|
1
|
Craig CF, Finkelstein DI, McQuade RM, Diwakarla S. Understanding the potential causes of gastrointestinal dysfunctions in multiple system atrophy. Neurobiol Dis 2023; 187:106296. [PMID: 37714308 DOI: 10.1016/j.nbd.2023.106296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 09/12/2023] [Accepted: 09/13/2023] [Indexed: 09/17/2023] Open
Abstract
Multiple system atrophy (MSA) is a rare, progressive neurodegenerative disorder characterised by autonomic, pyramidal, parkinsonian and/or cerebellar dysfunction. Autonomic symptoms of MSA include deficits associated with the gastrointestinal (GI) system, such as difficulty swallowing, abdominal pain and bloating, nausea, delayed gastric emptying, and constipation. To date, studies assessing GI dysfunctions in MSA have primarily focused on alterations of the gut microbiome, however growing evidence indicates other structural components of the GI tract, such as the enteric nervous system, the intestinal barrier, GI hormones, and the GI-driven immune response may contribute to MSA-related GI symptoms. Here, we provide an in-depth exploration of the physiological, structural, and immunological changes theorised to underpin GI dysfunction in MSA patients and highlight areas for future research in order to identify more suitable pharmaceutical treatments for GI symptoms in patients with MSA.
Collapse
Affiliation(s)
- Colin F Craig
- Gut Barrier and Disease Laboratory, Department of Anatomy & Physiology, The University of Melbourne, Parkville, VIC 3010, Australia
| | - David I Finkelstein
- Parkinson's Disease Laboratory, The Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3052, Australia
| | - Rachel M McQuade
- Gut Barrier and Disease Laboratory, Department of Anatomy & Physiology, The University of Melbourne, Parkville, VIC 3010, Australia; Australian Institute for Musculoskeletal Science (AIMSS), Western Centre for Health Research and Education (WCHRE), Sunshine Hospital, St Albans, VIC 3021, Australia
| | - Shanti Diwakarla
- Gut Barrier and Disease Laboratory, Department of Anatomy & Physiology, The University of Melbourne, Parkville, VIC 3010, Australia; Australian Institute for Musculoskeletal Science (AIMSS), Western Centre for Health Research and Education (WCHRE), Sunshine Hospital, St Albans, VIC 3021, Australia.
| |
Collapse
|
|
2
|
Schmitt V, Masanetz RK, Weidenfeller M, Ebbinghaus LS, Süß P, Rosshart SP, von Hörsten S, Zunke F, Winkler J, Xiang W. Gut-to-brain spreading of pathology in synucleinopathies: A focus on molecular signalling mediators. Behav Brain Res 2023; 452:114574. [PMID: 37423320 DOI: 10.1016/j.bbr.2023.114574] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 07/03/2023] [Accepted: 07/06/2023] [Indexed: 07/11/2023]
Abstract
Synucleinopathies are a group of neurodegenerative disorders, classically characterized by the accumulation of aggregated alpha synuclein (aSyn) in the central nervous system. Parkinson's disease (PD) and multiple system atrophy (MSA) are the two prominent members of this family. Current treatment options mainly focus on the motor symptoms of these diseases. However, non-motor symptoms, including gastrointestinal (GI) symptoms, have recently gained particular attention, as they are frequently associated with synucleinopathies and often arise before motor symptoms. The gut-origin hypothesis has been proposed based on evidence of an ascending spreading pattern of aggregated aSyn from the gut to the brain, as well as the comorbidity of inflammatory bowel disease and synucleinopathies. Recent advances have shed light on the mechanisms underlying the progression of synucleinopathies along the gut-brain axis. Given the rapidly expanding pace of research in the field, this review presents a summary of the latest findings on the gut-to-brain spreading of pathology and potential pathology-reinforcing mediators in synucleinopathies. Here, we focus on 1) gut-to-brain communication pathways, including neuronal pathways and blood circulation, and 2) potential molecular signalling mediators, including bacterial amyloid proteins, microbiota dysbiosis-induced alterations in gut metabolites, as well as host-derived effectors, including gut-derived peptides and hormones. We highlight the clinical relevance and implications of these molecular mediators and their possible mechanisms in synucleinopathies. Moreover, we discuss their potential as diagnostic markers in distinguishing the subtypes of synucleinopathies and other neurodegenerative diseases, as well as for developing novel individualized therapeutic options for synucleinopathies.
Collapse
Affiliation(s)
- Verena Schmitt
- Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
| | - Rebecca Katharina Masanetz
- Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
| | - Martin Weidenfeller
- Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
| | - Lara Savannah Ebbinghaus
- Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
| | - Patrick Süß
- Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
| | - Stephan P Rosshart
- Department of Microbiome Research, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
| | - Stephan von Hörsten
- Department for Experimental Therapy, University Hospital Erlangen, Preclinical Experimental Center, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
| | - Friederike Zunke
- Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
| | - Jürgen Winkler
- Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany
| | - Wei Xiang
- Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany.
| |
Collapse
|
|
3
|
Talman LS, Pfeiffer RF. Movement Disorders and the Gut: A Review. Mov Disord Clin Pract 2022; 9:418-428. [PMID: 35586541 PMCID: PMC9092751 DOI: 10.1002/mdc3.13407] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 12/20/2021] [Accepted: 12/21/2021] [Indexed: 11/07/2022] Open
Abstract
There is a close link between multiple movement disorders and gastrointestinal dysfunction. Gastrointestinal symptoms may precede the development of the neurologic syndrome or may arise following the neurologic presentation. This review will provide an overview of gastrointestinal accompaniments to several well-known as well as lesser known movement disorders. It will also highlight several disorders which may not be considered primary movement disorders but have an overlapping presentation of both gastrointestinal and movement abnormalities.
Collapse
Affiliation(s)
- Lauren S. Talman
- Department of NeurologyOregon Health & Science UniversityPortlandOregonUSA
| | - Ronald F. Pfeiffer
- Department of NeurologyOregon Health & Science UniversityPortlandOregonUSA
| |
Collapse
|
|
4
|
Kornum DS, Terkelsen AJ, Bertoli D, Klinge MW, Høyer KL, Kufaishi HHA, Borghammer P, Drewes AM, Brock C, Krogh K. Assessment of Gastrointestinal Autonomic Dysfunction: Present and Future Perspectives. J Clin Med 2021; 10:jcm10071392. [PMID: 33807256 PMCID: PMC8037288 DOI: 10.3390/jcm10071392] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 03/25/2021] [Accepted: 03/27/2021] [Indexed: 11/16/2022] Open
Abstract
The autonomic nervous system delicately regulates the function of several target organs, including the gastrointestinal tract. Thus, nerve lesions or other nerve pathologies may cause autonomic dysfunction (AD). Some of the most common causes of AD are diabetes mellitus and α-synucleinopathies such as Parkinson’s disease. Widespread dysmotility throughout the gastrointestinal tract is a common finding in AD, but no commercially available method exists for direct verification of enteric dysfunction. Thus, assessing segmental enteric physiological function is recommended to aid diagnostics and guide treatment. Several established assessment methods exist, but disadvantages such as lack of standardization, exposure to radiation, advanced data interpretation, or high cost, limit their utility. Emerging methods, including high-resolution colonic manometry, 3D-transit, advanced imaging methods, analysis of gut biopsies, and microbiota, may all assist in the evaluation of gastroenteropathy related to AD. This review provides an overview of established and emerging assessment methods of physiological function within the gut and assessment methods of autonomic neuropathy outside the gut, especially in regards to clinical performance, strengths, and limitations for each method.
