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Na HK, Li AA, Gottfried-Blackmore A, Podboy AJ, Esquivel MM, Joseph AA, Nguyen L, Hwang JH. Pyloric Dysfunction: A Review of the Mechanisms, Diagnosis, and Treatment. Gut Liver 2025; 19:327-345. [PMID: 40058793 PMCID: PMC12070220 DOI: 10.5009/gnl240421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 11/04/2024] [Accepted: 11/06/2024] [Indexed: 05/14/2025] Open
Abstract
Pyloric dysfunction is defined as hypertonia or spasm of the pyloric sphincter. The pylorus plays a key role in gastric emptying, but its function remains incompletely understood. Most studies have focused on gastroparesis regardless of the underlying pathophysiology. Few studies have reported pyloric dysfunction in patients with gastroparesis, and the diagnostic and treatment modalities for pyloric dysfunction are not well established. Recently developed diagnostic modalities assessing pyloric function, such as high-resolution antroduodenal manometry and endoluminal functional lumen imaging, are currently being evaluated. A variety of therapeutic interventions targeting the pylorus, including pharmacologic agents, intrapyloric botulinum injection, endoscopic balloon dilation, stent insertion, surgical pyloroplasty, and gastric peroral endoscopic pyloromyotomy, have been proposed. Among these, gastric peroral endoscopic pyloromyotomy has emerged as a novel, minimally invasive therapy with demonstrated efficacy and safety for refractory gastroparesis. This article reviews the pathophysiology of pyloric dysfunction and the potential diagnostic and therapeutic modalities based on the latest literature.
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Affiliation(s)
- Hee Kyong Na
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Andrew A. Li
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Andres Gottfried-Blackmore
- Department of Pharmacology and Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Alexander J. Podboy
- Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, VA, USA
| | - Micaela M. Esquivel
- Division of General Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Abel A. Joseph
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Linda Nguyen
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Joo Ha Hwang
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Division of General Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA
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Phokaewvarangkul O, Markaki I, Moes HR, Petrovic I, Schrag A, Bhidayasiri R. Vital nutrition: enhancing health in advanced Parkinson's disease with device-aided therapies. J Neural Transm (Vienna) 2025:10.1007/s00702-025-02935-x. [PMID: 40274626 DOI: 10.1007/s00702-025-02935-x] [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: 03/14/2025] [Accepted: 04/16/2025] [Indexed: 04/26/2025]
Abstract
Patients with advanced Parkinson's disease (PD) face a variety of nutritional challenges, including dysphagia, malnutrition, impaired absorption, gastrointestinal issues, and adverse drug interactions, in addition to body weight fluctuations. These challenges are especially significant for those utilising device-aided therapies (DATs), requiring personalised management strategies. Integrating dietitians into the multidisciplinary team (MDT) is vital for optimising nutrition, enhancing medication efficacy, and managing symptoms. This paper outlines strategies for supporting advanced PD patients using DATs, highlighting the critical role of dietitian assessments. Although there is no one-size-fits-all solution, dietary interventions are essential for improving motor function, preventing complications, and promoting overall health.
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Affiliation(s)
- Onanong Phokaewvarangkul
- Chulalongkorn Centre of Excellence for Parkinson's Disease & Related Disorders, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - Ioanna Markaki
- Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University, Stockholm, Sweden
| | - Harmen R Moes
- Department of Neurology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Igor Petrovic
- Neurology Clinic, University Clinical Center of Serbia, Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Anette Schrag
- Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK
| | - Roongroj Bhidayasiri
- Chulalongkorn Centre of Excellence for Parkinson's Disease & Related Disorders, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.
- The Academy of Science, The Royal Society of Thailand, Bangkok, Thailand.
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3
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Sampson TR, Tansey MG, West AB, Liddle RA. Lewy body diseases and the gut. Mol Neurodegener 2025; 20:14. [PMID: 39885558 PMCID: PMC11783828 DOI: 10.1186/s13024-025-00804-5] [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: 10/17/2024] [Accepted: 01/21/2025] [Indexed: 02/01/2025] Open
Abstract
Gastrointestinal (GI) involvement in Lewy body diseases (LBDs) has been observed since the initial descriptions of patients by James Parkinson. Recent experimental and human observational studies raise the possibility that pathogenic alpha-synuclein (⍺-syn) might develop in the GI tract and subsequently spread to susceptible brain regions. The cellular and mechanistic origins of ⍺-syn propagation in disease are under intense investigation. Experimental LBD models have implicated important contributions from the intrinsic gut microbiome, the intestinal immune system, and environmental toxicants, acting as triggers and modifiers to GI pathologies. Here, we review the primary clinical observations that link GI dysfunctions to LBDs. We first provide an overview of GI anatomy and the cellular repertoire relevant for disease, with a focus on luminal-sensing cells of the intestinal epithelium including enteroendocrine cells that express ⍺-syn and make direct contact with nerves. We describe interactions within the GI tract with resident microbes and exogenous toxicants, and how these may directly contribute to ⍺-syn pathology along with related metabolic and immunological responses. Finally, critical knowledge gaps in the field are highlighted, focusing on pivotal questions that remain some 200 years after the first descriptions of GI tract dysfunction in LBDs. We predict that a better understanding of how pathophysiologies in the gut influence disease risk and progression will accelerate discoveries that will lead to a deeper overall mechanistic understanding of disease and potential therapeutic strategies targeting the gut-brain axis to delay, arrest, or prevent disease progression.
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Affiliation(s)
- Timothy R Sampson
- Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, 30329, USA
- Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA
| | - Malú Gámez Tansey
- Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA
- Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL, 32610, USA
- McKnight Brain Institute, University of Florida, Gainesville, FL, 32610, USA
- Normal Fixel Institute of Neurological Diseases, Gainesville, FL, 32608, USA
| | - Andrew B West
- Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA.
- Duke Center for Neurodegeneration and Neurotherapeutic Research, Department of Pharmacology and Cancer Biology, Durham, NC, 27710, USA.
| | - Rodger A Liddle
- Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA.
- Duke Institute for Brain Sciences, Duke University, Durham, NC, 27710, USA.
- Department of Medicine, Duke University and Department of Veterans Affairs Health Care System, Durham, NC, 27710, USA.
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Gao V, Crawford CV, Burré J. The Gut-Brain Axis in Parkinson's Disease. Cold Spring Harb Perspect Med 2025; 15:a041618. [PMID: 38772708 PMCID: PMC11694753 DOI: 10.1101/cshperspect.a041618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/23/2024]
Abstract
Parkinson's disease (PD) involves both the central nervous system (CNS) and enteric nervous system (ENS), and their interaction is important for understanding both the clinical manifestations of the disease and the underlying disease pathophysiology. Although the neuroanatomical distribution of pathology strongly suggests that the ENS is involved in disease pathophysiology, there are significant gaps in knowledge about the underlying mechanisms. In this article, we review the clinical presentation and management of gastrointestinal dysfunction in PD. In addition, we discuss the current understanding of disease pathophysiology in the gut, including controversies about early involvement of the gut in disease pathogenesis. We also review current knowledge about gut α-synuclein and the microbiome, discuss experimental models of PD-linked gastrointestinal pathophysiology, and highlight areas for further research. Finally, we discuss opportunities to use the gut-brain axis for the development of biomarkers and disease-modifying treatments.
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Affiliation(s)
- Virginia Gao
- Appel Institute for Alzheimer's Disease Research and Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York 10021, USA
- Parkinson's Disease and Movement Disorders Institute, Department of Neurology, Weill Cornell Medicine, New York, New York 10065, USA
- Division of Movement Disorders, The Neurological Institute of New York, Columbia University Irving Medical Center, New York, New York 10033, USA
| | - Carl V Crawford
- Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, New York 10065, USA
| | - Jacqueline Burré
- Appel Institute for Alzheimer's Disease Research and Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York 10021, USA
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Kataoka H, Sugie K. Early-morning OFF in Parkinson's disease: A systematic literature review and current therapeutics. Clin Neurol Neurosurg 2024; 245:108493. [PMID: 39178635 DOI: 10.1016/j.clineuro.2024.108493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 07/25/2024] [Accepted: 08/01/2024] [Indexed: 08/26/2024]
Abstract
OBJECTIVE Early morning OFF (EMO) is one of the first motor complications to manifest and frequently signals the onset of additional motor complications in Parkinson's Disease (PD). Although EOM are frequently observed in patients with PD and many caregivers must help with their motor inability, the treatment is still unsatisfactory. The majority of research that has been conducted on the wearing-off state of patients with PD has focused on daytime symptoms; evening and early morning symptoms have received much less attention.This study aimed to review the clinical perspectives of current therapies for EMO. MATERIALS AND METHODS We reviewed the searching relevant publications from the key words such as morning off. A total of 456 publications were identified and we reviewed 21 clinical trials as well as other relevant clinical studies and reviews. RESULTS EMO are frequently disregarded or undervalued, which could have resulted in unintentional risks, inadequate management, and an increased burden of care. Oral medication is still the primary medical intervention for EMO. However, new developments in non-oral medications and advanced formulations aim to reduce the delay in experiencing the benefits of oral levodopa due to gastrointestinal problems. CONCLUSIONS The current therapies for EMO could be helpful in selecting a limited practical treatment. Advancements in non-oral medications and oral formulations hold promise for improving efficacy in EMO.
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Affiliation(s)
- Hiroshi Kataoka
- Department of Neurology, Nara Medical University, Nara, Japan.
| | - Kazuma Sugie
- Department of Neurology, Nara Medical University, Nara, Japan
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Isaacson S, Phillips O, Jimenez-Shahed J. Hope vs. Hype III: Rescue/on-demand therapies are preferable to device-assisted therapies in Parkinson disease. Parkinsonism Relat Disord 2024; 126:106079. [PMID: 38503575 DOI: 10.1016/j.parkreldis.2024.106079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 02/27/2024] [Indexed: 03/21/2024]
Affiliation(s)
- Stuart Isaacson
- Parkinson's Disease and Movement Disorders Center of Boca Raton, Boca Raton, 951 NW 13th St, Bldg. 5-E, Boca Raton, FL, 33486, USA.
| | - Oliver Phillips
- Geisel School of Medicine at Dartmouth, Hanover, 18 Old Etna Road, Lebanon, NH, 03756, USA.
| | - Joohi Jimenez-Shahed
- Icahn School of Medicine at Mount Sinai, Mount Sinai West, 1000 10th Ave. Suite 10c, New York City, NY, 10019, USA.
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Elkrewi EZ, Al Abdulqader AA, Khasanov R, Maas-Omlor S, Boettcher M, Wessel LM, Schäfer KH, Tapia-Laliena MÁ. Role of Inflammation and the NF-κB Signaling Pathway in Hirschsprung's Disease. Biomolecules 2024; 14:992. [PMID: 39199380 PMCID: PMC11352745 DOI: 10.3390/biom14080992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 07/24/2024] [Accepted: 08/05/2024] [Indexed: 09/01/2024] Open
Abstract
Hirschsprung's disease (HSCR, incidence 1/5000 live births) is caused by the failure of neural crest-derived precursors to migrate, survive, proliferate, or differentiate during the embryonic development of the Enteric Nervous System (ENS), which could be disrupted by many factors, including inflammatory processes. The NF-κB family controls several biological processes, including inflammation, neurogenesis, and cell migration. With the aim of studying the potential role of NF-κB in HSCR, we have analyzed the expression of the NF-κB main subunits and other NF-κB-related genes by RT-qPCR in HSCR tissue samples (sub-divided into ganglionic and aganglionic segments). We found decreased gene expression of the NF-κB main subunit RELA but also of NFKBIA, TNFA, TFGBR2, and ERBB3 in the pathologic distal aganglionic segments compared to the proximal ganglionic segments. Moreover, we could also confirm the lower protein expression of RelA/p65 in the aganglionic distal segments by immunofluorescence staining. Further, we show that the expression of RelA/p65 protein in the proximal segments concurs with lymphocyte infiltration in the bowel tissue, indicating a pro-inflammatory activation of p65 in the proximal ganglionic HSCR tissue in the patients analyzed. All in all, our findings suggest that the modulation of NF-κB signaling in the neuro-enteric system does obviously contribute to the pathological effects of HSCR.
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Affiliation(s)
- Enas Zoheer Elkrewi
- Department of Pediatric Surgery, Medical Faculty of Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1–3, 68167 Mannheim, Germany
| | - Ahmad A. Al Abdulqader
- Department of Pediatric Surgery, Medical Faculty of Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1–3, 68167 Mannheim, Germany
- Department of Surgery, College of Medicine, King Faisal University, Al Hofuf 31982, Saudi Arabia
| | - Rasul Khasanov
- Department of Pediatric Surgery, Medical Faculty of Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1–3, 68167 Mannheim, Germany
| | - Silke Maas-Omlor
- Working Group Enteric Nervous Systems (AGENS), University of Applied Sciences Kaiserslautern, Amerikastrasse 1,66482 Zweibrücken, Germany (K.-H.S.)
| | - Michael Boettcher
- Department of Pediatric Surgery, Medical Faculty of Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1–3, 68167 Mannheim, Germany
| | - Lucas M. Wessel
- Department of Pediatric Surgery, Medical Faculty of Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1–3, 68167 Mannheim, Germany
| | - Karl-Herbert Schäfer
- Working Group Enteric Nervous Systems (AGENS), University of Applied Sciences Kaiserslautern, Amerikastrasse 1,66482 Zweibrücken, Germany (K.-H.S.)
| | - María Ángeles Tapia-Laliena
- Department of Pediatric Surgery, Medical Faculty of Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1–3, 68167 Mannheim, Germany
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Chen L, Chen J, Wu M, Yan P, Zhou X. Analyzing the bibliometrics of brain-gut axis and Parkinson's disease. Front Neurol 2024; 15:1343303. [PMID: 38515447 PMCID: PMC10954898 DOI: 10.3389/fneur.2024.1343303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 02/21/2024] [Indexed: 03/23/2024] Open
Abstract
Background Parkinson's disease (PD), characterized by the loss of dopaminergic neurons, is a progressive neurodegenerative disorder. Recent research has revealed a significant connection between gut microbiota and PD. To gain insight into research interests, disciplinary contexts, and potential future directions, a comprehensive bibliometric analysis was conducted on the brain-gut axis and PD literature published between 2014 and 2023. Methods Relevant literature records were gathered from the Web of Science Core Collection on August 11, 2023. The data were then analyzed by Biblioshiny R packages and VOSviewer (version 1.6.19). Results The dataset revealed an upward trend in annual scientific publications on the brain-gut axis and PD, with an annual growth rate of 50.24%. China, the United States, and Italy were the top three most productive countries/regions. The journal "International Journal Of Molecular Sciences" published the most articles, while "Movement Disorders" received the highest number of citations. Professor Keshavarzian A emerged as the most prolific author, while Professor Scheperjans F held the highest h-index. Keyword analysis highlighted "alpha-synuclein" as the most frequent term, with "mouse model," "inflammation," and "risk" as emerging research topics. Additionally, "central nervous system" and "intestinal bacterial overgrowth" attracted increasing attention. Conclusion This study examined current trends and hotspots in the bibliometric landscape of the brain-gut axis and PD research. Future research directions should explore the functional and metabolic activities of gut microbiota. Additionally, transitioning from observational to interventional study designs offers the potential for personalized interventions and disease prediction. These findings can guide researchers in navigating the latest developments and shaping the future directions of this field.
