinical diagnosis of PD for years. In the future, these symptoms might serve as useful early indicators in the premotor stage. Disturbed gastric emptying is an important factor in unpredictable fluctuations. The most likely causes are degenerations of the dorsal vagal nucleus and the intramural plexus of the whole intestine. These degenerations are likely to develop prior to the degeneration of dopaminergic neurons of the substantia nigra. Diagnosis includes history, clinical examination, barium meal, breath test, scintiscan of stomach, and colonic transit time. Therapeutic efforts are limited when it comes to disturbed motility of the upper GI-tract. Hypersalivation can be reduced by anticholinergics or botulinum toxin injections; motility of the upper gastrointestinal tract is only moderately impacted on by domperidone. In constipation, the conservative therapeutic option is administration of macrogol (polyethylene glycol), which leads to marked improvement.
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Affiliation(s)
- Wolfgang H Jost
- Dept. of Neurology, Deutsche Klinik für Diagnostik, Wiesbaden, Germany.
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Abstract
Constipation and faecal incontinence are common symptoms among patients with spinal cord injury (SCI), myelomeningocoele (MMC), multiple sclerosis (MS), Parkinson's disease (PD) and stroke. Faecal incontinence in SCI, MMC and MS is mainly due to abnormal rectosigmoid compliance and rectoanal reflexes, loss of rectoanal sensibility and loss of voluntary control of the external anal sphincter. Constipation in SCI, MMC and MS is probably due to immobilisation, abnormal colonic contractility, tone and rectoanal reflexes or side effects from medication. In PD, dystonia of the external anal sphincter causes difficult rectal evacuation and the loss of dopaminergic neurons in the enteric nervous system probably causes slow-transit constipation. Changes after stroke remain to be studied. Though dietary adjustments, oral laxatives, suppositories and other conservative treatment modalities are commonly used, evidence for their use in patients with central neurological disorders is scarce. For patients with severe symptoms trans-anal irrigation, the Malone appendicostomy or a colostomy can be recommended.
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Affiliation(s)
- Klaus Krogh
- Neurogastroenterology Unit, Department of Hepatology and Gastroenterology V, Aarhus University Hospital, Norrebrogade 2, 8000 Aarhus C, Denmark.
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Petrovitch H, Abbott RD, Ross GW, Nelson J, Masaki KH, Tanner CM, Launer LJ, White LR. Bowel movement frequency in late-life and substantia nigra neuron density at death. Mov Disord 2009; 24:371-6. [PMID: 19006191 DOI: 10.1002/mds.22360] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Constipation is associated with future risk of Parkinson's disease (PD) and with incidental Lewy bodies (LB) in the locus ceruleus or substantia nigra (SN). Our purpose is to examine the independent association between bowel movement frequency in late-life and postmortem SN neuron density. Bowel movement frequency was assessed in the Honolulu-Asia Aging Study from 1991 to 1993 in 414 men aged 71 to 93 years with later postmortem evaluations. Brains were examined for LB in the SN and locus ceruleus and neurons were counted in four quadrants from a transverse section of SN. In nonsmokers, neuron densities (counts/mm(2)) for men with >1, 1, and <1 bowel movement daily were 18.5, 18.8, 10.1 (P < 0.001) for dorsomedial; 15.3, 16.4, 10.2 (P < 0.03) for ventromedial; and 18.6, 18.3, 10.9 (P = 0.011) for ventrolateral quadrants. Relationships were not significant in the dorsolateral quadrant or in any quadrant among smokers. After adjustment for age, time to death, coffee drinking, tricep skinfold thickness, excessive daytime sleepiness, cognitive function, PD, and incidental LB, density ratios in nonsmokers with 1 or more bowel movement(s) daily were significantly higher compared to those with <1 daily. Constipation is associated with low SN neuron density independent of the presence of LB.