Collapse
Affiliation(s)
- Ditte S. Kornum
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, DK8200 Aarhus, Denmark; (M.W.K.); (K.L.H.); (K.K.)
- Steno Diabetes Centre Aarhus, Aarhus University Hospital, DK8200 Aarhus, Denmark
- Correspondence:
| | - Astrid J. Terkelsen
- Department of Neurology, Aarhus University Hospital, DK8200 Aarhus, Denmark;
| | - Davide Bertoli
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, DK9100 Aalborg, Denmark; (D.B.); (A.M.D.); (C.B.)
| | - Mette W. Klinge
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, DK8200 Aarhus, Denmark; (M.W.K.); (K.L.H.); (K.K.)
| | - Katrine L. Høyer
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, DK8200 Aarhus, Denmark; (M.W.K.); (K.L.H.); (K.K.)
- Steno Diabetes Centre Aarhus, Aarhus University Hospital, DK8200 Aarhus, Denmark
| | - Huda H. A. Kufaishi
- Steno Diabetes Centre Copenhagen, Gentofte Hospital, DK2820 Gentofte, Denmark;
| | - Per Borghammer
- Department of Nuclear Medicine and PET-Centre, Aarhus University Hospital, DK8200 Aarhus, Denmark;
| | - Asbjørn M. Drewes
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, DK9100 Aalborg, Denmark; (D.B.); (A.M.D.); (C.B.)
- Steno Diabetes Centre North Jutland, Aalborg University Hospital, DK9100 Aalborg, Denmark
| | - Christina Brock
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, DK9100 Aalborg, Denmark; (D.B.); (A.M.D.); (C.B.)
- Steno Diabetes Centre North Jutland, Aalborg University Hospital, DK9100 Aalborg, Denmark
| | - Klaus Krogh
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, DK8200 Aarhus, Denmark; (M.W.K.); (K.L.H.); (K.K.)
- Steno Diabetes Centre Aarhus, Aarhus University Hospital, DK8200 Aarhus, Denmark
| |
Collapse
|
|
5
|
Chen X, Liu Y, Pan D, Cao M, Wang X, Wang L, Xu Y, Wang Y, Yan J, Liu J, Yang M. 68Ga-NOTA PET imaging for gastric emptying assessment in mice. BMC Gastroenterol 2021; 21:69. [PMID: 33581729 PMCID: PMC7881688 DOI: 10.1186/s12876-021-01642-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 02/03/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Positron emission tomography (PET) has the potential for visualization and quantification of gastric emptying (GE). The traditional Chinese medicine (TCM) has been recognized promising for constipation. This study aimed to establish a PET imaging method for noninvasive GE measurement and to evaluate the efficacy of a TCM on delayed GE caused by constipation using PET imaging. METHODS [68Ga]Ga-NOTA was synthesized as the tracer and sesame paste with different viscosity were selected as test meals. The dynamic PET scans were performed after [68Ga]Ga-NOTA mixed with test meals were administered to normal mice. Two methods were utilized for the quantification of PET imaging. A constipation mouse model was treated with maren chengqi decoction (MCD), and the established PET imaging scans were performed after the treatment. RESULTS [68Ga]Ga-NOTA was synthesized within 20 min, and its radiochemical purity was > 95%. PET images showed the dynamic process of GE. %ID/g, volume, and total activity correlated well with each other. Among which, the half of GE time derived from %ID/g for 4 test meals were 3.92 ± 0.87 min, 13.1 ± 1.25 min, 17.8 ± 1.31 min, and 59.7 ± 3.11 min, respectively. Constipation mice treated with MCD showed improved body weight and fecal conditions as well as ameliorated GE measured by [68Ga]Ga-NOTA PET. CONCLUSIONS A PET imaging method for noninvasive GE measurement was established with stable radiotracer, high image quality, and reliable quantification methods. The efficacy of MCD on delayed GE was demonstrated using PET.
Collapse
Affiliation(s)
- Xueyan Chen
- Department of Veterinary Medicine, Southwest University, Rongchang, Chongqing, 402460, China
| | - Yu Liu
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, Jiangsu, China
| | - Donghui Pan
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, Jiangsu, China
| | - Maoyu Cao
- Department of Veterinary Medicine, Southwest University, Rongchang, Chongqing, 402460, China
| | - Xinyu Wang
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, Jiangsu, China
| | - Lizhen Wang
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, Jiangsu, China
| | - Yuping Xu
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, Jiangsu, China
| | - Yan Wang
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, Jiangsu, China
| | - Junjie Yan
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, Jiangsu, China
| | - Juan Liu
- Department of Veterinary Medicine, Southwest University, Rongchang, Chongqing, 402460, China. .,Immunology Center, Medical Research Institute of Southwest University, Rongchang, Chongqing, 402460, China.
| | - Min Yang
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, Jiangsu, China.
| |
Collapse
|
|
6
|
Gastrointestinal dysfunction in movement disorders. Neurol Sci 2021; 42:1355-1365. [PMID: 33538914 DOI: 10.1007/s10072-021-05041-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 01/04/2021] [Indexed: 12/24/2022]
Abstract
PURPOSE OF REVIEW This article provides an overview of the clinical presentation, investigations, and treatment options for gastrointestinal tract (GIT) dysfunction in patients with Parkinson's disease (PD) and other movement disorders. RECENT FINDINGS GIT dysfunction commonly appears as constipation and fecal incontinence (mostly overflow, accompanied with sphincter failure in multiple system atrophy [MSA]). Bowel dysfunction (underactive) occurs irrespectively from the site of the neurologic lesion, which is in contrast to site-dependent bladder dysfunction (brain, overactive; periphery, underactive). GI emergencies may arise, including intestinal pseudo-obstruction, intussusception, volvulus, and stercoral ulcer (ulcer of the colon due to pressure and irritation resulting from severe, prolonged constipation). Bowel function tests in neurologic patients often show a combination of slow transit and anorectal dysfunction. Management for slow transit constipation includes bulking agents, softening agents, yogurt/probiotics, and prokinetic agents. Suppositories, botulinum toxin injections, and transanal irrigation are options for managing anorectal constipation. CONCLUSIONS Function of the bowel is commonly affected in PD and other movement disorders. Neurologists play an important role in assessing bowel symptoms in their patients and planning treatment strategies, often in collaboration with specialist teams.