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Affiliation(s)
- Lingshan Chen
- Medical Laboratory Specialty, The Second Hospital of Jinhua, Jinhua, Zhejiang Province, China
- School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jianfei Chen
- Medical Laboratory Specialty, The Second Hospital of Jinhua, Jinhua, Zhejiang Province, China
| | - Min Wu
- Medical Laboratory Specialty, The Second Hospital of Jinhua, Jinhua, Zhejiang Province, China
| | - Pingkang Yan
- Department of Gerontology, The Second Hospital of Jinhua, Jinhua, Zhejiang Province, China
| | - Xueping Zhou
- Department of Gerontology, The Second Hospital of Jinhua, Jinhua, Zhejiang Province, China
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Drouot M. [Dietary management of the Parkinson's patient: a necessity at every stage of the digestive system]. SOINS; LA REVUE DE REFERENCE INFIRMIERE 2024; 69:26-28. [PMID: 38453395 DOI: 10.1016/j.soin.2023.12.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/09/2024]
Abstract
Nutrition is a recurrent theme in the care of patients with Parkinson's disease. The aim of this article is to focus on the nutritional problems encountered in this pathology, and to clarify the role of the dietician in its management.
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Affiliation(s)
- Marion Drouot
- Service de neurologie, neuro-oncologie et hôpital de jour de neurologie et unité transversale de nutrition, centre hospitalier régional universitaire de Nancy, hôpital central, 29 avenue du Maréchal-de-Lattre-de-Tassigny CO n°34, 54035 Nancy cedex, France.
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Miyaue N, Ito Y, Yamanishi Y, Tada S, Ando R, Yabe H, Nagai M. Optimization of oral entacapone administration in patients undergoing levodopa-carbidopa intestinal gel treatment. J Neurol Sci 2024; 457:122901. [PMID: 38280299 DOI: 10.1016/j.jns.2024.122901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 01/22/2024] [Accepted: 01/22/2024] [Indexed: 01/29/2024]
Abstract
BACKGROUND Levodopa-carbidopa intestinal gel (LCIG) treatment markedly reduces motor fluctuations in patients with Parkinson's disease; however, some patients undergoing LCIG treatment may demonstrate clinical deterioration in the afternoon. Entacapone, a catechol-O-methyltransferase inhibitor, may be a promising adjunctive option for LCIG-treated patients; however, the optimal timing of oral entacapone administration to ameliorate clinical symptoms in the afternoon remains unexplored. This study aimed to investigate the optimal timing of oral entacapone administration in patients with Parkinson's disease undergoing LCIG treatment. METHODS Pharmacokinetic analysis and symptom assessment were performed on three days: a day without entacapone administration, day with oral entacapone administration at 13:00, and day with oral entacapone administration at 15:00. RESULTS Eight LCIG-treated patients were enrolled, of whom seven completed this study. The relative plasma concentrations of levodopa with entacapone administration at 13:00 were gradually increased, especially at 18:00 and were significantly higher than those without entacapone administration (127.10 ± 25.06% vs. 97.51 ± 22.20%). The relative plasma concentrations of 3-O-methyldopa were gradually increased without entacapone administration, whereas those with entacapone administration at 13:00 were lower than those without entacapone administration, especially at 17:00 (97.47 ± 3.70% vs. 110.71 ± 9.84%). Administering oral entacapone at 15:00 increased and decreased the relative plasma concentrations of levodopa and 3-O-methyldopa, respectively, but without significant difference. The "Off" time was shorter with entacapone administration at 13:00 (0.43 ± 0.79 h) and at 15:00 (0.57 ± 0.79 h) than that without entacapone administration (1.14 ± 1.46 h). CONCLUSIONS The concomitant use of oral entacapone in the early afternoon may be effective in improving afternoon symptoms in patients undergoing LCIG treatment.
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Affiliation(s)
- Noriyuki Miyaue
- Department of Clinical Pharmacology and Therapeutics, Ehime University Graduate School of Medicine, Tohon, Ehime, Japan; Department of Neurology, Saiseikai Matsuyama Hospital, Matsuyama, Ehime, Japan.
| | - Yuko Ito
- Department of Clinical Pharmacology and Therapeutics, Ehime University Graduate School of Medicine, Tohon, Ehime, Japan
| | - Yuki Yamanishi
- Department of Clinical Pharmacology and Therapeutics, Ehime University Graduate School of Medicine, Tohon, Ehime, Japan
| | - Satoshi Tada
- Department of Clinical Pharmacology and Therapeutics, Ehime University Graduate School of Medicine, Tohon, Ehime, Japan
| | - Rina Ando
- Department of Clinical Pharmacology and Therapeutics, Ehime University Graduate School of Medicine, Tohon, Ehime, Japan
| | - Hayato Yabe
- Department of Neurology, Saiseikai Matsuyama Hospital, Matsuyama, Ehime, Japan
| | - Masahiro Nagai
- Department of Clinical Pharmacology and Therapeutics, Ehime University Graduate School of Medicine, Tohon, Ehime, Japan
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11
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van der Berg I, Schootemeijer S, Overbeek K, Bloem BR, de Vries NM. Dietary Interventions in Parkinson's Disease. JOURNAL OF PARKINSON'S DISEASE 2024; 14:1-16. [PMID: 38277304 PMCID: PMC10836553 DOI: 10.3233/jpd-230366] [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: 11/19/2023] [Indexed: 01/28/2024]
Abstract
Several dietary patterns and nutritional supplements have been linked to the development, progression, and symptomatic treatment of Parkinson's disease (PD). Most of the evidence, at this point, is preliminary and based largely on observational studies. Interventional studies are scarce, so the evidence on effectiveness remains inconclusive. Dietary interventions could, analogous to exercise, potentially have a beneficial effect on disease symptoms as well as on the progression of the disease and should therefore be researched in high quality studies. Further work is also needed to study whether dietary interventions, when applied to an at-risk population, have any potential to postpone the onset of manifest PD. In this paper, we summarize all ongoing clinical trials on dietary interventions in PD. We found 10 ongoing studies, all aimed at a different intervention. These studies are mostly exploratory in nature or represent phase I or phase II trials focusing on safety, biological responses, and symptomatic effects. Taken together, we conclude that research on dietary interventions in persons with PD is still in its early days. The results of the various ongoing trials are expected to generate new hypotheses and will help to shape the agenda for future research on this important topic.
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Affiliation(s)
- Indy van der Berg
- Department of Neurology, Center of Expertise for Parkinson & Movement Disorders, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Nijmegen, The Netherlands
| | - Sabine Schootemeijer
- Department of Neurology, Center of Expertise for Parkinson & Movement Disorders, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Nijmegen, The Netherlands
| | - Karin Overbeek
- Department of Neurology, Center of Expertise for Parkinson & Movement Disorders, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Nijmegen, The Netherlands
| | - Bastiaan R. Bloem
- Department of Neurology, Center of Expertise for Parkinson & Movement Disorders, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Nijmegen, The Netherlands
| | - Nienke M. de Vries
- Department of Neurology, Center of Expertise for Parkinson & Movement Disorders, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Nijmegen, The Netherlands
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12
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Jia X, Chen Q, Zhang Y, Asakawa T. Multidirectional associations between the gut microbiota and Parkinson's disease, updated information from the perspectives of humoral pathway, cellular immune pathway and neuronal pathway. Front Cell Infect Microbiol 2023; 13:1296713. [PMID: 38173790 PMCID: PMC10762314 DOI: 10.3389/fcimb.2023.1296713] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 11/27/2023] [Indexed: 01/05/2024] Open
Abstract
The human gastrointestinal tract is inhabited by a diverse range of microorganisms, collectively known as the gut microbiota, which form a vast and complex ecosystem. It has been reported that the microbiota-gut-brain axis plays a crucial role in regulating host neuroprotective function. Studies have shown that patients with Parkinson's disease (PD) have dysbiosis of the gut microbiota, and experiments involving germ-free mice and fecal microbiota transplantation from PD patients have revealed the pathogenic role of the gut microbiota in PD. Interventions targeting the gut microbiota in PD, including the use of prebiotics, probiotics, and fecal microbiota transplantation, have also shown efficacy in treating PD. However, the causal relationship between the gut microbiota and Parkinson's disease remains intricate. This study reviewed the association between the microbiota-gut-brain axis and PD from the perspectives of humoral pathway, cellular immune pathway and neuronal pathway. We found that the interactions among gut microbiota and PD are very complex, which should be "multidirectional", rather than conventionally regarded "bidirectional". To realize application of the gut microbiota-related mechanisms in the clinical setting, we propose several problems which should be addressed in the future study.
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Affiliation(s)
- Xiaokang Jia
- School of Traditional Chinese Medicine, Hainan Medical University, Haikou, Hainan, China
| | - Qiliang Chen
- School of Basic Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Yuanyuan Zhang
- Department of Acupuncture and Moxibustion, The Affiliated Traditional Chinese Medicine (TCM) Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Tetsuya Asakawa
- Institute of Neurology, National Clinical Research Center for Infectious Diseases, the Third People’s Hospital of Shenzhen, Shenzhen, Guangdong, China
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Chang JJ, Gadi SR, Videnovic A, Kuo B, Pasricha TS. Impact of outpatient gastroenterology consult on pharmacotherapy and management of gastrointestinal symptoms in Parkinson's Disease. Clin Park Relat Disord 2023; 9:100215. [PMID: 37700817 PMCID: PMC10493246 DOI: 10.1016/j.prdoa.2023.100215] [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: 05/08/2023] [Revised: 08/14/2023] [Accepted: 08/23/2023] [Indexed: 09/14/2023] Open
Abstract
Background & aims Gastrointestinal (GI) symptoms are common in Parkinson's Disease (PD) patients, and GI dysmotility is thought to induce motor fluctuations, requiring escalation of levodopa therapy. The role of GI consultation in managing such symptoms, however, is unclear. In this study, we investigate the possible association between GI dysmotility symptoms and escalated LEDD therapy, as well as factors associated with GI consultation for PD symptom management. Methods This was a retrospective case-study of 248 PD patients evaluated by outpatient neurology at Massachusetts General Brigham Healthcare from 2018 to 2022. Logistic regression, t-test, and Fisher exact tests were performed to identify factors associated with GI consult, change in LEDD with consult, and association of consultation with GI diagnoses and treatments, respectively. Results Among 248 PD patients, 12.9% received GI consultation despite 96.8% having GI symptoms. Bloating was the primary symptom associated with receiving GI consultation (OR 3.59 [95% CI 1.47-8.88], p = 0.005). GI consultation increased the odds of receiving GI-specific medications (78.2% vs 46.3%, p = 0.001) and specialized GI diagnoses like gastroparesis (9.4% vs 0.46%, p < 0.001) and pelvic floor dysfunction (15.6% vs 0%, p < 0.0001). Interestingly, LEDD tended not to change after GI consultation, and dysmotility symptoms, including bloating, did not predict need for higher LEDD. Conclusions While treating symptoms of dysmotility may not ameliorate levodopa-based motor fluctuations as much as previously thought, GI consultations are underutilized in PD, and patients who receive GI consultation are more likely to have changes in GI diagnosis and treatment.
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Affiliation(s)
| | - Sanjay R.V. Gadi
- Department of Medicine, Duke University Health System, Durham, NC, United States
- Harvard Medical School, Boston, MA, United States
| | - Aleksandar Videnovic
- Neurological Clinical Research Institute, Department of Neurology, Massachusetts General Hospital, Boston, MA, United States
- Harvard Medical School, Boston, MA, United States
| | - Braden Kuo
- Harvard Medical School, Boston, MA, United States
- Center for Neurointestinal Health, Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA, United States
| | - Trisha S. Pasricha
- Harvard Medical School, Boston, MA, United States
- Center for Neurointestinal Health, Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA, United States
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14
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Montanari M, Imbriani P, Bonsi P, Martella G, Peppe A. Beyond the Microbiota: Understanding the Role of the Enteric Nervous System in Parkinson's Disease from Mice to Human. Biomedicines 2023; 11:1560. [PMID: 37371655 DOI: 10.3390/biomedicines11061560] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 05/23/2023] [Accepted: 05/25/2023] [Indexed: 06/29/2023] Open
Abstract
The enteric nervous system (ENS) is a nerve network composed of neurons and glial cells that regulates the motor and secretory functions of the gastrointestinal (GI) tract. There is abundant evidence of mutual communication between the brain and the GI tract. Dysfunction of these connections appears to be involved in the pathophysiology of Parkinson's disease (PD). Alterations in the ENS have been shown to occur very early in PD, even before central nervous system (CNS) involvement. Post-mortem studies of PD patients have shown aggregation of α-synuclein (αS) in specific subtypes of neurons in the ENS. Subsequently, αS spreads retrogradely in the CNS through preganglionic vagal fibers to this nerve's dorsal motor nucleus (DMV) and other central nervous structures. Here, we highlight the role of the ENS in PD pathogenesis based on evidence observed in animal models and using a translational perspective. While acknowledging the putative role of the microbiome in the gut-brain axis (GBA), this review provides a comprehensive view of the ENS not only as a "second brain", but also as a window into the "first brain", a potentially crucial element in the search for new therapeutic approaches that can delay and even cure the disease.