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46
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Sakakibara R, Uchiyama T, Yamanishi T, Shirai K, Hattori T. Bladder and bowel dysfunction in Parkinson's disease. J Neural Transm (Vienna) 2008; 115:443-60. [PMID: 18327532 DOI: 10.1007/s00702-007-0855-9] [Citation(s) in RCA: 94] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2007] [Accepted: 11/01/2007] [Indexed: 12/14/2022]
Abstract
Bladder dysfunction (urinary urgency/frequency) and bowel dysfunction (constipation) are common non-motor disorders in Parkinson's disease (PD). In contrast to motor disorder, the pelvic autonomic dysfunction is often non-responsive to levodopa treatment. Brain pathology mostly accounts for the bladder dysfunction (appearance of overactivity) via altered dopamine-basal ganglia circuit, which normally suppresses the micturition reflex. In contrast, peripheral enteric pathology mostly accounts for the bowel dysfunction (slow transit and decreased phasic contraction) via altered dopamine-enteric nervous system circuit, which normally promotes the peristaltic reflex. In addition, weak strain and paradoxical anal contraction might be the results of brain pathology. Pathophysiology of the pelvic organ dysfunction in PD differs from that in multiple system atrophy; therefore it might aid the differential diagnosis. Drugs to treat bladder dysfunction in PD include anticholinergic agents. Drugs to treat bowel dysfunction in PD include dietary fibers, peripheral dopaminergic antagonists, and selective serotonergic agonists. These treatments might be beneficial not only in maximizing patients' quality of life, but also in promoting intestinal absorption of levodopa and avoiding gastrointestinal emergency.
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Affiliation(s)
- R Sakakibara
- Department of Internal Medicine, Toho University, Sakura, Japan.
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47
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Poewe W. Dysautonomia and cognitive dysfunction in Parkinson's disease. Mov Disord 2007; 22 Suppl 17:S374-8. [DOI: 10.1002/mds.21681] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
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Abstract
There is growing recognition that gastrointestinal dysfunction is common in Parkinson's disease (PD). Virtually all parts of the gastrointestinal tract can be affected, in some cases early in the disease course. Weight loss is common but poorly understood in people with PD. Dysphagia can result from dysfunction at the mouth, pharynx, and oesophagus and may predispose individuals to aspiration (accidental inhalation of food or liquid). Gastroparesis can produce various symptoms in patients with PD and may cause erratic absorption of drugs given to treat the disorder. Bowel dysfunction can consist of both slowed colonic transit with consequent reduced bowel-movement frequency, and difficulty with the act of defecation itself with excessive straining and incomplete emptying. Recognition of these gastrointestinal complications can lead to earlier and potentially more effective therapeutic intervention.
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49
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Abstract
Hippocrates noted that "it is a general rule, that intestines become sluggish with age", though the precise mechanisms for this association remains uncertain even today.
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Affiliation(s)
- K Winge
- Department of Neurology, Bispebjerg University Hospital, DK-2400 Copenhagen, Denmark.
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50
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Abbott RD, Petrovitch H, White LR, Masaki KH, Tanner CM, Curb JD, Grandinetti A, Blanchette PL, Popper JS, Ross GW. Frequency of bowel movements and the future risk of Parkinson's disease. Neurology 2001; 57:456-62. [PMID: 11502913 DOI: 10.1212/wnl.57.3.456] [Citation(s) in RCA: 557] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Constipation is frequent in PD, although its onset in relation to clinical PD has not been well described. Demonstration that constipation can precede clinical PD could provide important clues to understanding disease progression and etiology. The purpose of this report is to examine the association between the frequency of bowel movements and the future risk of PD. METHODS Information on the frequency of bowel movements was collected from 1971 to 1974 in 6790 men aged 51 to 75 years without PD in the Honolulu Heart Program. Follow-up for incident PD occurred over a 24-year period. RESULTS Ninety-six men developed PD an average of 12 years into follow-up. Age-adjusted incidence declined consistently from 18.9/10,000 person-years in men with <1 bowel movement/day to 3.8/10,000 person-years in those with >2/day (p = 0.005). After adjustment for age, pack-years of cigarette smoking, coffee consumption, laxative use, jogging, and the intake of fruits, vegetables, and grains, men with <1 bowel movement/day had a 2.7-fold excess risk of PD versus men with 1/day (95% CI: 1.3, 5.5; p = 0.007). The risk of PD in men with <1 bowel movement/day increased to a 4.1-fold excess when compared with men with 2/day (95% CI: 1.7, 9.6; p = 0.001) and to a 4.5-fold excess versus men with >2/day (95% CI: 1.2, 16.9; p = 0.025). CONCLUSIONS Findings indicate that infrequent bowel movements are associated with an elevated risk of future PD. Further study is needed to determine whether constipation is part of early PD processes or is a marker of susceptibility or environmental factors that may cause PD.
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Affiliation(s)
- R D Abbott
- Division of Biostatistics and Epidemiology, University of Virginia School of Medicine, Charlottesville, USA.
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