Collapse
|
|
7
|
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.
Collapse
|
|
8
|
Du J, Huang P, Qian Y, Yang X, Cui S, Lin Y, Gao C, Zhang P, He Y, Xiao Q, Chen S. Fecal and Blood Microbial 16s rRNA Gene Alterations in Chinese Patients with Multiple System Atrophy and Its Subtypes. JOURNAL OF PARKINSONS DISEASE 2020; 9:711-721. [PMID: 31381527 PMCID: PMC6839480 DOI: 10.3233/jpd-191612] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Background and Objective: To explore the alterations of microbial 16s ribosomal (rRNA) gene in the feces and blood of Chinese patients with multiple system atrophy (MSA) and its relationships with clinical features. Methods: 40 MSA patients (MSA-P/MSA-C: 23/17) and their healthy spouses were recruited. Fecal and blood microbiota were investigated by high-throughput IllUmina Miseq sequencing targeted on the V3-V4 functional region of 16s rRNA gene. The relationships between microbiota and clinical characteristics were analyzed. Results: The abundances of Lactobacillus, Gordonibacter, Phascolarctobacterium, and Haemophilus in feces and abundances of Leucobacter, and Bacteroides in blood were different between MSA patients and healthy controls (HC). Combining the taxa from feces and blood, six genera were identified to be predictive of MSA, achieving an area under the curve (AUC) of 0.853. The abundances of Phascolarctobacterium and Ruminococcus in feces were lower in MSA-P than those in MSA-C. The abundances of Blastococcus, Bacillus, and Acinetobacter in blood were different between MSA subtypes. These five genera differentiated MSA subtypes with an AUC of 0.898. Functional predictions indicated that gene functions involving biosynthetic metabolism and bacterial secretion systems were significantly different between the MSA and HC. The differential genera were associated with disease duration, anxiety, and autonomic dysfunctions. Conclusions: We confirmed the alterations of microbial 16s rRNA gene in the feces and blood occurs in Chinese patients with MSA. Microbiota dysbiosis was related to MSA clinical manifestations. Elucidating these differences in microbiomes will be helpful to improve our knowledge of the microbiota in the pathogenesis of MSA.
Collapse
Affiliation(s)
- Juanjuan Du
- Department of Neurology, Ruijin Hospital and Ruijin Hospital North affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Pei Huang
- Department of Neurology and The Collaborative Innovation Center for Brain Science, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yiwei Qian
- Department of Neurology and The Collaborative Innovation Center for Brain Science, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaodong Yang
- Department of Neurology and The Collaborative Innovation Center for Brain Science, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shishuang Cui
- Department of Neurology and The Collaborative Innovation Center for Brain Science, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yiqi Lin
- Department of Neurology and The Collaborative Innovation Center for Brain Science, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chao Gao
- Department of Neurology and The Collaborative Innovation Center for Brain Science, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Pingchen Zhang
- Department of Neurology and The Collaborative Innovation Center for Brain Science, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yixi He
- Department of Neurology and The Collaborative Innovation Center for Brain Science, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qin Xiao
- Department of Neurology and The Collaborative Innovation Center for Brain Science, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shengdi Chen
- Department of Neurology and The Collaborative Innovation Center for Brain Science, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| |
Collapse
|
|
9
|
Pfeiffer RF, Isaacson SH, Pahwa R. Clinical implications of gastric complications on levodopa treatment in Parkinson's disease. Parkinsonism Relat Disord 2020; 76:63-71. [PMID: 32461054 DOI: 10.1016/j.parkreldis.2020.05.001] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 04/09/2020] [Accepted: 05/01/2020] [Indexed: 12/16/2022]
Abstract
Disorders of the gastrointestinal (GI) tract are common and distressing nonmotor symptoms of Parkinson's disease (PD) that can adversely affect levodopa absorption and lead to OFF periods, also known as motor fluctuations. Gastroparesis, which is primarily defined as delayed gastric emptying (DGE), and Helicobacter pylori infection, which is present with increased frequency in PD, are among the most common and important GI disorders reported in PD that may impair oral levodopa absorption and increase OFF time. Symptoms of gastroparesis include nausea, vomiting, postprandial bloating, fullness, early satiety, abdominal pain, and weight loss. DGE has been reported in a substantial fraction of individuals with PD. Symptoms of H. pylori infection include gastritis and peptic ulcers. Studies have found that DGE and H. pylori infection are correlated with delayed peak levodopa plasma levels and increased incidence of motor fluctuations. Therapeutic strategies devised to minimize the potential that gastric complications will impair oral levodopa absorption and efficacy in PD patients include treatments that circumvent the GI tract, such as apomorphine injection, levodopa intestinal gel delivery, levodopa inhalation powder, and deep brain stimulation. Other strategies aim at improving gastric emptying in PD patients, primarily including prokinetic agents.
Collapse
Affiliation(s)
- Ronald F Pfeiffer
- Department of Neurology, Oregon Health and Science University, Portland, OR, USA.
| | - Stuart H Isaacson
- Parkinson's Disease and Movement Disorders Center of Boca Raton, Boca Raton, FL, USA
| | - Rajesh Pahwa
- Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA
| |
Collapse
|
|
10
|
Chelban V, Vichayanrat E, Schottlaende L, Iodice V, Houlden H. Autonomic dysfunction in genetic forms of synucleinopathies. Mov Disord 2019; 33:359-371. [PMID: 29508456 DOI: 10.1002/mds.27343] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 01/01/2018] [Accepted: 01/19/2018] [Indexed: 12/31/2022] Open
Abstract
The discovery of genetic links between alpha-synuclein and PD has opened unprecedented opportunities for research into a new group of diseases, now collectively known as synucleinopathies. Autonomic dysfunction, including cardiac sympathetic denervation, has been reported in familial forms of synucleinopathies that have Lewy bodies at the core of their pathogenesis. SNCA mutations and multiplications, LRRK2 disease with Lewy bodies as well as other common, sporadic forms of idiopathic PD, MSA, pure autonomic failure, and dementia with Lewy bodies have all been associated with dysautonomia. By contrast, in familial cases of parkinsonism without Lewy bodies, such as in PARK2, the autonomic profile remains normal throughout the course of the disease. The degeneration of the central and peripheral autonomic systems in genetic as well as sporadic forms of neurodegenerative synucleinopathies correlates with the accumulation of alpha-synuclein immunoreactive-containing inclusions. Given that dysautonomia has a significant impact on the quality of life of sufferers and autonomic symptoms are generally treatable, a prompt diagnostic testing and treatment should be provided. Moreover, new evidence suggests that autonomic dysfunction can be used as an outcome prediction factor in some forms of synucleinopathies or premotor diagnostic markers that could be used in the future to define further research avenues. In this review, we describe the autonomic dysfunction of genetic synucleinopathies in comparison to the dysautonomia of sporadic forms of alpha-synuclein accumulation and provide the reader with an up-to-date overview of the current understanding in this fast-growing field. © 2018 International Parkinson and Movement Disorder Society.