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Affiliation(s)
- Martina Montanari
- Laboratory of Neurophysiology and Plasticity, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy
- Department of Systems Neuroscience, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Paola Imbriani
- Laboratory of Neurophysiology and Plasticity, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy
- Clinical Neuroscience, IRCCS Fondazione Santa Lucia, 00179 Rome, Italy
| | - Paola Bonsi
- Laboratory of Neurophysiology and Plasticity, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy
| | - Giuseppina Martella
- Laboratory of Neurophysiology and Plasticity, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy
| | - Antonella Peppe
- Clinical Neuroscience, IRCCS Fondazione Santa Lucia, 00179 Rome, Italy
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15
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Leta V, Klingelhoefer L, Longardner K, Campagnolo M, Levent HÇ, Aureli F, Metta V, Bhidayasiri R, Chung-Faye G, Falup-Pecurariu C, Stocchi F, Jenner P, Warnecke T, Ray Chaudhuri K. Gastrointestinal barriers to levodopa transport and absorption in Parkinson's disease. Eur J Neurol 2023; 30:1465-1480. [PMID: 36757008 DOI: 10.1111/ene.15734] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/29/2023] [Accepted: 01/31/2023] [Indexed: 02/10/2023]
Abstract
Levodopa is the gold standard for the symptomatic treatment of Parkinson's disease (PD). There are well documented motor and non-motor fluctuations, however, that occur almost inevitably once levodopa is started after a variable period in people with PD. Whilst brain neurodegenerative processes play a part in the pathogenesis of these fluctuations, a range of barriers across the gastrointestinal (GI) tract can alter levodopa pharmacokinetics, ultimately contributing to non-optimal levodopa response and symptoms fluctuations. GI barriers to levodopa transport and absorption include dysphagia, delayed gastric emptying, constipation, Helicobacter pylori infection, small intestinal bacterial overgrowth and gut dysbiosis. In addition, a protein-rich diet and concomitant medication intake can further alter levodopa pharmacokinetics. This can result in unpredictable or sub-optimal levodopa response, 'delayed on' or 'no on' phenomena. In this narrative review, we provided an overview on the plethora of GI obstacles to levodopa transport and absorption in PD and their implications on levodopa pharmacokinetics and development of motor fluctuations. In addition, management strategies to address GI dysfunction in PD are highlighted, including use of non-oral therapies to bypass the GI tract.
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Affiliation(s)
- Valentina Leta
- Parkinson's Foundation Center of Excellence at King's College Hospital, London, UK.,Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London and National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre, Institute of Psychology, Psychiatry and Neurosciences, King's College London, London, UK
| | | | - Katherine Longardner
- Parkinson and Other Movement Disorders Center, Department of Neurosciences, University of California San Diego, La Jolla, California, USA
| | - Marta Campagnolo
- Department of Neurosciences (DNS), University of Padova, Padova, Italy
| | | | - Federico Aureli
- Department of Biomedical and NeuroMotor Sciences (DIBINEM), Alma Mater Studiorum-University of Bologna, Bologna, Italy
| | - Vinod Metta
- Parkinson's Foundation Center of Excellence at King's College Hospital, London, UK.,Kings College Hospital London, Dubai, United Arab Emirates
| | - Roongroj Bhidayasiri
- Chulalongkorn Centre of Excellence for Parkinson's Disease and Related Disorders, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.,Academy of Science, Royal Society of Thailand, Bangkok, Thailand
| | - Guy Chung-Faye
- Parkinson's Foundation Center of Excellence at King's College Hospital, London, UK.,Kings College Hospital London, Dubai, United Arab Emirates
| | | | - Fabrizio Stocchi
- Department of Neurology, University San Raffaele Roma and IRCCS San Raffaele Pisana, Rome, Italy
| | - Peter Jenner
- Institute of Pharmaceutical Sciences, Faculty of Life Science and Medicine, King's College London, London, UK
| | - Tobias Warnecke
- Department of Neurology and Neurorehabilitation, Klinikum Osnabrueck-Academic Teaching Hospital of the WWU Muenster, Osnabrueck, Germany
| | - K Ray Chaudhuri
- Parkinson's Foundation Center of Excellence at King's College Hospital, London, UK.,Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London and National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre, Institute of Psychology, Psychiatry and Neurosciences, King's College London, London, UK
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16
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Weisbach E, Friedman J, Akbar U. Nausea as a non-motor fluctuation in Parkinson's disease. Clin Park Relat Disord 2022; 8:100178. [PMID: 36594070 PMCID: PMC9804130 DOI: 10.1016/j.prdoa.2022.100178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 10/18/2022] [Accepted: 10/26/2022] [Indexed: 12/24/2022] Open
Affiliation(s)
- Emily Weisbach
- Neurology, Brown University Warren Alpert Medical School, Providence, RI, USA,Corresponding author at: 593 Eddy Street, Providence, RI 02903, USA.
| | - Joseph Friedman
- Neurology, Brown University Warren Alpert Medical School, Providence, RI, USA,Movement Disorders Program, Butler Hospital, Providence, RI, USA
| | - Umer Akbar
- Neurology, Brown University Warren Alpert Medical School, Providence, RI, USA
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17
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Olubodun-Obadun TG, Ishola IO, Adeyemi OO. Impact of environmental toxicants exposure on gut-brain axis in Parkinson disease. Drug Metab Pers Ther 2022; 37:329-336. [PMID: 35377569 DOI: 10.1515/dmpt-2021-0144] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 01/25/2022] [Indexed: 12/16/2022]
Abstract
Parkinson disease (PD) is a major public health challenge as many of the current drugs used in its management provide symptomatic relieve without preventing the underlying cause of the neurodegeneration. Similarly, the non-motor complications of PD, especially the gastrointestinal tract (GIT) disturbance increases the disease burden on both the PD patient and caregivers. Different theories have been postulated regarding the mechanisms or pathways involved in PD pathology but gut-brain axis involvement has gained much more momentum. This pathway was first suggested by Braak and colleagues in 2003, where they suggested that PD starts from the GIT before spreading to the brain. However, human exposure to environmental toxicants known to inhibit mitochondrial complex I activity such as rotenone, paraquat and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are well associated with PD. Several reports have shown that oral exposure of laboratory animals to rotenone causes mitochondria dysfunction, GIT disturbance, overexpression of alpha synuclein and microbiota imbalance. This review focuses on the mechanism(s) through which rotenone induces PD pathogenesis and potential for therapeutic small molecules targeting these processes at the earliest stages of the disease. We also focused on the interaction between the GI microbiota and PD pathology.
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Affiliation(s)
- Taiwo G Olubodun-Obadun
- Department of Pharmacology, Therapeutics and Toxicology, College of Medicine, University of Lagos, Lagos, Lagos State, Nigeria
| | - Ismail O Ishola
- Department of Pharmacology, Therapeutics and Toxicology, College of Medicine, University of Lagos, Lagos, Lagos State, Nigeria
| | - Olufunmilayo O Adeyemi
- Department of Pharmacology, Therapeutics and Toxicology, College of Medicine, University of Lagos, Lagos, Lagos State, Nigeria
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18
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Wang W, Jiang S, Xu C, Tang L, Liang Y, Zhao Y, Zhu G. Interactions between gut microbiota and Parkinson's disease: The role of microbiota-derived amino acid metabolism. Front Aging Neurosci 2022; 14:976316. [PMID: 36408101 PMCID: PMC9667037 DOI: 10.3389/fnagi.2022.976316] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 08/29/2022] [Indexed: 11/05/2022] Open
Abstract
Non-motor symptoms (NMS) of Parkinson's disease (PD), such as constipation, sleep disorders, and olfactory deficits, may emerge up to 20 years earlier than motor symptoms. A series of evidence indicates that the pathology of PD may occur from the gastrointestinal tract to the brain. Numerous studies support that the gut microbiota communicates with the brain through the immune system, special amino acid metabolism, and the nervous system in PD. Recently, there is growing recognition that the gut microbiota plays a vital role in the modulation of multiple neurochemical pathways via the “gut microbiota-brain axis” (GMBA). Many gut microbiota metabolites, such as fatty acids, amino acids, and bile acids, convey signaling functions as they mediate the crosstalk between gut microbiota and host physiology. Amino acids' abundance and species alteration, including glutamate and tryptophan, may disturb the signaling transmission between nerve cells and disrupt the normal basal ganglia function in PD. Specific amino acids and their receptors are considered new potential targets for ameliorating PD. The present study aimed to systematically summarize all available evidence on the gut microbiota-derived amino acid metabolism alterations associated with PD.
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Affiliation(s)
- Wang Wang
- Department of Neurology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shujun Jiang
- Chinese Medicine Modernization and Big Data Research Center, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Chengcheng Xu
- Department of Neurology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Lili Tang
- Department of Neurology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yan Liang
- Department of Neurology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yang Zhao
- Department of Neurology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- *Correspondence: Yang Zhao
| | - Guoxue Zhu
- Department of Neurology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Chinese Medicine Modernization and Big Data Research Center, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Guoxue Zhu
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19
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Bergquist F, Ehrnebo M, Nyholm D, Johansson A, Lundin F, Odin P, Svenningsson P, Hansson F, Bring L, Eriksson E, Dizdar N. Pharmacokinetics of Intravenously (DIZ101), Subcutaneously (DIZ102), and Intestinally (LCIG) Infused Levodopa in Advanced Parkinson Disease. Neurology 2022; 99:e965-e976. [PMID: 35705502 PMCID: PMC9519246 DOI: 10.1212/wnl.0000000000200804] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 04/14/2022] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND AND OBJECTIVES Intestinal levodopa/carbidopa gel infusion (LCIG) is superior to oral treatment in advanced Parkinson disease. The primary objective of this trial was to investigate whether continuous subcutaneous or intravenous infusion with a continuously buffered acidic levodopa/carbidopa solution yields steady-state plasma concentrations of levodopa that are equivalent in magnitude, and noninferior in variability, to those obtained with LCIG in patients with advanced Parkinson disease. METHODS A concentrated acidic levodopa/carbidopa (8:1) solution buffered continuously and administered intravenously (DIZ101) or subcutaneously (DIZ102) was compared with an approved LCIG in a randomized, 3-period crossover, open-label, multicenter trial. Formulations were infused for 16 hours to patients with Parkinson disease who were using LCIG as their regular treatment. Patients were recruited from several university neurology clinics but came to the same phase I unit for treatment. Pharmacokinetic variables and safety including dermal tolerance are reported. The primary outcomes were bioequivalence and noninferior variability of DIZ101 and DIZ102 vs LCIG with respect to levodopa plasma concentrations. RESULTS With dosing adjusted to estimated bioavailability, DIZ101 and DIZ102 produced levodopa plasma levels within standard bioequivalence limits compared with LCIG in the 18 participants who received all treatments. Although the levodopa bioavailability for DIZ102 was complete, it was 80% for LCIG. Therapeutic concentrations of levodopa were reached as quickly with subcutaneous administration of DIZ102 as with LCIG and remained stable throughout the infusions. Owing to poor uptake of LCIG, carbidopa levels in plasma were higher with DIZ101 and DIZ102 than with the former. All individuals receiving any of the treatments (n = 20) were included in the evaluation of safety and tolerability. Reactions at the infusion sites were mild and transient. DISCUSSION It is feasible to rapidly achieve high and stable levodopa concentrations by means of continuous buffering of a subcutaneously administered acidic levodopa/carbidopa-containing solution. TRIAL REGISTRATION INFORMATION ClinicalTrials.gov identifier: NCT03419806. Registration first posted on February 5, 2018, first patient enrolled on February 16, 2018.
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Affiliation(s)
- Filip Bergquist
- From the Department of Pharmacology (F.B., E.E.), University of Gothenburg; Neurology (F.B.), Sahlgrenska University Hospital, Göteborg; Department of Pharmaceutical Biosciences (M.E.), Uppsala University; Pharm Assist Sweden AB (M.E.), Uppsala; Department of Neuroscience (D.N.), Uppsala University; Department of Clinical Neurosciences (A.J., P.S.), Karolinska Institutet (A.J., P.S.), Solna; Department of Biomedical and Clinical Sciences (F.L., N.D.), Linköping University (F.L., N.D.); Neurology (P.O.), Department of Clinical Sciences, Lund University; CTC Clinical Trial Consultants AB (F.H.), Uppsala; and Dizlin Pharmaceuticals (L.B.) Gothenburg, Sweden.