Collapse
Affiliation(s)
- Viorica Chelban
- Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom, and National Hospital for Neurology and Neurosurgery, London, United Kingdom.,Department of Neurology and Neurosurgery, Institute of Emergency Medicine, Chisinau, Republic of Moldova
| | - Ekawat Vichayanrat
- Autonomic Unit, National Hospital for Neurology and Neurosurgery, UCL NHS Trust, London, United Kingdom
| | - Lucia Schottlaende
- Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom, and National Hospital for Neurology and Neurosurgery, London, United Kingdom.,Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
| | - Valeria Iodice
- Autonomic Unit, National Hospital for Neurology and Neurosurgery, UCL NHS Trust, London, United Kingdom.,Institute of Neurology, University College London, London, United Kingdom
| | - Henry Houlden
- Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom, and National Hospital for Neurology and Neurosurgery, London, United Kingdom
| |
Collapse
|
|
11
|
Abstract
PURPOSE OF REVIEW Patients with Parkinson's disease (PD) often display gastrointestinal and genitourinary autonomic symptoms years or even decades prior to diagnosis. These symptoms are thought to be caused in part by pathological α-synuclein inclusions in the peripheral autonomic and enteric nervous systems. It has been proposed that the initial α-synuclein aggregation may in some PD patients originate in peripheral nerve terminals and then spread centripetally to the spinal cord and brainstem. In vivo imaging methods can directly quantify the degeneration of the autonomic nervous system as well as the functional consequences such as perturbed motility. Here, we review the methodological principles of these imaging techniques and the major findings in patients with PD and atypical parkinsonism. RECENT FINDINGS Loss of sympathetic and parasympathetic nerve terminals in PD can be visualized using radiotracer imaging, including 123I-MIBG scintigraphy, and 18F-dopamine and 11C-donepezil PET. Recently, ultrasonographical studies disclosed reduced diameter of the vagal nerves in PD patients. Radiological and radioisotope techniques have demonstrated dysmotility and prolonged transit time throughout all subdivisions of the gastrointestinal tract in PD. The prevalence of objective dysfunction as measured with these imaging methods is often considerably higher compared to the prevalence of subjective symptoms experienced by the patients. Degeneration of the autonomic nervous system may play a key role in the pathogenesis of PD. In vivo imaging techniques provide powerful and noninvasive tools to quantify the degree and extent of this degeneration and its functional consequences.
Collapse
Affiliation(s)
- Karoline Knudsen
- Department of Nuclear Medicine and PET Centre Aarhus University Hospital, Institute of Clinical Medicine Aarhus University, Norrebrogade 44, Building 10, 8000, Aarhus C, Denmark
| | - Per Borghammer
- Department of Nuclear Medicine and PET Centre Aarhus University Hospital, Institute of Clinical Medicine Aarhus University, Norrebrogade 44, Building 10, 8000, Aarhus C, Denmark.
| |
Collapse
|
|
12
|
Knudsen K, Szwebs M, Hansen AK, Borghammer P. Gastric emptying in Parkinson's disease - A mini-review. Parkinsonism Relat Disord 2018; 55:18-25. [PMID: 29891432 DOI: 10.1016/j.parkreldis.2018.06.003] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 04/30/2018] [Accepted: 06/03/2018] [Indexed: 02/06/2023]
Abstract
Patients with Parkinson's disease (PD) experience a range of non-motor symptoms, including constipation and other gastrointestinal problems. These symptoms are sometimes present in the prodromal disease phase. An improved understanding of the underlying pathophysiology is needed considering that PD has been hypothesized to originate in the gut. Delayed gastric emptying time (GET) is often listed as a prevalent gastrointestinal symptom in PD, but the true prevalence is controversial. The aim of this short review was to investigate if GET in PD is dependent on the applied measuring methodology. A systemic search of Pubmed identified 15 relevant studies, including six using gold standard method gastric scintigraphy and nine using 13C-octanoate breath tests. Overall, gastric scintigraphy studies showed a non-significant GET delay (standardized mean difference (SMD) 0.42) in PD patients. After exclusion of one outlier study, GET was significantly increased (SMD 0.59). In contrast, highly significant GET delay (SMD 1.70) was seen in breath test studies. A limitation of the meta-analyses was reuse of the same control group in some studies. In summary, the marked GET delay observed in breath test studies is not confirmed by gold standard gastric scintigraphy studies. This discrepancy can perhaps be explained by breath test being an indirect GET measure, depending not only on mechanic stomach emptying but also intestinal absorption and liver metabolism. Thus, multi-modality studies under standardized conditions are needed to elucidate the prevalence and severity of gastric dysmotility in PD, along with contributions from other factors including intestinal absorption and permeability.
Collapse
Affiliation(s)
- Karoline Knudsen
- Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark.
| | - Martha Szwebs
- Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark
| | - Allan K Hansen
- Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark
| | - Per Borghammer
- Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark
| |
Collapse
|
|
13
|
Palma JA, Kaufmann H. Treatment of autonomic dysfunction in Parkinson disease and other synucleinopathies. Mov Disord 2018; 33:372-390. [PMID: 29508455 PMCID: PMC5844369 DOI: 10.1002/mds.27344] [Citation(s) in RCA: 146] [Impact Index Per Article: 20.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 01/11/2018] [Accepted: 01/24/2018] [Indexed: 12/12/2022] Open
Abstract
Dysfunction of the autonomic nervous system afflicts most patients with Parkinson disease and other synucleinopathies such as dementia with Lewy bodies, multiple system atrophy, and pure autonomic failure, reducing quality of life and increasing mortality. For example, gastrointestinal dysfunction can lead to impaired drug pharmacodynamics causing a worsening in motor symptoms, and neurogenic orthostatic hypotension can cause syncope, falls, and fractures. When recognized, autonomic problems can be treated, sometimes successfully. Discontinuation of potentially causative/aggravating drugs, patient education, and nonpharmacological approaches are useful and should be tried first. Pathophysiology-based pharmacological treatments that have shown efficacy in controlled trials of patients with synucleinopathies have been approved in many countries and are key to an effective management. Here, we review the treatment of autonomic dysfunction in patients with Parkinson disease and other synucleinopathies, summarize the nonpharmacological and current pharmacological therapeutic strategies including recently approved drugs, and provide practical advice and management algorithms for clinicians, with focus on neurogenic orthostatic hypotension, supine hypertension, dysphagia, sialorrhea, gastroparesis, constipation, neurogenic overactive bladder, underactive bladder, and sexual dysfunction. © 2018 International Parkinson and Movement Disorder Society.
Collapse
Affiliation(s)
- Jose-Alberto Palma
- Department of Neurology, Dysautonomia Center, New York University School of Medicine, New York, New York, USA
| | - Horacio Kaufmann
- Department of Neurology, Dysautonomia Center, New York University School of Medicine, New York, New York, USA
| |
Collapse
|
|
14
|
Engen PA, Dodiya HB, Naqib A, Forsyth CB, Green SJ, Voigt RM, Kordower JH, Mutlu EA, Shannon KM, Keshavarzian A. The Potential Role of Gut-Derived Inflammation in Multiple System Atrophy. JOURNAL OF PARKINSONS DISEASE 2018; 7:331-346. [PMID: 28234259 DOI: 10.3233/jpd-160991] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Recent evidence suggests that Parkinson's disease (PD) is associated with intestinal microbiota dysbiosis, abnormal intestinal permeability, and intestinal inflammation. OBJECTIVE Our study aimed to determine if these gut abnormalities are present in another synucleinopathy, multiple system atrophy (MSA). METHODS In six MSA and 11 healthy control subjects, we performed immunohistochemistry studies of colonic sigmoid mucosa to evaluate the intestinal barrier marker Zonula Occludens-1 and the endotoxin-related inflammation marker Toll-like-receptor-4 expression. We also assessed colonic sigmoid mucosal and fecal microbiota compositions using high-throughput 16S ribosomal RNA gene amplicon sequencing. RESULTS MSA subjects showed disrupted tight junction protein Zonula Occludens-1 structure in sigmoid mucosa tissue suggesting intestinal barrier dysfunction. The lipopolysaccharide specific inflammatory receptor Toll-like-receptor-4 was significantly higher in the colonic sigmoid mucosa in MSA relative to healthy controls. Microbiota analysis suggested high relative abundance of gram-negative, putative "pro-inflammatory" bacteria in various family and genus level taxa, from the phylum Bacteroidetes and Proteobacteria, in MSA feces and mucosa. At the taxonomic level of genus, putative "anti-inflammatory" butyrate-producing bacteria were less abundant in MSA feces. Predictive functional analysis indicated that the relative abundance of a number of genes involved in metabolism were lower in MSA feces, whereas the relative abundance of genes involved in lipopolysaccharide biosynthesis were higher in both MSA feces and mucosa compared to healthy controls. CONCLUSIONS This proof-of-concept study provides preliminary evidence that like PD, MSA subjects display evidence of disrupted intestinal barrier integrity, increased marker of endotoxin-related intestinal inflammation, and pro-inflammatory colonic microbiota.
Collapse
Affiliation(s)
- Phillip A Engen
- Department of Internal Medicine, Division of Gastroenterology, Rush University Medical Center, Chicago, IL, USA
| | - Hemraj B Dodiya
- Department of Internal Medicine, Division of Gastroenterology, Rush University Medical Center, Chicago, IL, USA.,Department of Pharmacology, Rush University Medical Center, Chicago, IL, USA
| | - Ankur Naqib
- DNA Services Facility, Research Resources Center, University of Illinois at Chicago, Chicago, IL, USA
| | - Christopher B Forsyth
- Department of Internal Medicine, Division of Gastroenterology, Rush University Medical Center, Chicago, IL, USA.,Department of Biochemistry, Rush University Medical Center, Chicago, IL, USA
| | - Stefan J Green
- DNA Services Facility, Research Resources Center, University of Illinois at Chicago, Chicago, IL, USA.,Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Robin M Voigt
- Department of Internal Medicine, Division of Gastroenterology, Rush University Medical Center, Chicago, IL, USA
| | - Jeffrey H Kordower
- Department of Neurology, Rush University Medical Center, Chicago, IL, USA
| | - Ece A Mutlu
- Department of Internal Medicine, Division of Gastroenterology, Rush University Medical Center, Chicago, IL, USA
| | - Kathleen M Shannon
- Department of Neurology, University of Wisconsin School of Public Health, Madison, WI, USA
| | - Ali Keshavarzian
- Department of Internal Medicine, Division of Gastroenterology, Rush University Medical Center, Chicago, IL, USA.,Department of Pharmacology, Rush University Medical Center, Chicago, IL, USA.,Department of Physiology, Rush University Medical Center, Chicago, IL, USA.,Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands
| |
Collapse
|
|
15
|
Wollmer E, Klein S. A review of patient-specific gastrointestinal parameters as a platform for developing in vitro models for predicting the in vivo performance of oral dosage forms in patients with Parkinson’s disease. Int J Pharm 2017; 533:298-314. [DOI: 10.1016/j.ijpharm.2017.08.126] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Revised: 08/25/2017] [Accepted: 08/31/2017] [Indexed: 02/06/2023]
|
|
16
|
Jost WH. An update on the recognition and treatment of autonomic symptoms in Parkinson’s disease. Expert Rev Neurother 2017. [DOI: 10.1080/14737175.2017.1345307] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Affiliation(s)
- Wolfgang H. Jost
- Parkinson-Klinik Ortenau, Wolfach, Germany
- Depatment of Neurology, University of Freiburg, Freiburg/Breisgau, Germany
| |
Collapse
|
|
17
|
|
|
18
|
Delayed Gastric Emptying in Advanced Parkinson Disease: Correlation With Therapeutic Doses. Clin Nucl Med 2017; 42:83-87. [PMID: 27941374 DOI: 10.1097/rlu.0000000000001470] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
INTRODUCTION Gastrointestinal dysfunction is often described in patients with Parkinson disease (PD), and gastrointestinal symptoms are usually attributed to gastroparesis. The consequent delayed gastric emptying (GE) may be an important pharmacokinetic mechanism underlying some of the response fluctuations that develop after long-term levodopa (L-dopa) therapy.The aim of this prospective study was to assess GE time by a liquid meal scintigraphy, in PD patients, and to correlate them with demographic, clinical, and therapeutic data. METHODS Scintigraphy with radiolabeled albumin nanocolloids added to acidified orange juice was performed in 51 consecutive PD patients 1 hour after their usual dopaminergic therapy first dose and after a 12-hour fast. Demographic, neurologic, gastrointestinal, and pharmacologic data were collected. RESULTS Fifty-one patients were divided into 2 groups using the cutoff point obtained in normal subjects (40 minutes): group 1 included 29 patients with GE T½ of 27.60 ± 7.30 minutes (normal), group 2 showed a GE T½ of 84.90 ± 53.80 minutes (delayed). The most striking significant difference between the 2 groups was the dopa-decarboxylase inhibitor mean dose that was significantly higher in the group of patients with delayed GE (201.32 ± 97.26 vs 127.65 ± 79.74; P = 0.005). CONCLUSIONS The impairment of gastric motility, frequently represented in PD patients, occurs in approximately 42% of patients with motor complications. A mechanism that may explain the GE delay is the effect of L-dopa on dopaminergic receptors in the stomach. Therefore, the dosage of dopa-decarboxylase inhibitor, increasing the L-dopa concentration, may contribute to GE delay and its consequent effect on drug delivery and efficacy.