| | - Mats Ehrnebo
- From the Department of Pharmacology (F.B., E.E.), University of Gothenburg; Neurology (F.B.), Sahlgrenska University Hospital, Göteborg; Department of Pharmaceutical Biosciences (M.E.), Uppsala University; Pharm Assist Sweden AB (M.E.), Uppsala; Department of Neuroscience (D.N.), Uppsala University; Department of Clinical Neurosciences (A.J., P.S.), Karolinska Institutet (A.J., P.S.), Solna; Department of Biomedical and Clinical Sciences (F.L., N.D.), Linköping University (F.L., N.D.); Neurology (P.O.), Department of Clinical Sciences, Lund University; CTC Clinical Trial Consultants AB (F.H.), Uppsala; and Dizlin Pharmaceuticals (L.B.) Gothenburg, Sweden
| | - Dag Nyholm
- From the Department of Pharmacology (F.B., E.E.), University of Gothenburg; Neurology (F.B.), Sahlgrenska University Hospital, Göteborg; Department of Pharmaceutical Biosciences (M.E.), Uppsala University; Pharm Assist Sweden AB (M.E.), Uppsala; Department of Neuroscience (D.N.), Uppsala University; Department of Clinical Neurosciences (A.J., P.S.), Karolinska Institutet (A.J., P.S.), Solna; Department of Biomedical and Clinical Sciences (F.L., N.D.), Linköping University (F.L., N.D.); Neurology (P.O.), Department of Clinical Sciences, Lund University; CTC Clinical Trial Consultants AB (F.H.), Uppsala; and Dizlin Pharmaceuticals (L.B.) Gothenburg, Sweden
| | - Anders Johansson
- From the Department of Pharmacology (F.B., E.E.), University of Gothenburg; Neurology (F.B.), Sahlgrenska University Hospital, Göteborg; Department of Pharmaceutical Biosciences (M.E.), Uppsala University; Pharm Assist Sweden AB (M.E.), Uppsala; Department of Neuroscience (D.N.), Uppsala University; Department of Clinical Neurosciences (A.J., P.S.), Karolinska Institutet (A.J., P.S.), Solna; Department of Biomedical and Clinical Sciences (F.L., N.D.), Linköping University (F.L., N.D.); Neurology (P.O.), Department of Clinical Sciences, Lund University; CTC Clinical Trial Consultants AB (F.H.), Uppsala; and Dizlin Pharmaceuticals (L.B.) Gothenburg, Sweden
| | - Fredrik Lundin
- From the Department of Pharmacology (F.B., E.E.), University of Gothenburg; Neurology (F.B.), Sahlgrenska University Hospital, Göteborg; Department of Pharmaceutical Biosciences (M.E.), Uppsala University; Pharm Assist Sweden AB (M.E.), Uppsala; Department of Neuroscience (D.N.), Uppsala University; Department of Clinical Neurosciences (A.J., P.S.), Karolinska Institutet (A.J., P.S.), Solna; Department of Biomedical and Clinical Sciences (F.L., N.D.), Linköping University (F.L., N.D.); Neurology (P.O.), Department of Clinical Sciences, Lund University; CTC Clinical Trial Consultants AB (F.H.), Uppsala; and Dizlin Pharmaceuticals (L.B.) Gothenburg, Sweden
| | - Per Odin
- From the Department of Pharmacology (F.B., E.E.), University of Gothenburg; Neurology (F.B.), Sahlgrenska University Hospital, Göteborg; Department of Pharmaceutical Biosciences (M.E.), Uppsala University; Pharm Assist Sweden AB (M.E.), Uppsala; Department of Neuroscience (D.N.), Uppsala University; Department of Clinical Neurosciences (A.J., P.S.), Karolinska Institutet (A.J., P.S.), Solna; Department of Biomedical and Clinical Sciences (F.L., N.D.), Linköping University (F.L., N.D.); Neurology (P.O.), Department of Clinical Sciences, Lund University; CTC Clinical Trial Consultants AB (F.H.), Uppsala; and Dizlin Pharmaceuticals (L.B.) Gothenburg, Sweden
| | - Per Svenningsson
- From the Department of Pharmacology (F.B., E.E.), University of Gothenburg; Neurology (F.B.), Sahlgrenska University Hospital, Göteborg; Department of Pharmaceutical Biosciences (M.E.), Uppsala University; Pharm Assist Sweden AB (M.E.), Uppsala; Department of Neuroscience (D.N.), Uppsala University; Department of Clinical Neurosciences (A.J., P.S.), Karolinska Institutet (A.J., P.S.), Solna; Department of Biomedical and Clinical Sciences (F.L., N.D.), Linköping University (F.L., N.D.); Neurology (P.O.), Department of Clinical Sciences, Lund University; CTC Clinical Trial Consultants AB (F.H.), Uppsala; and Dizlin Pharmaceuticals (L.B.) Gothenburg, Sweden
| | - Fredrik Hansson
- From the Department of Pharmacology (F.B., E.E.), University of Gothenburg; Neurology (F.B.), Sahlgrenska University Hospital, Göteborg; Department of Pharmaceutical Biosciences (M.E.), Uppsala University; Pharm Assist Sweden AB (M.E.), Uppsala; Department of Neuroscience (D.N.), Uppsala University; Department of Clinical Neurosciences (A.J., P.S.), Karolinska Institutet (A.J., P.S.), Solna; Department of Biomedical and Clinical Sciences (F.L., N.D.), Linköping University (F.L., N.D.); Neurology (P.O.), Department of Clinical Sciences, Lund University; CTC Clinical Trial Consultants AB (F.H.), Uppsala; and Dizlin Pharmaceuticals (L.B.) Gothenburg, Sweden
| | - Leif Bring
- From the Department of Pharmacology (F.B., E.E.), University of Gothenburg; Neurology (F.B.), Sahlgrenska University Hospital, Göteborg; Department of Pharmaceutical Biosciences (M.E.), Uppsala University; Pharm Assist Sweden AB (M.E.), Uppsala; Department of Neuroscience (D.N.), Uppsala University; Department of Clinical Neurosciences (A.J., P.S.), Karolinska Institutet (A.J., P.S.), Solna; Department of Biomedical and Clinical Sciences (F.L., N.D.), Linköping University (F.L., N.D.); Neurology (P.O.), Department of Clinical Sciences, Lund University; CTC Clinical Trial Consultants AB (F.H.), Uppsala; and Dizlin Pharmaceuticals (L.B.) Gothenburg, Sweden
| | - Elias Eriksson
- From the Department of Pharmacology (F.B., E.E.), University of Gothenburg; Neurology (F.B.), Sahlgrenska University Hospital, Göteborg; Department of Pharmaceutical Biosciences (M.E.), Uppsala University; Pharm Assist Sweden AB (M.E.), Uppsala; Department of Neuroscience (D.N.), Uppsala University; Department of Clinical Neurosciences (A.J., P.S.), Karolinska Institutet (A.J., P.S.), Solna; Department of Biomedical and Clinical Sciences (F.L., N.D.), Linköping University (F.L., N.D.); Neurology (P.O.), Department of Clinical Sciences, Lund University; CTC Clinical Trial Consultants AB (F.H.), Uppsala; and Dizlin Pharmaceuticals (L.B.) Gothenburg, Sweden
| | - Nil Dizdar
- From the Department of Pharmacology (F.B., E.E.), University of Gothenburg; Neurology (F.B.), Sahlgrenska University Hospital, Göteborg; Department of Pharmaceutical Biosciences (M.E.), Uppsala University; Pharm Assist Sweden AB (M.E.), Uppsala; Department of Neuroscience (D.N.), Uppsala University; Department of Clinical Neurosciences (A.J., P.S.), Karolinska Institutet (A.J., P.S.), Solna; Department of Biomedical and Clinical Sciences (F.L., N.D.), Linköping University (F.L., N.D.); Neurology (P.O.), Department of Clinical Sciences, Lund University; CTC Clinical Trial Consultants AB (F.H.), Uppsala; and Dizlin Pharmaceuticals (L.B.) Gothenburg, Sweden
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20
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Vagus nerve stimulation increases stomach-brain coupling via a vagal afferent pathway. Brain Stimul 2022; 15:1279-1289. [PMID: 36067977 DOI: 10.1016/j.brs.2022.08.019] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 06/27/2022] [Accepted: 08/24/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Maintaining energy homeostasis is vital and supported by vagal signaling between digestive organs and the brain. Previous research has established a gastric network in the brain that is phase synchronized with the rhythm of the stomach, but tools to perturb its function were lacking. OBJECTIVE To evaluate whether stomach-brain coupling can be acutely increased by non-invasively stimulating vagal afferent projections to the brain. METHODS Using a single-blind randomized crossover design, we investigated the effect of acute right-sided transcutaneous auricular vagus nerve stimulation (taVNS) versus sham stimulation on stomach-brain coupling. RESULTS In line with preclinical research, taVNS increased stomach-brain coupling in the nucleus of the solitary tract (NTS) and the midbrain while boosting coupling across the brain. Crucially, in the cortex, taVNS-induced changes in coupling occurred primarily in transmodal regions and were associated with changes in hunger ratings as indicators of the subjective metabolic state. CONCLUSIONS taVNS increases stomach-brain coupling via an NTS-midbrain pathway that signals gut-induced reward, indicating that communication between the brain and the body is effectively modulated by vago-vagal signaling. Such insights may help us better understand the role of vagal afferents in orchestrating the recruitment of the gastric network which could pave the way for novel neuromodulatory treatments.
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21
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Safarpour D, Brumbach BH, Arena M, Quinn J, Diamond S, Nutt JG, Pfeiffer R. Gastrointestinal Motility and Response to Levodopa in Parkinson's Disease: A Proof-of-Concept Study. Mov Disord 2022; 37:2153-2158. [PMID: 35969014 DOI: 10.1002/mds.29176] [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: 04/22/2022] [Revised: 06/24/2022] [Accepted: 07/18/2022] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Simultaneous measurement of gastrointestinal transit time (GITT) and plasma levodopa concentration (PLC) is crucial to understanding the effect of dysfunctional motility on levodopa response in patients with Parkinson's disease (PwPD). OBJECTIVE The aim is to determine if altered segmental GITT correlates with clinical response and PLC variability in PwPD. METHODS Ten typical and 10 erratic responders ingested the SmartPill (SP) wireless motility capsule. Serial PLC and finger tapping, obtained every 30 minutes for 3 hours after SP/levodopa ingestion, evaluated the correlation between GITT, clinical response, and PLC. Glucose breath testing assessed small intestinal bacterial overgrowth (SIBO). RESULTS GITT was not significantly different in "typical" and "erratic" responders. SIBO was positive in half of the erratic and negative in most typical responders. CONCLUSION SP is a feasible technology for assessing GITT in PwPD. A larger study may be able to significantly differentiate/correlate GITT in different segments of the GI tract with response to levodopa. © 2022 International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Delaram Safarpour
- Department of Neurology, Oregon Health & Science University, Portland, Oregon, USA
| | - Barbara H Brumbach
- OHSU-PSU School of Public Health, Biostatistics and Design Program, Oregon Health & Science University, Portland, Oregon, USA
| | - Monica Arena
- Department of Neurology, Oregon Health & Science University, Portland, Oregon, USA
| | - Joseph Quinn
- Department of Neurology, Oregon Health & Science University, Portland, Oregon, USA
| | - Sarah Diamond
- Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA
| | - Jay G Nutt
- Department of Neurology, Oregon Health & Science University, Portland, Oregon, USA
| | - RonaldF Pfeiffer
- Department of Neurology, Oregon Health & Science University, Portland, Oregon, USA
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22
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Bhidayasiri R, Phuenpathom W, Tan AH, Leta V, Phumphid S, Chaudhuri KR, Pal PK. Management of dysphagia and gastroparesis in Parkinson's disease in real-world clinical practice - Balancing pharmacological and non-pharmacological approaches. Front Aging Neurosci 2022; 14:979826. [PMID: 36034128 PMCID: PMC9403060 DOI: 10.3389/fnagi.2022.979826] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 07/18/2022] [Indexed: 12/23/2022] Open
Abstract
Gastrointestinal (GI) issues are commonly experienced by patients with Parkinson's disease (PD). Those that affect the lower GI tract, such as constipation, are the most frequently reported GI problems among patients with PD. Upper GI issues, such as swallowing dysfunction (dysphagia) and delayed gastric emptying (gastroparesis), are also common in PD but are less well recognized by both patients and clinicians and, therefore, often overlooked. These GI issues may also be perceived by the healthcare team as less of a priority than management of PD motor symptoms. However, if left untreated, both dysphagia and gastroparesis can have a significant impact on the quality of life of patients with PD and on the effectiveness on oral PD medications, with negative consequences for motor control. Holistic management of PD should therefore include timely and effective management of upper GI issues by utilizing both non-pharmacological and pharmacological approaches. This dual approach is key as many pharmacological strategies have limited efficacy in this setting, so non-pharmacological approaches are often the best option. Although a multidisciplinary approach to the management of GI issues in PD is ideal, resource constraints may mean this is not always feasible. In 'real-world' practice, neurologists and PD care teams often need to make initial assessments and treatment or referral recommendations for their patients with PD who are experiencing these problems. To provide guidance in these cases, this article reviews the published evidence for diagnostic and therapeutic management of dysphagia and gastroparesis, including recommendations for timely and appropriate referral to GI specialists when needed and guidance on the development of an effective management plan.
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Affiliation(s)
- Roongroj Bhidayasiri
- Chulalongkorn Centre of Excellence for Parkinson’s Disease and Related Disorders, Department of Medicine, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
- Academy of Science, Royal Society of Thailand, Bangkok, Thailand
| | - Warongporn Phuenpathom
- Chulalongkorn Centre of Excellence for Parkinson’s Disease and Related Disorders, Department of Medicine, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - Ai Huey Tan
- Division of Neurology, Department of Medicine, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Valentina Leta
- Department of Basic and Clinical Neurosciences, The Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology & Neuroscience, Parkinson’s Foundation Centre of Excellence, King’s College London, London, United Kingdom
| | - Saisamorn Phumphid
- Chulalongkorn Centre of Excellence for Parkinson’s Disease and Related Disorders, Department of Medicine, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - K. Ray Chaudhuri
- Department of Basic and Clinical Neurosciences, The Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology & Neuroscience, Parkinson’s Foundation Centre of Excellence, King’s College London, London, United Kingdom
| | - Pramod Kumar Pal
- National Institute of Mental Health and Neurosciences, Bengaluru, India
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23
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GÜNEŞ M, KARAVANA SY. Non-Oral Drug Delivery in Parkinson’s Disease: Current Applications and Future. Turk J Pharm Sci 2022; 19:343-352. [DOI: 10.4274/tjps.galenos.2021.95226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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24
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Nyholm D, Jost WH. Levodopa–entacapone–carbidopa intestinal gel infusion in advanced Parkinson’s disease: real-world experience and practical guidance. Ther Adv Neurol Disord 2022; 15:17562864221108018. [PMID: 35785401 PMCID: PMC9244918 DOI: 10.1177/17562864221108018] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 05/31/2022] [Indexed: 11/24/2022] Open
Abstract
As Parkinson’s disease (PD) progresses, treatment needs to be adapted to maintain symptom control. Once patients develop advanced PD, an optimised regimen of oral and transdermal medications may no longer provide adequate relief of OFF periods and motor complications can emerge. At this point, patients may wish to consider a device-aided therapy (DAT) that provides continuous dopaminergic stimulation to help overcome these issues. Levodopa–entacapone–carbidopa intestinal gel (LECIG) infusion is a recently developed DAT option. The aim of this article is twofold: (1) to give an overview of the pharmacokinetics of LECIG infusion and clinical experience to date of its use in patients with advanced PD, including real-world data and patient-reported outcomes from a cohort of patients treated in Sweden, the first country where it was introduced, and (2) based on that information to provide practical guidance for healthcare teams starting patients on LECIG infusion, whether they are transitioning from oral medications or from other DATs, including recommendations for stepwise dosing calculation and titration. In terms of clinical efficacy, LECIG infusion has been shown to have a similar effect on motor function to standard levodopa–carbidopa intestinal gel (LCIG) infusion but, due to the presence of entacapone in LECIG, the bioavailability of levodopa is increased such that lower overall levodopa doses can be given to achieve therapeutically effective plasma concentrations. From a practical standpoint, LECIG infusion is delivered using a smaller cartridge and pump system than LCIG infusion. In addition, for patients previously treated with LCIG infusion who have an existing percutaneous endoscopic transgastric jejunostomy (PEG-J) system, this is compatible with the LECIG infusion system. As it is a relatively new product, the long-term efficacy and safety of LECIG infusion remain to be established; however, real-world data will continue to be collected and analysed to provide this information and help inform future clinical decisions.