Collapse
|
|
19
|
Jost WH. Autonomic Dysfunction in Parkinson's Disease: Cardiovascular Symptoms, Thermoregulation, and Urogenital Symptoms. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2017; 134:771-785. [DOI: 10.1016/bs.irn.2017.04.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
|
|
20
|
Trahair LG, Kimber TE, Flabouris K, Horowitz M, Jones KL. Gastric emptying, postprandial blood pressure, glycaemia and splanchnic flow in Parkinson's disease. World J Gastroenterol 2016; 22:4860-4867. [PMID: 27239112 PMCID: PMC4873878 DOI: 10.3748/wjg.v22.i20.4860] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Revised: 01/27/2016] [Accepted: 02/20/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To determine gastric emptying, blood pressure, mesenteric artery blood flow, and blood glucose responses to oral glucose in Parkinson's disease. METHODS Twenty-one subjects (13 M, 8 F; age 64.2 ± 1.6 years) with mild to moderate Parkinson's disease (Hoehn and Yahr score 1.4 ± 0.1, duration of known disease 6.3 ± 0.9 years) consumed a 75 g glucose drink, labelled with 20 MBq (99m)Tc-calcium phytate. Gastric emptying was quantified with scintigraphy, blood pressure and heart rate with an automated device, superior mesenteric artery blood flow by Doppler ultrasonography and blood glucose by glucometer for 180 min. Autonomic nerve function was evaluated with cardiovascular reflex tests and upper gastrointestinal symptoms by questionnaire. RESULTS The mean gastric half-emptying time was 106 ± 9.1 min, gastric emptying was abnormally delayed in 3 subjects (14%). Systolic and diastolic blood pressure fell (P < 0.001) and mesenteric blood flow and blood glucose (P < 0.001 for both) increased, following the drink. Three subjects (14%) had definite autonomic neuropathy and 8 (38%) had postprandial hypotension. There were no significant relationships between changes in blood pressure, heart rate or mesenteric artery blood flow with gastric emptying. Gastric emptying was related to the score for autonomic nerve function (R = 0.55, P < 0.01). There was an inverse relationship between the blood glucose at t = 30 min (R = -0.52, P < 0.05), while the blood glucose at t = 180 min was related directly (R = 0.49, P < 0.05), with gastric emptying. CONCLUSION In mild to moderate Parkinson's disease, gastric emptying is related to autonomic dysfunction and a determinant of the glycaemic response to oral glucose.
Collapse
|
|
21
|
Unchanged gastric emptying and visceral perception in early Parkinson's disease after a high caloric test meal. J Neurol 2015; 262:1946-53. [DOI: 10.1007/s00415-015-7799-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Revised: 05/23/2015] [Accepted: 05/25/2015] [Indexed: 02/07/2023]
|
|
22
|
Zheng LF, Song J, Fan RF, Chen CL, Ren QZ, Zhang XL, Feng XY, Zhang Y, Li LS, Zhu JX. The role of the vagal pathway and gastric dopamine in the gastroparesis of rats after a 6-hydroxydopamine microinjection in the substantia nigra. Acta Physiol (Oxf) 2014; 211:434-46. [PMID: 24410908 DOI: 10.1111/apha.12229] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2013] [Revised: 08/09/2013] [Accepted: 01/06/2014] [Indexed: 12/14/2022]
Abstract
AIM Gastroparesis is a common non-motor system symptom of Parkinson's disease (PD). However, the mechanism responsible for the gastric motor abnormality is not clear. We previously reported on the impaired gastric motility in 6-hydroxydopamine (6-OHDA) rats, which were treated with a bilateral microinjection of 6-OHDA in the substantia nigra (SN). We hypothesize that the enhanced dopamine system and reduced acetylcholine (Ach) in gastric tissues might contribute to the delayed gastric emptying observed in PD. METHODS A strain gauge force transducer, digital X-ray imaging system, Western blot, immunofluorescence and Radio Immunoassay were used in this study. RESULTS Dopaminergic neurones in the SN were greatly reduced following the bilateral microinjection of 6-OHDA. 6-OHDA rats exhibited impaired gastric motility and delayed gastric emptying, accompanied by increased dopamine content and the overexpression of D2 receptors in the stomach. The administration of the D2 receptor antagonist domperidone relieved gastric dysmotility in 6-OHDA rats, but the D1 receptor antagonist SCH23390 failed to do so. Subdiaphragmatic vagotomy prevented the increase in the gastric dopamine content and D2 receptor expression and improved gastric dysmotility in 6-OHDA rats. CONCLUSION Dopaminergic deficiency in the SN results in impaired gastric motility, possibly as a result of the enhanced activity of dopamine system and reduced Ach in gastric tissue. The vagus nerve plays an important role in peripheral gastric motility disorder.
Collapse
Affiliation(s)
- L.-F. Zheng
- Department of Physiology and Pathophysiology; School of Basic Medical Sciences; Capital Medical University; Beijing China
| | - J. Song
- Department of Physiology and Pathophysiology; School of Basic Medical Sciences; Capital Medical University; Beijing China
| | - R.-F. Fan
- Department of Physiology and Pathophysiology; School of Basic Medical Sciences; Capital Medical University; Beijing China
| | - C.-L. Chen
- Department of Physiology and Pathophysiology; School of Basic Medical Sciences; Capital Medical University; Beijing China
| | - Q.-Z. Ren
- Department of Physiology and Pathophysiology; School of Basic Medical Sciences; Capital Medical University; Beijing China
| | - X.-L. Zhang
- Department of Physiology and Pathophysiology; School of Basic Medical Sciences; Capital Medical University; Beijing China
| | - X.-Y. Feng
- Department of Physiology and Pathophysiology; School of Basic Medical Sciences; Capital Medical University; Beijing China
| | - Y. Zhang
- Department of Physiology and Pathophysiology; School of Basic Medical Sciences; Capital Medical University; Beijing China
| | - L.-S. Li
- Department of Physiology and Pathophysiology; School of Basic Medical Sciences; Capital Medical University; Beijing China
| | - J.-X. Zhu
- Department of Physiology and Pathophysiology; School of Basic Medical Sciences; Capital Medical University; Beijing China
| |
Collapse
|
|
23
|
Marrinan S, Emmanuel AV, Burn DJ. Delayed gastric emptying in Parkinson's disease. Mov Disord 2013; 29:23-32. [PMID: 24151126 DOI: 10.1002/mds.25708] [Citation(s) in RCA: 110] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2013] [Revised: 07/30/2013] [Accepted: 09/03/2013] [Indexed: 12/16/2022] Open
Abstract
Gastrointestinal symptoms are evident in all stages of Parkinson's disease (PD). Most of the gastrointestinal abnormalities associated with PD are attributable to impaired motility. At the level of the stomach, this results in delayed gastric emptying. The etiology of delayed gastric emptying in PD is probably multifactorial but is at least partly related to Lewy pathology in the enteric nervous system and discrete brainstem nuclei. Delayed gastric emptying occurs in both early and advanced PD but is underdetected in routine clinical practice. Recognition of delayed gastric emptying is important because it can cause an array of upper gastrointestinal symptoms, but additionally it has important implications for the absorption and action of levodopa. Delayed gastric emptying contributes significantly to response fluctuations seen in people on long-term l-dopa therapy. Neurohormonal aspects of the brain-gut axis are pertinent to discussions regarding the pathophysiology of delayed gastric emptying in PD and are also hypothesized to contribute to the pathogenesis of PD itself. Ghrelin is a gastric-derived hormone with potential as a therapeutic agent for delayed gastric emptying and also as a novel neuroprotective agent in PD. Recent findings relating to ghrelin in the context of PD and gastric emptying are considered. This article highlights the pathological abnormalities that may account for delayed gastric emptying in PD. It also considers the wider relevance of abnormal gastric pathology to our current understanding of the etiology of PD.
Collapse
Affiliation(s)
- Sarah Marrinan
- Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom
| | | | | |
Collapse
|
|
24
|
Ueda M, Nakajima N, Nagayama H, Nishiyama Y, Ishii K, Katayama Y. Therapeutic response to pramipexole in a patient with multiple system atrophy with predominant parkinsonism: positron emission tomography and pharmacokinetic assessments. Intern Med 2013; 52:1731-5. [PMID: 23903508 DOI: 10.2169/internalmedicine.52.9442] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Multiple system atrophy with predominant parkinsonism (MSA-P) usually shows poor responsiveness to dopaminergic medications. We herein describe a patient with MSA-P who exhibited a good response to pramipexole but not to an ordinary dose of L-dopa. Positron emission tomography (PET) displayed severely impaired presynaptic dopaminergic availability and relatively preserved postsynaptic D2 receptor binding capacity. The pharmacokinetic analyses demonstrated relatively low bioavailability for L-dopa and adequate plasma levels of pramipexole, even at baseline, on a stable daily dose. The PET features and pharmacokinetic differences between L-dopa and pramipexole indicate the presence of unique therapeutic responses to dopaminergic medications in the patient.
Collapse
Affiliation(s)
- Masayuki Ueda
- Department of Neurology, Nippon Medical School, Japan.
| | | | | | | | | | | |
Collapse
|
|
25
|
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]
|
|
26
|
Arai E, Arai M, Uchiyama T, Higuchi Y, Aoyagi K, Yamanaka Y, Yamamoto T, Nagano O, Shiina A, Maruoka D, Matsumura T, Nakagawa T, Katsuno T, Imazeki F, Saeki N, Kuwabara S, Yokosuka O. Subthalamic deep brain stimulation can improve gastric emptying in Parkinson's disease. Brain 2012; 135:1478-1485. [PMID: 22522940 DOI: 10.1093/brain/aws086] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
It is established that deep brain stimulation of the subthalamic nucleus improves motor function in advanced Parkinson's disease, but its effects on autonomic function remain to be elucidated. The present study was undertaken to investigate the effects of subthalamic deep brain stimulation on gastric emptying. A total of 16 patients with Parkinson's disease who underwent bilateral subthalamic deep brain stimulation were enrolled. Gastric emptying was expressed as the peak time of (13)CO(2) excretion (T(max)) in the (13)C-acetate breath test and was assessed in patients with and without administration of 100-150 mg levodopa/decarboxylase inhibitor before surgery, and with and without subthalamic deep brain stimulation at 3 months post-surgery. The pattern of (13)CO(2) excretion curve was analysed. To evaluate potential factors related to the effect of subthalamic deep brain stimulation on gastric emptying, we also examined the association between gastric emptying, clinical characteristics, the equivalent dose of levodopa and serum ghrelin levels. The peak time of (13)CO(2) excretion (T(max)) values for gastric emptying in patients without and with levodopa/decarboxylase inhibitor treatment were 45.6 ± 22.7 min and 42.5 ± 13.6 min, respectively (P = not significant), thus demonstrating levodopa resistance. The peak time of (13)CO(2) excretion (T(max)) values without and with subthalamic deep brain stimulation after surgery were 44.0 ± 17.5 min and 30.0 ± 12.5 min (P < 0.001), respectively, which showed that subthalamic deep brain stimulation was effective. Simultaneously, the pattern of the (13)CO(2) excretion curve was also significantly improved relative to surgery with no stimulation (P = 0.002), although the difference with and without levodopa/decarboxylase inhibitor was not significant. The difference in peak time of (13)CO(2) excretion (T(max)) values without levodopa/decarboxylase inhibitor before surgery and without levodopa/decarboxylase inhibitor and subthalamic deep brain stimulation after surgery was not significant, although motor dysfunction improved and the levodopa equivalent dose decreased after surgery. There was little association between changes in ghrelin levels (Δghrelin) and changes in T(max) values (ΔT(max)) in the subthalamic deep brain stimulation trial after surgery (r = -0.20), and no association between changes in other characteristics and ΔT(max) post-surgery in the subthalamic deep brain stimulation trial. These results showed that levodopa/decarboxylase inhibitor did not influence gastric emptying and that subthalamic deep brain stimulation can improve the dysfunction in patients with Parkinson's disease possibly by altering the neural system that controls gastrointestinal function after subthalamic deep brain stimulation. This is the first report to show the effectiveness of subthalamic deep brain stimulation on gastrointestinal dysfunction as a non-motor symptom in Parkinson's disease.
Collapse
Affiliation(s)
- Eiji Arai
- Department of Medicine and Clinical Oncology (K1), Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chiba-City, Japan.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
27
|
Abstract
Severe autonomic failure occurs in approximately 1 in 1,000 people. Such patients are remarkable for the striking and sometimes paradoxic responses they manifest to a variety of physiologic and pharmacologic stimuli. Orthostatic hypotension is often the finding most commonly noted by physicians, but a myriad of additional and less understood findings also occur. These findings include supine hypertension, altered drug sensitivity, hyperresponsiveness of blood pressure to hypo/hyperventilation, sleep apnea, and other neurologic disturbances. In this article the authors will review the clinical pathophysiology that underlies autonomic failure, with a particular emphasis on those aspects most relevant to the care of such patients in the perioperative setting. Strategies used by clinicians in diagnosis and treatment of these patients, and the effect of these interventions on the preoperative, intraoperative, and postoperative care that these patients undergo is a crucial element in the optimized management of care in these patients.