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25
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Beckers M, Bloem BR, Verbeek MM. Mechanisms of peripheral levodopa resistance in Parkinson's disease. NPJ Parkinsons Dis 2022; 8:56. [PMID: 35546556 PMCID: PMC9095610 DOI: 10.1038/s41531-022-00321-y] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Accepted: 04/08/2022] [Indexed: 02/07/2023] Open
Abstract
Parkinson’s disease (PD) is an increasingly common neurodegenerative condition. The disease has a significant negative impact on quality of life, but a personalized management approach can help reduce disability. Pharmacotherapy with levodopa remains the cornerstone of treatment, and a gratifying and sustained response to this treatment is a supportive criterion that argues in favor of an underlying diagnosis of PD. Yet, in daily practice, it is not uncommon to encounter patients who appear to have true PD, but who nevertheless seem to lose the responsiveness to levodopa (secondary non-responders). Some patients may even fail to respond altogether (primary non-responders). Here, we address how two mechanisms of “peripheral resistance” may underlie this failing response to levodopa in persons with PD. The first explanation relates to impaired bowel motility leading to secondary bacterial overgrowth, and more specifically, to the excessive bacterial production of the enzyme tyrosine decarboxylase (TDC). This enzyme may convert levodopa to dopamine in the gut, thereby hampering entry into the circulation and, subsequently, into the brain. The second explanation relates to the systemic induction of the enzyme aromatic l-amino acid decarboxylase (AADC), leading to premature conversion of levodopa into dopamine, again limiting the bioavailability within the brain. We discuss these two mechanisms and focus on the clinical implications, potential treatments and directions for future research.
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Affiliation(s)
- Milan Beckers
- Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands. .,Radboudumc Center of Expertise for Parkinson & Movement Disorders, Nijmegen, The Netherlands.
| | - Bastiaan R Bloem
- Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.,Radboudumc Center of Expertise for Parkinson & Movement Disorders, Nijmegen, The Netherlands
| | - Marcel M Verbeek
- Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.,Radboudumc Center of Expertise for Parkinson & Movement Disorders, Nijmegen, The Netherlands.,Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
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26
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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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27
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Siebner TH, Fuglsang S, Madelung CF, Løkkegaard A, Bendtsen F, Hove JD, Damgaard M, Madsen JL, Siebner HR. Gastric Emptying Is Not Delayed and Does Not Correlate With Attenuated Postprandial Blood Flow Increase in Medicated Patients With Early Parkinson's Disease. Front Neurol 2022; 13:828069. [PMID: 35280265 PMCID: PMC8910363 DOI: 10.3389/fneur.2022.828069] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 01/24/2022] [Indexed: 11/13/2022] Open
Abstract
Background We have recently used phase-contrast magnetic resonance imaging (PC-MRI) to demonstrate an attenuated postprandial blood flow response in the superior mesenteric artery (SMA) in 23 medicated patients with Parkinson's disease (PD) compared to 23 age- and sex-matched healthy controls. Objective To investigate in a sub-sample of the original cohort whether the observed blood flow response in SMA after oral food intake is related to a delay in gastric emptying. Methods We studied 15 patients with PD in an “ON-medication” state with a mean disease duration of 3.9 ± 2.2 years and 15 healthy age- and sex-matched individuals. Participants underwent dynamic gastric scintigraphy 0, 30, 60, 120, 180 and 240 minutes after the intake of a standardized radiolabeled test meal. Gastric emptying was compared between groups. 14 of the 15 PD patients and 12 of the 15 healthy control subjects had previously undergone serial postprandial PC-MRI measurements. In these individuals, we tested for a relationship between gastric emptying and postprandial blood flow response in the SMA. Results The dynamics of gastric emptying did not differ between groups (p = 0.68). There was substantial inter-subject variability of gastric emptying in PD patients and healthy participants. Only a single PD patient had delayed gastric emptying. In those participants who had undergone PC-MRI, postprandial increase in SMA blood flow was attenuated in PD compared to healthy controls as reported previously (p = 0.006). Gastric emptying did not correlate with the timing and amplitude of postprandial blood flow increase in SMA. Conclusion Our preliminary results, obtained in a small group of early-stage PD patients who continued their usual dopamine replacement therapy, suggest that variations in gastric emptying after solid meal intake is within the normal range in the majority of cases. There is also no evidence for a tight relationship between the attenuated postprandial blood flow response in the SMA and normal variations in gastric emptying.
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Affiliation(s)
- Thomas Hartwig Siebner
- Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital—Amager and Hvidovre, Copenhagen, Denmark
- Department of Cardiology, Copenhagen University Hospital—Amager and Hvidovre, Copenhagen, Denmark
- *Correspondence: Thomas Hartwig Siebner
| | - Stefan Fuglsang
- Department of Clinical Physiology and Nuclear Medicine, Centre for Functional Imaging and Research, Copenhagen University Hospital—Amager and Hvidovre, Copenhagen, Denmark
| | - Christopher Fugl Madelung
- Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital—Amager and Hvidovre, Copenhagen, Denmark
- Department of Neurology, Copenhagen University Hospital—Bispebjerg and Frederiksberg, Copenhagen, Denmark
| | - Annemette Løkkegaard
- Department of Neurology, Copenhagen University Hospital—Bispebjerg and Frederiksberg, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Flemming Bendtsen
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
- Gastrounit, Medical Division, Copenhagen University Hospital—Amager and Hvidovre, Copenhagen, Denmark
| | - Jens Dahlgaard Hove
- Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital—Amager and Hvidovre, Copenhagen, Denmark
- Department of Cardiology, Copenhagen University Hospital—Amager and Hvidovre, Copenhagen, Denmark
| | - Morten Damgaard
- Department of Clinical Physiology and Nuclear Medicine, Centre for Functional Imaging and Research, Copenhagen University Hospital—Amager and Hvidovre, Copenhagen, Denmark
| | - Jan Lysgård Madsen
- Department of Clinical Physiology and Nuclear Medicine, Centre for Functional Imaging and Research, Copenhagen University Hospital—Amager and Hvidovre, Copenhagen, Denmark
| | - Hartwig Roman Siebner
- Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital—Amager and Hvidovre, Copenhagen, Denmark
- Department of Neurology, Copenhagen University Hospital—Bispebjerg and Frederiksberg, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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28
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Malaty IA, Martinez-Martin P, Chaudhuri KR, Odin P, Skorvanek M, Jimenez-Shahed J, Soileau MJ, Lindvall S, Domingos J, Jones S, Alobaidi A, Jalundhwala YJ, Kandukuri PL, Onuk K, Bergmann L, Femia S, Lee MY, Wright J, Antonini A. Does the 5-2-1 criteria identify patients with advanced Parkinson's disease? Real-world screening accuracy and burden of 5-2-1-positive patients in 7 countries. BMC Neurol 2022; 22:35. [PMID: 35073872 PMCID: PMC8785442 DOI: 10.1186/s12883-022-02560-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 01/19/2022] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND The burden of Parkinson's disease (PD) worsens with disease progression. However, the lack of objective and uniform disease classification challenges our understanding of the incremental burden in patients with advanced Parkinson's disease (APD) and suboptimal medication control. The 5-2-1 criteria was proposed by clinical consensus to identify patients with advancing PD. Our objective was to evaluate the screening accuracy and incremental clinical burden, healthcare resource utilization (HCRU), and humanistic burden in PD patients meeting the 5-2-1 screening criteria. METHODS Data were drawn from the Adelphi Parkinson's Disease Specific Program (DSP™), a multi-country point-in-time survey (2017-2020). People with PD who were naive to device-aided therapy and on oral PD therapy were included. Patients meeting the 5-2-1 screening criteria had one or more of the three clinical indicators of APD: (i) ≥5 doses of oral levodopa/day, OR (ii) "off" symptoms for ≥2 h of waking day, OR (iii) ≥1 h of troublesome dyskinesia. Clinician assessment of PD stage was used as the reference in this study. Clinical screening accuracy of the 5-2-1 criteria was assessed using area under the curve and multivariable logistic regression models. Incremental clinical, HCRU, and humanistic burden were assessed by known-group comparisons between 5 and 2-1-positive and negative patients. RESULTS From the analytic sample (n = 4714), 33% of patients met the 5-2-1 screening criteria. Among physician-classified APD patients, 78.6% were 5-2-1 positive. Concordance between clinician judgment and 5-2-1 screening criteria was > 75%. 5-2-1-positive patients were nearly 7-times more likely to be classified as APD by physician judgment. Compared with the 5-2-1-negative group, 5-2-1-positive patients had significantly higher clinical, HCRU, and humanistic burden across all measures. In particular, 5-2-1-positive patients had 3.8-times more falls, 3.6-times higher annual hospitalization rate, and 3.4-times greater dissatisfaction with PD treatment. 5-2-1-positive patients also had significantly lower quality of life and worse caregiver burden. CONCLUSIONS 5-2-1 criteria demonstrated potential as a screening tool for identifying people with APD with considerable clinical, humanistic, and HCRU burden. The 5-2-1 screening criteria is an objective and reliable tool that may aid the timely identification and treatment optimization of patients inadequately controlled on oral PD medications.
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Affiliation(s)
- Irene A. Malaty
- University of Florida, Fixel Institute for Neurological Diseases, Gainesville, FL USA
| | - Pablo Martinez-Martin
- Center for Networked Biomedical Research in Neurodegenerative Diseases (CIBERNED), Carlos III Institute of Health, Madrid, Spain
| | - K. Ray Chaudhuri
- Parkinson Foundation Centre of Excellence, King’s College Hospital and King’s College, London, UK
| | - Per Odin
- University of Lund, Lund, Sweden
| | - Matej Skorvanek
- Department of Neurology, P. J. Šafárik University, Košice, Slovakia
- Department of Neurology, University Hospital of L. Pasteur, Košice, Slovakia
| | - Joohi Jimenez-Shahed
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY USA
| | | | | | - Josefa Domingos
- European Parkinson’s Disease Association (EPDA), Sevenoaks, UK
- Grupo de patologia médica, nutrição e exercício clínico (PaMNEC) do CiiEM, Almada, Portugal
| | - Sarah Jones
- Parkinson & Movement Disorder Alliance, Tucson, USA
| | - Ali Alobaidi
- AbbVie Inc., North Chicago, IL USA
- University of Illinois at Chicago, Chicago, IL USA
| | | | | | | | | | | | | | | | - Angelo Antonini
- Parkinson and Movement Disorders Unit, Department of Neuroscience, University of Padua, Padova, Italy
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Menozzi E, Macnaughtan J, Schapira AHV. The gut-brain axis and Parkinson disease: clinical and pathogenetic relevance. Ann Med 2021; 53:611-625. [PMID: 33860738 PMCID: PMC8078923 DOI: 10.1080/07853890.2021.1890330] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 02/10/2021] [Indexed: 12/16/2022] Open
Abstract
Gastrointestinal disorders are one of the most significant non-motor problems affecting people with Parkinson disease (PD). Pathogenetically, the gastrointestinal tract has been proposed to be the initial site of pathological changes in PD. Intestinal inflammation and alterations in the gut microbiota may contribute to initiation and progression of pathology in PD. However, the mechanisms underlying this "gut-brain" axis in PD remain unclear. PD patients can display a large variety of gastrointestinal symptoms, leading to reduced quality of life and psychological distress. Gastrointestinal disorders can also limit patients' response to medications, and consequently negatively impact on neurological outcomes. Despite an increasing research focus, gastrointestinal disorders in PD remain poorly understood and their clinical management often suboptimal. This review summarises our understanding of the relevance of the "gut-brain" axis to the pathogenesis of PD, discusses the impact of gastrointestinal disorders in patients with PD, and provides clinicians with practical guidance to their management.
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Affiliation(s)
- Elisa Menozzi
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK
| | - Jane Macnaughtan
- Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
| | - Anthony H. V. Schapira
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK
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30
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Cristina NM, Lucia D. Nutrition and Healthy Aging: Prevention and Treatment of Gastrointestinal Diseases. Nutrients 2021; 13:4337. [PMID: 34959889 PMCID: PMC8706789 DOI: 10.3390/nu13124337] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 11/18/2021] [Accepted: 11/23/2021] [Indexed: 12/16/2022] Open
Abstract
Nutritional well-being is a fundamental aspect for the health, autonomy and, therefore, the quality of life of all people, but especially of the elderly. It is estimated that at least half of non-institutionalized elderly people need nutritional intervention to improve their health and that 85% have one or more chronic diseases that could improve with correct nutrition. Although prevalence estimates are highly variable, depending on the population considered and the tool used for its assessment, malnutrition in the elderly has been reported up to 50%. Older patients are particularly at risk of malnutrition, due to multiple etiopathogenetic factors which can lead to a reduction or utilization in the intake of nutrients, a progressive loss of functional autonomy with dependence on food, and psychological problems related to economic or social isolation, e.g., linked to poverty or loneliness. Changes in the aging gut involve the mechanical disintegration of food, gastrointestinal motor function, food transit, intestinal wall function, and chemical digestion of food. These alterations progressively lead to the reduced ability to supply the body with adequate levels of nutrients, with the consequent development of malnutrition. Furthermore, studies have shown that the quality of life is impaired both in gastrointestinal diseases, but especially in malnutrition. A better understanding of the pathophysiology of malnutrition in elderly people is necessary to promote the knowledge of age-related changes in appetite, food intake, homeostasis, and body composition in order to better develop effective prevention and intervention strategies to achieve healthy aging.