Collapse
|
|
28
|
Tanaka Y, Kato T, Nishida H, Yamada M, Koumura A, Sakurai T, Hayashi Y, Kimura A, Hozumi I, Araki H, Murase M, Nagaki M, Moriwaki H, Inuzuka T. Is there delayed gastric emptying in patients with multiple system atrophy? An analysis using the 13C-acetate breath test. J Neurol 2012; 259:1448-52. [DOI: 10.1007/s00415-011-6372-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2011] [Revised: 12/05/2011] [Accepted: 12/10/2011] [Indexed: 10/14/2022]
|
|
29
|
Quigley EMM, O'Mahony S, Heetun Z. Motility disorders in the patient with neurologic disease. Gastroenterol Clin North Am 2011; 40:741-64. [PMID: 22100115 DOI: 10.1016/j.gtc.2011.09.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2023]
Abstract
Gastrointestinal symptoms are common in the patient with chronic neurologic disease and may loom large in terms of impact on quality of life and on nutrition and mobility. A knowledge of the range of gastrointestinal disorders associated with a given neurologic disease, together with an understanding of the risks and benefits of various therapeutic options and approaches, should aid gastroenterologists in their efforts to contribute to the care of these patients. In most instances a multidisciplinary team (neurologist/neurosurgeon, gastroenterologist, nutritionist, therapist, specialist nurse) aware of the wishes and needs of the family and their carers and mindful of the nature and the natural history of the underlying disease process are best placed to assess and manage these problems.
Collapse
Affiliation(s)
- Eamonn M M Quigley
- Department of Medicine, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
| | | | | |
Collapse
|
|
30
|
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: 188] [Impact Index Per Article: 12.5] [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.
Collapse
Affiliation(s)
- Ronald F Pfeiffer
- Department of Neurology, University of Tennessee Health Science Center, 855 Monroe Avenue, Memphis, TN 38163, USA.
| |
Collapse
|
|
31
|
Sakakibara Y, Asahina M, Suzuki A, Hattori T. Gastric myoelectrical differences between Parkinson's disease and multiple system atrophy. Mov Disord 2010; 24:1579-86. [PMID: 19514051 DOI: 10.1002/mds.22265] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The electrogastrogram (EGG) was recorded for 24 hours in 17 Parkinson's disease (PD) patients, 17 multiple system atrophy (MSA) patients, and 8 healthy control subjects to elucidate the differences in the EGG findings between the two diseases. Eight EGG segments (3 preprandial, 3 postprandial, and 2 sleep segments) were selected from the total recording for spectral analysis, from which we obtained the dominant frequency (DF), instability coefficient of DF (ICDF), and low (LFR%), normal (NFR%), and high (HFR%) range power percentages of the total power. PD patients showed irregular slow waves, high HFR%, and high ICDF, whereas MSA patients showed regular slow waves and low ICDF. Although DF and NFR% increased after meal in controls, postprandial increases in DF and NFR% were less significant in both patient groups compared to the controls. The PD patients presented gastric dysrhythmias indicating gastric pacemaker disturbances. The MSA patients showed regular slow waves with low variability of the slow wave rhythm (low ICDF), which might have resulted from the involvement of gastric autonomic nerve function.
Collapse
|
|
32
|
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.
Collapse
Affiliation(s)
- Wolfgang H Jost
- Dept. of Neurology, Deutsche Klinik für Diagnostik, Wiesbaden, Germany.
| |
Collapse
|
|
33
|
Nishiwaki S, Araki H, Shirakami Y, Kawaguchi J, Kawade N, Iwashita M, Tagami A, Hatakeyama H, Hayashi T, Maeda T, Saitoh K. Inhibition of gastroesophageal reflux by semi-solid nutrients in patients with percutaneous endoscopic gastrostomy. JPEN J Parenter Enteral Nutr 2009; 33:513-9. [PMID: 19487579 DOI: 10.1177/0148607108327045] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Aspiration is one of the major complications after percutaneous endoscopic gastrostomy (PEG). The administration of semi-solid nutrients by means of gastrostomy tube has recently been reported to be effective in preventing aspiration pneumonia. The effects of semi-solid nutrients on gastroesophageal reflux, intragastric distribution, and gastric emptying were evaluated. METHODS Semi-solid nutrients were prepared by liquid nutrients mixed with agar at the concentration of 0.5%. The distribution of the administered radiolabeled liquid and semi-solid nutrients was monitored by a scintillation camera for 15 post-PEG patients. The percentage of esophageal reflux, the distribution of the proximal and distal stomach, and the gastric emptying time were evaluated. RESULTS The percentage of gastroesophageal reflux was significantly decreased in semi-solid nutrients (0.82 +/- 1.27%) compared with liquid nutrients (3.75 +/- 4.25%), whereas the gastric emptying time was not different. The distribution of semi-solid nutrients was not different from liquid nutrients in the early phase, whereas higher retention of liquid nutrients in the proximal stomach was observed in the late phase. CONCLUSIONS Gastroesophageal reflux was significantly inhibited by semi-solid nutrients. One of the mechanisms of the inhibition is considered to be an improvement in the transition from the proximal to distal stomach in semi-solid nutrients.
Collapse
Affiliation(s)
- Shinji Nishiwaki
- Department of Internal Medicine, Nishimino Kosei Hospital, and Department of Gastroenterology, Graduate School of Medicine, Gifu University, Oshikoshi 986, Yoro-cho, Yoro-gun, Gifu 503-1394, Japan.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
34
|
Krygowska-Wajs A, Cheshire WP, Wszolek ZK, Hubalewska-Dydejczyk A, Jasinska-Myga B, Farrer MJ, Moskala M, Sowa-Staszczak A. Evaluation of gastric emptying in familial and sporadic Parkinson disease. Parkinsonism Relat Disord 2009; 15:692-6. [PMID: 19451015 DOI: 10.1016/j.parkreldis.2009.04.003] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2008] [Revised: 03/27/2009] [Accepted: 04/11/2009] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To assess for the presence of gastric dysmotility in familial and sporadic Parkinson disease (PD). METHODS 10 subjects with familial Parkinson disease (fPD), 35 subjects with sporadic Parkinson disease (sPD), and 15 controls, all from academic tertiary care movement disorders centers, were studied. fPD was defined as the presence of at least 2 affected individuals within 2-3 consecutive generations in a family. Molecular genetic analysis has not revealed, thus far, any known genomic abnormality in these families. Gastric emptying was assessed by dynamic abdominal scintigraphy over 92 min following ingestion of a solid meal containing 99mTc-labeled colloid of 40 MBq activity. The main outcome measures were gastric emptying half-time and radiotracer activity over the gastric area at 46 and at 92 min. RESULTS Gastric emptying time was delayed in 60% of subjects with PD. In comparison to mean t(1/2) of 38 +/- 7 min in controls, mean t(1/2) was 58 +/- 25 min in fPD (p = 0.02) and 46 +/- 25 min in sPD (p = 0.10). Both fPD and sPD groups included subjects with delayed gastric emptying at an early stage of disease. CONCLUSIONS Patients with fPD showed significantly delayed gastric emptying in comparison to normal age-matched individuals. Further studies of gastrointestinal dysfunction in PD, particularly fPD, are warranted.
Collapse
Affiliation(s)
- Anna Krygowska-Wajs
- Department of Neurology, Collegium Medicum Jagiellonian University, Krakow, Poland.
| | | | | | | | | | | | | | | |
Collapse
|