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Affiliation(s)
- Neri Maria Cristina
- Division of Gastroenterology, Geriatric Institute Pio Albergo Trivulzio, 20146 Milan, Italy
| | - d’Alba Lucia
- Department of Gastroenterology and Endoscopy, San Camillo Forlanini Hospital, 00149 Rome, Italy;
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31
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Sigurdsson HP, Raw R, Hunter H, Baker MR, Taylor JP, Rochester L, Yarnall AJ. Noninvasive vagus nerve stimulation in Parkinson's disease: current status and future prospects. Expert Rev Med Devices 2021; 18:971-984. [PMID: 34461787 DOI: 10.1080/17434440.2021.1969913] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Parkinson's disease (PD) is a common progressive neurodegenerative disorder with multifactorial etiology. While dopaminergic medication is the standard therapy in PD, it provides limited symptomatic treatment and non-pharmacological interventions are currently being trialed. AREAS COVERED Recent pathophysiological theories of Parkinson's suggest that aggregated α-synuclein form in the gut and spread to nuclei in the brainstem via autonomic connections. In this paper, we review the novel hypothesis that noninvasive vagus nerve stimulation (nVNS), targeting efferent and afferent vagal projections, is a promising therapeutic tool to improve gait and cognitive control and ameliorate non-motor symptoms in people with Parkinson's. We conducted an unstructured search of the literature for any studies employing nVNS in PD as well as for studies examining the efficacy of nVNS on improving cognitive function and where nVNS has been applied to co-occurring conditions in PD. EXPERT OPINION Evidence of nVNS as a novel therapeutic to improve gait in PD is preliminary, but early signs indicate the possibility that nVNS may be useful to target dopa-resistant gait characteristics in early PD. The evidence for nVNS as a therapeutic tool is, however, limited and further studies are needed in both brain health and disease.
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Affiliation(s)
- Hilmar P Sigurdsson
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Rachael Raw
- Department of General Internal Medicine, South Tees Hospitals NHS Foundation Trust, Middlesbrough, UK
| | - Heather Hunter
- Department of Research, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Mark R Baker
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.,Department of Clinical Neurophysiology, Newcastle upon Tyne NHS Hospitals Foundation Trust, Newcastle upon Tyne, UK
| | - John-Paul Taylor
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Lynn Rochester
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.,Department of Neurosciences, Newcastle upon Tyne NHS Hospitals Foundation Trust, Newcastle upon Tyne, UK
| | - Alison J Yarnall
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.,Department of Older People's Medicine, Newcastle upon Tyne NHS Hospitals Foundation Trust, Newcastle upon Tyne, UK
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Ivan IF, Irincu VL, Diaconu Ș, Falup-Pecurariu O, Ciopleiaș B, Falup-Pecurariu C. Gastro-intestinal dysfunctions in Parkinson's disease (Review). Exp Ther Med 2021; 22:1083. [PMID: 34447476 DOI: 10.3892/etm.2021.10517] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 06/16/2021] [Indexed: 12/14/2022] Open
Abstract
In patients with Parkinson's disease (PD), gastrointestinal dysfunction occurs from the early stages of the disease and even in the pre-motor phase. This condition can include the entire digestive tract, with symptoms ranging from delays in gastric emptying to dysphagia, constipation and even malnutrition. Excess saliva accumulates in the mouth due to the low frequency of swallowing. Dysphagia develops in about 50% of patients and may be a reflection of both central nervous system and enteric nervous system disorder. Gastroparesis can cause a variety of symptoms, including nausea, and also may be responsible for some of the motor fluctuations observed with levodopa therapy. Intestinal dysfunction in PD may be the result of both delayed colon transit and impaired anorectal muscle coordination. In addition, recent studies have demonstrated the role of Helicobacter pylori infection in the pathogenesis of diseases but also the occurrence of motor fluctuations by affecting the absorption of anti-parkinsonian medication. In this review, the main gastrointestinal dysfunctions associated with PD are presented.
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Affiliation(s)
- Irina-Florina Ivan
- Department of Neurology, County Emergency Clinic Hospital, 500365 Brașov, Romania
| | | | - Ștefania Diaconu
- Faculty of Medicine, Transilvania University, 500036 Brașov, Romania
| | | | - Bogdan Ciopleiaș
- Department of Neurology, County Emergency Clinic Hospital, 500365 Brașov, Romania
| | - Cristian Falup-Pecurariu
- Department of Neurology, County Emergency Clinic Hospital, 500365 Brașov, Romania.,Faculty of Medicine, Transilvania University, 500036 Brașov, Romania
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Peng A, Ji S, Li W, Lai W, Qiu X, He S, Dong B, Huang C, Chen L. Gastric Electrical Dysarrhythmia in Probable Rapid Eye Movement Sleep Behavior Disorder. Front Neurol 2021; 12:687215. [PMID: 34512510 PMCID: PMC8427525 DOI: 10.3389/fneur.2021.687215] [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] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 07/13/2021] [Indexed: 02/05/2023] Open
Abstract
Background: Subjective gastrointestinal complaints have been repeatedly reported in patients with REM sleep behavior disorder (RBD), but objective evidence is scarce. We aimed to objectively investigate the gastrointestinal dysfunction in individuals with probable RBD (pRBD) using an electrogastrogram. Methods: Thirty-two participants with pRBD and 60 age- and gender-matched healthy controls were enrolled. pRBD was diagnosed based on questionnaires and further assessed by experienced neurologists. After thorough assessment of participants' subjective gastrointestinal symptoms, preprandial and postprandial gastric activities were measured using an electrogastrogram. Dominant frequency, dominant power ratio, and the ratio of preprandial to postprandial power were analyzed. Results: Among the gastric symptoms, hiccup (34.8 vs. 9.6%, p = 0.017) and postprandial gastric discomfort (43.5 vs. 15.4%, p = 0.017) were more frequent in participants with pRBD than in controls. The dominant frequency on the electrode overlying the gastric pyloric antrum was lower in pRBD than in healthy controls (2.9 [2.6-2.9] vs. 2.9 [2.9-3.2] cpm, p = 0.006). A reduced dominant power ratio from the same electrode was also found in individuals with pRBD (60.7 [58.0-64.5] vs. 64.2 [58.7-69.6] %, p = 0.046). Conclusion: Patients with pRBD have a higher rate of gastric dysfunction, which presented as irregular slow wave rhythmicity on an electrogastrogram.
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Affiliation(s)
- Anjiao Peng
- Department of Neurology and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Shuming Ji
- Department of Project Design and Statistics, West China Hospital, Sichuan University, Chengdu, China
| | - Wanling Li
- Department of Neurology and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Wanlin Lai
- Department of Neurology and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Xiangmiao Qiu
- Department of Neurology and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Shixu He
- Department of Neurology and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Bosi Dong
- Department of Neurology and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Cheng Huang
- Department of Rehabilitation Medicine Center, West China Hospital of Sichuan University, Chengdu, China
| | - Lei Chen
- Department of Neurology and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
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Chetty D, Abrahams S, van Coller R, Carr J, Kenyon C, Bardien S. Movement of prion-like α-synuclein along the gut-brain axis in Parkinson's disease: A potential target of curcumin treatment. Eur J Neurosci 2021; 54:4695-4711. [PMID: 34043864 DOI: 10.1111/ejn.15324] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 05/06/2021] [Accepted: 05/23/2021] [Indexed: 12/11/2022]
Abstract
A pathological hallmark of the neurodegenerative disorder, Parkinson's disease (PD), is aggregation of toxic forms of the presynaptic protein, α-synuclein in structures known as Lewy bodies. α-Synuclein pathology is found in both the brain and gastrointestinal tracts of affected individuals, possibly due to the movement of this protein along the vagus nerve that connects the brain to the gut. In this review, we discuss current insights into the spread of α-synuclein pathology along the gut-brain axis, which could be targeted for therapeutic interventions. The prion-like propagation of α-synuclein, and the clinical manifestations of gastrointestinal dysfunction in individuals living with PD, are discussed. There is currently insufficient evidence that surgical alteration of the vagus nerve, or removal of gut-associated lymphoid tissues, such as the appendix and tonsils, are protective against PD. Furthermore, we propose curcumin as a potential candidate to prevent the spread of α-synuclein pathology in the body by curcumin binding to α-synuclein's non-amyloid β-component (NAC) domain. Curcumin is an active component of the food spice turmeric and is known for its antioxidant, anti-inflammatory, and potentially neuroprotective properties. We hypothesize that once α-synuclein is bound to curcumin, both molecules are subsequently excreted from the body. Therefore, dietary supplementation with curcumin over one's lifetime has potential as a novel approach to complement existing PD treatment and/or prevention strategies. Future studies are required to validate this hypothesis, but if successful, this could represent a significant step towards improved nutrient-based therapeutic interventions and preventative strategies for this debilitating and currently incurable disorder.
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Affiliation(s)
- Devina Chetty
- Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Shameemah Abrahams
- Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Riaan van Coller
- Faculty of Health Sciences, School of Medicine, Department of Neurology, University of Pretoria, Pretoria, South Africa
| | - Jonathan Carr
- Division of Neurology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Colin Kenyon
- Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.,DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, South African Medical Research Council Centre for Tuberculosis Research, Stellenbosch University, Cape Town, South Africa.,South African Medical Research Council Centre for Tuberculosis Research, Stellenbosch University, Cape Town, South Africa
| | - Soraya Bardien
- Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
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Li X, Feng X, Jiang Z, Jiang Z. Association of small intestinal bacterial overgrowth with Parkinson's disease: a systematic review and meta-analysis. Gut Pathog 2021; 13:25. [PMID: 33863370 PMCID: PMC8051095 DOI: 10.1186/s13099-021-00420-w] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 04/01/2021] [Indexed: 12/18/2022] Open
Abstract
Objective Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease after Alzheimer's disease (AD) worldwide. The prevalence of small intestinal bacterial overgrowth (SIBO) in PD patients is high. We conducted this comprehensive systematic review and meta-analysis to determine the association between SIBO and PD. Methods A comprehensive literature search of the PubMed, Cochrane Library and EMBASE databases was performed to identify studies correlating SIBO with PD. Studies were screened, and relevant data were extracted and analysed. We calculated the pooled prevalence of SIBO in all individuals with PD and compared the prevalence of SIBO between the two groups to calculate an odds ratio (OR) and 95% confidence interval (CI). Egger’s test was performed to assess publication bias. Results Eleven studies with 973 participants met the inclusion criteria. The pooled prevalence of SIBO in patients with PD was 46% (95% CI 36–56). A random-effects model was applied given the heterogeneity (I2 = 83%) detected among the studies. Egger’s test indicated no publication bias (p = 0.0657). Subgroup analyses showed that the prevalence of SIBO was greater in studies including patients diagnosed using the lactulose hydrogen breath test (LBT) (51%, 95% CI 37–65) than in those including patients diagnosed using the glucose hydrogen breath test (GBT) (35%, 95% CI 20–50), and the prevalence of SIBO in PD was highest (55%, 95% CI 38–72) in patients diagnosed by the LBT and GBT. The prevalence of SIBO was 52% (95% CI 40–64) among patients from Western countries and 33% (95% CI 22–43) among patients from Eastern countries. The pooled OR of SIBO in PD patients compared with healthy controls was 5.22 (95% CI 3.33–8.19, p < 0.00001). We did not identify an obvious predictor of SIBO in PD patients. Conclusion In conclusion, our meta-analysis found a strong association between SIBO and PD with approximately half of PD patients testing positive for SIBO. These relationships significantly differed based on diagnostic test and geographic area.
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Affiliation(s)
- Xiaoqing Li
- Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Xin Feng
- Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Zhongxiang Jiang
- Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Zheng Jiang
- Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
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Huang KS, Pan BL, Lai WA, Bin PJ, Yang YH, Chou CP. Could prokinetic agents protect long-term nasogastric tube-dependent patients from being hospitalized for pneumonia? A nationwide population-based case-crossover study. PLoS One 2021; 16:e0249645. [PMID: 33819293 PMCID: PMC8021154 DOI: 10.1371/journal.pone.0249645] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 03/23/2021] [Indexed: 11/18/2022] Open
Abstract
Background Some studies have indicated that the use of prokinetic agents may reduce pneumonia risk in some populations. Nasogastric tube insertion is known to increase the risk of pneumonia because it disrupts lower esophageal sphincter function. The aim of this study was to evaluate whether prokinetic agents could protect long-term nasogastric tube-dependent patients in Taiwan from being hospitalized for pneumonia. Methods A case-crossover study design was applied in this study. Long-term nasogastric tube-dependent patients who had a first-time admission to a hospital due to pneumonia from 1996 to 2013 that was recorded in the Taiwan National Health Insurance Research Database were included. The case period was set to be 30 days before admission, and two control periods were selected for analysis. Prokinetic agent use during those three periods was then assessed for the included patients. Conditional logistic regression was used to calculate the odds ratio (OR) for pneumonia admission with the use of prokinetic agents. Results A total of 639 first-time hospitalizations for pneumonia among patients with long-term nasogastric tube dependence were included. After adjusting the confounding factors for pneumonia, no negative association between prokinetic agent use and pneumonia hospitalization was found, and the adjusted OR was 1.342 (95% CI 0.967–1.86). In subgroup analysis, the adjusted ORs were 1.401 (0.982–1.997), 1.256 (0.87–1.814), 0.937 (0.607–1.447) and 2.222 (1.196–4.129) for elderly, stroke, diabetic and parkinsonism patients, respectively. Conclusion Prokinetic agent use had no negative association with pneumonia admission among long-term nasogastric tube-dependent patients in Taiwan.
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Affiliation(s)
- Kun-Siang Huang
- Department of Family Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Bo-Lin Pan
- Department of Family Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Wei-An Lai
- Department of Family Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Pin-Jie Bin
- Department of Family Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Yao-Hsu Yang
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan
- Health Information and Epidemiology Laboratory of Chang Gung Memorial Hospital, Chiayi, Taiwan
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chia-Pei Chou
- Department of Family Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
- * E-mail:
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37
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Schaffernicht G, Shang Q, Stievenard A, Bötzel K, Dening Y, Kempe R, Toussaint M, Gündel D, Kranz M, Reichmann H, Vanbesien-Mailliot C, Brust P, Dieterich M, Funk RHW, Ravens U, Pan-Montojo F. Pathophysiological Changes in the Enteric Nervous System of Rotenone-Exposed Mice as Early Radiological Markers for Parkinson's Disease. Front Neurol 2021; 12:642604. [PMID: 33841309 PMCID: PMC8030242 DOI: 10.3389/fneur.2021.642604] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 02/25/2021] [Indexed: 12/02/2022] Open
Abstract
Parkinson's disease (PD) is known to involve the peripheral nervous system (PNS) and the enteric nervous system (ENS). Functional changes in PNS and ENS appear early in the course of the disease and are responsible for some of the non-motor symptoms observed in PD patients like constipation, that can precede the appearance of motor symptoms by years. Here we analyzed the effect of the pesticide rotenone, a mitochondrial Complex I inhibitor, on the function and neuronal composition of the ENS by measuring intestinal contractility in a tissue bath and by analyzing related protein expression. Our results show that rotenone changes the normal physiological response of the intestine to carbachol, dopamine and electric field stimulation (EFS). Changes in the reaction to EFS seem to be related to the reduction in the cholinergic input but also related to the noradrenergic input, as suggested by the non-adrenergic non-cholinergic (NANC) reaction to the EFS in rotenone-exposed mice. The magnitude and direction of these alterations varies between intestinal regions and exposure times and is associated with an early up-regulation of dopaminergic, cholinergic and adrenergic receptors and an irregular reduction in the amount of enteric neurons in rotenone-exposed mice. The early appearance of these alterations, that start occurring before the substantia nigra is affected in this mouse model, suggests that these alterations could be also observed in patients before the onset of motor symptoms and makes them ideal potential candidates to be used as radiological markers for the detection of Parkinson's disease in its early stages.
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Affiliation(s)
- Gabriela Schaffernicht
- Department of Neurology, University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.,Munich Cluster for Systems Neurology, SyNergy, Munich, Germany
| | - Qi Shang
- Department of Neurology, University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.,Munich Cluster for Systems Neurology, SyNergy, Munich, Germany
| | - Alicia Stievenard
- Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, Lille, France
| | - Kai Bötzel
- Department of Neurology, University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany
| | - Yanina Dening
- Department of Neurology, University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.,Munich Cluster for Systems Neurology, SyNergy, Munich, Germany
| | - Romy Kempe
- Department of Pharmacology and Toxicology, TU-Dresden, Dresden, Germany
| | - Magali Toussaint
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Leipzig, Germany
| | - Daniel Gündel
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Leipzig, Germany
| | - Mathias Kranz
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Leipzig, Germany
| | - Heinz Reichmann
- Department of Neurology, Technische Universität Dresden, Dresden, Germany.,Center for Regenerative Therapies Dresden, Dresden, Germany
| | - Christel Vanbesien-Mailliot
- Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, Lille, France
| | - Peter Brust
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Leipzig, Germany
| | - Marianne Dieterich
- Department of Neurology, University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.,Munich Cluster for Systems Neurology, SyNergy, Munich, Germany.,German Center for Vertigo and Balance Disorders, University Hospital, LMU Munich, Munich, Germany
| | - Richard H W Funk
- Center for Regenerative Therapies Dresden, Dresden, Germany.,Institute for Anatomy, Technical University (TU)-Dresden, Dresden, Germany
| | - Ursula Ravens
- Department of Pharmacology and Toxicology, TU-Dresden, Dresden, Germany.,Institute for Experimental Cardiovascular Medicine, University Heart Center, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Francisco Pan-Montojo
- Department of Neurology, University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.,Munich Cluster for Systems Neurology, SyNergy, Munich, Germany
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Impact of gastrointestinal tract variability on oral drug absorption and pharmacokinetics: An UNGAP review. Eur J Pharm Sci 2021; 162:105812. [PMID: 33753215 DOI: 10.1016/j.ejps.2021.105812] [Citation(s) in RCA: 164] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 02/19/2021] [Accepted: 03/16/2021] [Indexed: 12/17/2022]
Abstract
The absorption of oral drugs is frequently plagued by significant variability with potentially serious therapeutic consequences. The source of variability can be traced back to interindividual variability in physiology, differences in special populations (age- and disease-dependent), drug and formulation properties, or food-drug interactions. Clinical evidence for the impact of some of these factors on drug pharmacokinetic variability is mounting: e.g. gastric pH and emptying time, small intestinal fluid properties, differences in pediatrics and the elderly, and surgical changes in gastrointestinal anatomy. However, the link of colonic factors variability (transit time, fluid composition, microbiome), sex differences (male vs. female) and gut-related diseases (chronic constipation, anorexia and cachexia) to drug absorption variability has not been firmly established yet. At the same time, a way to decrease oral drug pharmacokinetic variability is provided by the pharmaceutical industry: clinical evidence suggests that formulation approaches employed during drug development can decrease the variability in oral exposure. This review outlines the main drivers of oral drug exposure variability and potential approaches to overcome them, while highlighting existing knowledge gaps and guiding future studies in this area.
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Baert F, Vlaemynck G, Beeckman AS, Van Weyenberg S, Matthys C. Dysphagia management in Parkinson's disease: Comparison of the effect of thickening agents on taste, aroma, and texture. J Food Sci 2021; 86:1039-1047. [PMID: 33521981 DOI: 10.1111/1750-3841.15595] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 12/01/2020] [Accepted: 12/15/2020] [Indexed: 11/27/2022]
Abstract
Dysphagia is a frequent symptom in Parkinson's disease (PD). Thickening liquids facilitates safe swallowing, however, low treatment compliance is a major issue, due to patients' dislike of thickened liquids. Some studies suggest a negative impact of gum-based thickeners, currently most used in clinical practice, on sensory properties compared to starch-based thickeners. This has not yet been investigated in PD. This study's aim was to compare taste, texture, and aroma of gum-based and starch-based thickened soups in participants with PD. Gum-based resource thicken up clear (RTUC) and starch-based kitchen products potato starch (PS) and quinoa flour (QF) were evaluated in broccoli soup. Texture, aroma, and taste were characterized by rheology, volatile, and sensory profiling. Thickened soups were evaluated in participants with PD and controls through a paired comparison test. Reduced release of 61.4%, 46.2%, and 38.5% of volatiles was observed after thickening with RTUC, PS, and QF, respectively. Overall taste intensity was reduced in RTUC- and PS-thickened soup, respectively. Taste and aroma of PS-thickened soup were considered more intense by 70.3% and 63.8% of all participants, respectively (n = 36 PD, n = 41 controls), 56.3% preferred the PS-thickened soup's texture . Taste and aroma of QF-thickened soup were considered more intense by 68.1% and 65.6% of all participants, respectively (n = 47 PD, n = 31 controls), 58.0% preferred the QF-thickened soup's texture. Starch-based thickeners demonstrated higher taste and aroma intensity. However, volatile and sensory profiling demonstrated reduced taste and aroma in all thickeners. Combining kitchen products with flavor enhancers may increase palatability of thickened beverages.
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Affiliation(s)
- Florence Baert
- Department Technology and Food, Flanders Research Institute for Agriculture, Fisheries and Food, Brusselsesteenweg 370, Melle, 9090, Belgium.,Clinical and Experimental Endocrinology, Department of Chronic Diseases, Metabolism, KU Leuven, O&N I Herestraat 49 - box 902, Leuven, 3000, Belgium
| | - Geertrui Vlaemynck
- Department Technology and Food, Flanders Research Institute for Agriculture, Fisheries and Food, Brusselsesteenweg 370, Melle, 9090, Belgium
| | - Anne-Sophie Beeckman
- Speech Language Therapy, Postgraduate Course Dysphagia, Artevelde University of Applied Sciences, Campus Kantienberg, Voetweg 66, Gent, 9000, Belgium.,Speech Language Therapy, AZ Maria Middelares, Buitenring Sint-Denijs 30, Gent, 9000, Belgium
| | - Stephanie Van Weyenberg
- Department Technology and Food, Flanders Research Institute for Agriculture, Fisheries and Food, Brusselsesteenweg 370, Melle, 9090, Belgium
| | - Christophe Matthys
- Clinical and Experimental Endocrinology, Department of Chronic Diseases, Metabolism, KU Leuven, O&N I Herestraat 49 - box 902, Leuven, 3000, Belgium.,Department of Endocrinology, University Hospitals Leuven, Campus Gasthuisberg, Herestraat 49, Leuven, 3000, Belgium
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40
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Albuquerque JCS, Mendes TS, BrandÃo MGSA, Frota AF, Reis TDDSD, Aguiar LMV, GraÇa JRVD. STRUCTURAL BASES OF GASTROINTESTINAL MOTILITY CHANGES IN PARKINSON'S DISEASE: STUDY IN RATS. ACTA ACUST UNITED AC 2021; 33:e1548. [PMID: 33470378 PMCID: PMC7812683 DOI: 10.1590/0102-672020200003e1548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Accepted: 07/12/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Gastrointestinal disorders are frequently reported in patients with Parkinson's disease whose disorders reduce the absorption of nutrients and drugs, worsening the clinical condition of patients. However, the mechanisms involved in modifying gastrointestinal pathophysiology have not yet been fully explained. AIM To evaluate its effects on gastrointestinal motility and the involvement of the vagal and splanchnic pathways. METHODS Male Wistar rats (250-300 g, n = 84) were used and divided into two groups. Group I (6-OHDA) received an intrastriatal injection of 6-hydroxydopamine (21 µg/animal). Group II (control) received a saline solution (NaCl, 0.9%) under the same conditions. The study of gastric emptying, intestinal transit, gastric compliance and operations (vagotomy and splanchnotomy) were performed 14 days after inducing neurodegeneration. Test meal (phenol red 5% glucose) was used to assess the rate of gastric emptying and intestinal transit. RESULTS Parkinson's disease delayed gastric emptying and intestinal transit at all time periods studied; however, changes in gastric compliance were not observed. The delay in gastric emptying was reversed by pretreatment with vagotomy and splanchnotomy+celiac gangliectomy, thus suggesting the involvement of such pathways in the observed motor disorders. CONCLUSION Parkinson's disease compromises gastric emptying, as well as intestinal transit, but does not alter gastric compliance. The delay in gastric emptying was reversed by truncal vagotomy, splanchnotomy and celiac ganglionectomy, suggesting the involvement of such pathways in delaying gastric emptying.
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Affiliation(s)
| | | | | | - Annyta Fernandes Frota
- Department of Biochemistry and Molecular Biology, Federal University of Ceará, Pici Campus, Fortaleza, CE, Brazil
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41
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Kenna JE, Bakeberg MC, Gorecki AM, Chin Yen Tay A, Winter S, Mastaglia FL, Anderton RS. Characterization of Gastrointestinal Symptom Type and Severity in Parkinson's Disease: A Case-Control Study in an Australian Cohort. Mov Disord Clin Pract 2021; 8:245-253. [PMID: 33553495 DOI: 10.1002/mdc3.13134] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Revised: 11/19/2020] [Accepted: 12/02/2020] [Indexed: 12/15/2022] Open
Abstract
Background While constipation is a well-known non-motor symptom which may precede the onset of the classical motor symptoms of PD, there have been few comprehensive studies of gastrointestinal (GI) symptoms in people with PD (PwP). Objectives To investigate the spectrum of GI symptoms in an Australian PwP cohort and their relationship to use of anti-parkinsonian medications dietary habits and smoking. Methods The prevalence and severity of GI symptoms were compared in a group of 163 PwP and 113 healthy control subjects using the Gastrointestinal Symptom Rating Scale (GSRS). Corrected linear regression models were used to determine differences between PwP and controls, and to investigate the influence of different classes of anti-Parkinsonian medications. Results PwP reported a greater frequency of constipation and GI-associated illnesses when compared to healthy controls. Total GSRS scores (P < 0.0001), upper GI symptoms (P < 0.0001), and hypoactive GI Symptoms (P < 0.0001) were all significantly greater in the PD cohort than controls. Further analyses revealed a positive association between the use of anti-Parkinsonian medications and total GSRS scores (P < 0.001), as well as upper GI symptoms (P < 0.001) and hypoactive GI function (P < 0.001). Conclusions This study illustrates the frequency and array of GI symptoms in a large PD cohort. The findings indicate that anti-parkinsonian medications play an important role in the presentation and development of GI symptoms.
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Affiliation(s)
- Jade E Kenna
- Perron Institute for Neurological and Translational Science Nedlands Western Australia Australia.,Centre for Neuromuscular and Neurological Disorders University of Western Australia Perth Western Australia Australia.,Centre for Clinical Neurosciences and Neurological Research St. Vincent's Hospital Melbourne Melbourne Australia
| | - Megan C Bakeberg
- Perron Institute for Neurological and Translational Science Nedlands Western Australia Australia.,Centre for Neuromuscular and Neurological Disorders University of Western Australia Perth Western Australia Australia
| | - Anastazja M Gorecki
- Perron Institute for Neurological and Translational Science Nedlands Western Australia Australia.,School of Biological Sciences University of Western Australia Perth Australia
| | - Alfred Chin Yen Tay
- School of Biological Sciences University of Western Australia Perth Australia.,Marshall Centre for Infectious Diseases Research and Training Nedlands Western Australia Australia
| | - Samantha Winter
- Perron Institute for Neurological and Translational Science Nedlands Western Australia Australia.,Institute for Health Research and School of Health Sciences University of Notre Dame Australia Fremantle Western Australia Australia
| | - Frank L Mastaglia
- Perron Institute for Neurological and Translational Science Nedlands Western Australia Australia.,Centre for Neuromuscular and Neurological Disorders University of Western Australia Perth Western Australia Australia
| | - Ryan S Anderton
- Perron Institute for Neurological and Translational Science Nedlands Western Australia Australia.,Centre for Neuromuscular and Neurological Disorders University of Western Australia Perth Western Australia Australia.,Institute for Health Research and School of Health Sciences University of Notre Dame Australia Fremantle Western Australia Australia
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Hajji N, Wannes D, Jabri MA, Rtibi K, Tounsi H, Abdellaoui A, Sebai H. Purgative/laxative actions of Globularia alypum aqueous extract on gastrointestinal-physiological function and against loperamide-induced constipation coupled to oxidative stress and inflammation in rats. Neurogastroenterol Motil 2020; 32:e13858. [PMID: 32337785 DOI: 10.1111/nmo.13858] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 03/24/2020] [Accepted: 03/28/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Chronic constipation is a gastrointestinal functional disorder which affects patient quality of life. Therefore, many studies were oriented to search herbal laxative agents. In this study, we investigated the effect of Globularia alypum L. leaves aqueous extract (GAAE) against loperamide (LOP)-produced constipation. METHODS Animals were given LOP (3 mg/kg, b.w., i.p.) and GAAE (100, 200, and 400 mg/kg, b.w., p.o.) or yohimbine (2 mg/kg, b.w., i.p.), simultaneously, for 1 week. Gastric-emptying test and intestinal transit were determined. Colon histology was examined, and oxidative status was evaluated using biochemical-colorimetric methods. KEY RESULTS GAAE ameliorates significantly gastric emptying (64% to 76.5%) and intestinal transit (66.65% to 84.73%). LOP negatively influenced defecation parameters and generated a stress situation. GAAE administration in contrast ameliorated those parameters and re-established oxidative balance. CONCLUSION GAAE showed a modest action against oxidative stress and decreased LOP effect and thereby can be considered a pharmacological agent in constipation.
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Affiliation(s)
- Najla Hajji
- Laboratoire de Physiologie Fonctionnelle et Valorisation des Bio-Ressources, Institut Supérieur de Biotechnologie de Béja, Université de Jendouba, Béja, Tunisia
| | - Dalanda Wannes
- Laboratoire de Physiologie Fonctionnelle et Valorisation des Bio-Ressources, Institut Supérieur de Biotechnologie de Béja, Université de Jendouba, Béja, Tunisia
| | - Mohamed-Amine Jabri
- Laboratoire de Physiologie Fonctionnelle et Valorisation des Bio-Ressources, Institut Supérieur de Biotechnologie de Béja, Université de Jendouba, Béja, Tunisia
| | - Kais Rtibi
- Laboratoire de Physiologie Fonctionnelle et Valorisation des Bio-Ressources, Institut Supérieur de Biotechnologie de Béja, Université de Jendouba, Béja, Tunisia
| | - Haifa Tounsi
- Laboratoire d'anatomie Pathologique Humaine et Expérimentalse, Institut Pasteur de Tunis, Tunis, Tunisia
| | - Afifa Abdellaoui
- Laboratoire d'anatomie Pathologique Humaine et Expérimentalse, Institut Pasteur de Tunis, Tunis, Tunisia
| | - Hichem Sebai
- Laboratoire de Physiologie Fonctionnelle et Valorisation des Bio-Ressources, Institut Supérieur de Biotechnologie de Béja, Université de Jendouba, Béja, Tunisia
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43
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Safirstein BE, Ellenbogen A, Zhao P, Henney HR, Kegler-Ebo DM, Oh C. Pharmacokinetics of Inhaled Levodopa Administered With Oral Carbidopa in the Fed State in Patients With Parkinson's Disease. Clin Ther 2020; 42:1034-1046. [DOI: 10.1016/j.clinthera.2020.04.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 03/26/2020] [Accepted: 04/07/2020] [Indexed: 12/13/2022]
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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: 37] [Impact Index Per Article: 7.4] [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.
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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
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45
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Suganuma Y, Shimizu T, Sato T, Morii T, Fujita H, Harada Sassa M, Yamada Y. Magnitude of slowing gastric emptying by glucagon-like peptide-1 receptor agonists determines the amelioration of postprandial glucose excursion in Japanese patients with type 2 diabetes. J Diabetes Investig 2020; 11:389-399. [PMID: 31301103 PMCID: PMC7078094 DOI: 10.1111/jdi.13115] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 05/08/2019] [Accepted: 07/07/2019] [Indexed: 12/25/2022] Open
Abstract
AIMS/INTRODUCTION Pharmacological levels of glucagon-like peptide-1 (GLP-1) can decelerate gastric emptying (GE) and reduce postprandial glucose levels. Most previous studies have used liquid meals to evaluate GE. We evaluated the effects of GLP-1 receptor agonists (GLP-1 RAs) on GE and postprandial glucose excursion in Japanese type 2 diabetes mellitus patients using a combination of solid and liquid meals. MATERIALS AND METHODS In this single-center, prospective, open-label study, nine healthy individuals and 17 patients with type 2 diabetes mellitus consumed a 460-kcal combination of a solid and liquid meal labeled with 13 C-acetic acid. GE was measured from t = 0 to 150 min in a continuous 13 C breath test. Eight participants with type 2 diabetes mellitus were administered GLP-1 RAs, and we examined the relationship between GE and blood glucose excursion. RESULTS There were no differences in the average GE coefficient (GEC) and lag time between the healthy and type 2 diabetes mellitus groups. However, the type 2 diabetes mellitus group showed larger GEC variations (P < 0.05). The coefficient of variation of R-R intervals was a significant predictor of GEC in type 2 diabetes mellitus patients (P < 0.01). The short-acting GLP-1 RA reduced the GEC at 1 month (P = 0.012), whereas the long-acting GLP-1 RA did not significantly change the GEC after treatment. A positive relationship was observed between postprandial glucose excursion from T0 min to T60 min and the GEC (r2 = 0.75; P < 0.01). CONCLUSIONS The reduction in GE rate by the administration of GLP-1 RAs can predict the improvement in postprandial glucose excursion in type 2 diabetes mellitus patients.
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Affiliation(s)
- Yumi Suganuma
- Department of Endocrinology, Diabetes and Geriatric MedicineAkita University Graduate School of MedicineAkitaJapan
| | - Tatsunori Shimizu
- Department of Endocrinology, Diabetes and Geriatric MedicineAkita University Graduate School of MedicineAkitaJapan
| | - Takehiro Sato
- Department of Endocrinology, Diabetes and Geriatric MedicineAkita University Graduate School of MedicineAkitaJapan
| | - Tsukasa Morii
- Department of Endocrinology, Diabetes and Geriatric MedicineAkita University Graduate School of MedicineAkitaJapan
| | - Hiroki Fujita
- Department of Endocrinology, Diabetes and Geriatric MedicineAkita University Graduate School of MedicineAkitaJapan
| | - Mariko Harada Sassa
- Institute for Advancement of Clinical and Translational ScienceKyoto University HospitalKyotoJapan
| | - Yuichiro Yamada
- Department of Endocrinology, Diabetes and Geriatric MedicineAkita University Graduate School of MedicineAkitaJapan
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46
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Simões RM, Castro Caldas A, Ferreira JJ. Inhaled levodopa for intermittent treatment of OFF episodes in patients with Parkinson's disease. Expert Rev Clin Pharmacol 2020; 13:85-101. [PMID: 32011195 DOI: 10.1080/17512433.2020.1724535] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Introduction: Many patients with advanced Parkinson's disease (PD) have inadequate control of motor symptoms despite optimized treatment. Predictable and unpredictable OFF periods severely interfere with the quality of life. A drug that easily and rapidly reverts the OFF state is still needed. Subcutaneous apomorphine, the only approved drug for this indication, although efficacious, is not widely used probably due to its potential side effects and complicated administration.Levodopa is the most efficacious drug for the treatment of PD motor symptoms. However, issues related to the oral route and intestinal absorption in later disease stages render this route lengthy and inefficacious.Areas covered: Literature on the development of an inhaled formulation of levodopa has been reviewed. Significant advances in the field of pulmonary delivery systems and in dry powders have enabled the development of a new formulation of levodopa that can be inhaled and adequate blood levels rapidly achieved, bypassing intestinal absorption. Several clinical trials have reported efficacy, safety, and tolerability data. Some pulmonary-related adverse events have been reported but are mostly mild.Expert opinion: This new way of administering levodopa is likely to be very welcome and may fill a gap for OFF rescue treatments, at least for some patients.
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Affiliation(s)
- Rita Moiron Simões
- Neurology Department, Hospital Beatriz Ângelo, Loures, Portugal.,CNS-Campus Neurológico Sénior, Torres Vedras, Portugal
| | - Ana Castro Caldas
- CNS-Campus Neurológico Sénior, Torres Vedras, Portugal.,Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Joaquim J Ferreira
- CNS-Campus Neurológico Sénior, Torres Vedras, Portugal.,Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.,Laboratory of Clinical Pharmacology and Therapeutics, Universidade de Lisboa, Lisbon, Portugal
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47
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Kaut O, Janocha L, Weismüller TJ, Wüllner U. Transcutaneous vagal nerve stimulation improves gastroenteric complaints in Parkinson’s disease patients. NeuroRehabilitation 2019; 45:449-451. [DOI: 10.3233/nre-192909] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Oliver Kaut
- Department of Neurology, University Clinic Bonn, Bonn, Germany
| | - Laura Janocha
- Department of Neurology, University Clinic Bonn, Bonn, Germany
| | | | - Ullrich Wüllner
- Department of Neurology, University Clinic Bonn, Bonn, Germany
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
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48
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Chen Z, Li G, Liu J. Autonomic dysfunction in Parkinson's disease: Implications for pathophysiology, diagnosis, and treatment. Neurobiol Dis 2019; 134:104700. [PMID: 31809788 DOI: 10.1016/j.nbd.2019.104700] [Citation(s) in RCA: 152] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Revised: 11/13/2019] [Accepted: 12/02/2019] [Indexed: 12/17/2022] Open
Abstract
Parkinson's disease (PD) is a neurodegenerative disease with a 200 year-long research history. Our understanding about its clinical phenotype and pathogenesis remains limited, although dopaminergic replacement therapy has significantly improved patient outcomes. Autonomic dysfunction is an essential category of non-motor phenotypes that has recently become a cutting edge field that directs frontier research in PD. In this review, we initially describe the epidemiology of dysautonomic symptoms in PD. Then, we perform a meticulous analysis of the pathophysiology of autonomic dysfunction in PD and propose that the peripheral autonomic nervous system may be a key route for α-synuclein pathology propagation from the periphery to the central nervous system. In addition, we recommend that constipation, orthostatic hypotension, urinary dysfunction, erectile dysfunction, and pure autonomic failure should be viewed as prodromal dysautonomic markers in PD prediction and diagnosis. Finally, we summarize the strategies currently available for the treatment of autonomic dysfunction in PD and suggest that high-quality, better-designed, randomized clinical trials should be conducted in the future.
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Affiliation(s)
- Zhichun Chen
- Department of Neurology, Institute of Neurology, Ruijin Hospital affiliated with the Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guanglu Li
- Department of Neurology, Institute of Neurology, Ruijin Hospital affiliated with the Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Liu
- Department of Neurology, Institute of Neurology, Ruijin Hospital affiliated with the Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Sampath C, Kalpana R, Ansah T, Charlton C, Hale A, Channon KM, Srinivasan S, Gangula PR. Impairment of Nrf2- and Nitrergic-Mediated Gastrointestinal Motility in an MPTP Mouse Model of Parkinson's Disease. Dig Dis Sci 2019; 64:3502-3517. [PMID: 31187328 PMCID: PMC6858486 DOI: 10.1007/s10620-019-05693-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Accepted: 05/31/2019] [Indexed: 12/31/2022]
Abstract
BACKGROUND Gastrointestinal (GI) motility dysfunction is the most common non-motor symptom of Parkinson's disease (PD). Studies have indicated that GI motility functions are impaired before the onset of PD. AIMS To investigate the underlying mechanism of PD-induced GI dysmotility in MPTP (1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine)-induced animal model. METHODS C57BL/6 mice were administered with or without a selective dopamine neurotoxin, MPTP, to induce parkinsonian symptoms. In addition to in vivo studies, in vitro experiments were also conducted in colon specimens using l-methyl-4-phenylpyridinium (MPP+), a metabolic product of MPTP. Gastric emptying, colon motility, nitrergic relaxation, and western blot experiments were performed as reported. RESULTS MPTP-induced PD mice showed decreased expression of nuclear factor erythroid 2-related factor (Nrf2) and its target phase II genes in gastric and colon neuromuscular tissues. Decreased levels of tetrahydrobiopterin (BH4, a critical cofactor for nNOS dimerization) associated with uncoupling of nNOS in gastric and colon tissues exposed to MPTP. Impaired enteric nitrergic system led to delayed gastric emptying and slower colonic motility compared to the control mice. In vitro results in colon specimens confirm that activation of Nrf2 restored MPP+-induced suppression of alpha-synuclein, tyrosine hydroxylase (TH), Nrf2, and heme oxygenase-1. In vitro exposure to L-NAME [N(w)-nitro-L-arginine methyl ester], a NOS synthase inhibitor, reduced protein expression of TH in colon tissue homogenates. CONCLUSIONS Loss of Nrf2/BH4/nNOS expression in PD impairs antioxidant gene expression, which deregulates NO synthesis, thereby contributing to the development of GI dysmotility and constipation. Nitric oxide appears to be important to maintain dopamine synthesis in the colon.
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Affiliation(s)
- C Sampath
- Department of ODS and Research, School of Dentistry, Meharry Medical College, 1005 Dr. D.B. Todd Jr. Blvd, Nashville, TN, 37208, USA
| | - R Kalpana
- Department of ODS and Research, School of Dentistry, Meharry Medical College, 1005 Dr. D.B. Todd Jr. Blvd, Nashville, TN, 37208, USA
| | - T Ansah
- Department of Cancer Biology Physiology Pharmacology and Neuroscience, School of Medicine, Meharry Medical College, Nashville, TN, USA
| | - C Charlton
- Department of Cancer Biology Physiology Pharmacology and Neuroscience, School of Medicine, Meharry Medical College, Nashville, TN, USA
| | - A Hale
- Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - K M Channon
- Oxford Heart Centre, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - S Srinivasan
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, GA, USA
- Atlanta VA Health Care System, Decatur, Atlanta, GA, USA
| | - P R Gangula
- Department of ODS and Research, School of Dentistry, Meharry Medical College, 1005 Dr. D.B. Todd Jr. Blvd, Nashville, TN, 37208, USA.
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50
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Durcan R, Donaghy PC, Barnett NA, Olsen K, Yarnall AJ, Taylor JP, McKeith I, O'Brien JT, Thomas AJ. Prevalence and severity of symptoms suggestive of gastroparesis in prodromal dementia with Lewy bodies. Int J Geriatr Psychiatry 2019; 34:990-998. [PMID: 30901488 DOI: 10.1002/gps.5100] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Accepted: 03/17/2019] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Lewy body disease is postulated, by the Braak model, to originate in the enteric nervous system, before spreading to the central nervous system. Therefore, a high prevalence of gastroparesis symptoms would be expected in prodromal dementia with Lewy bodies (DLB) and be highest in those with a dopaminergic deficit on imaging. The aim of this study was to explore whether gastroparesis symptoms are an early diagnostic marker of prodromal DLB and explore the relationship between symptoms and dopaminergic imaging findings on FP-CIT SPECT. METHODS We recruited 75 patients over 60 with mild cognitive impairment (MCI), 48 with MCI with suspected Lewy body disease (MCI-LB) and 27 with MCI with suspected Alzheimer's disease (MCI-AD). All patients completed the Gastroparesis Cardinal Symptom Index (GSCI) questionnaire and also underwent FP-CIT [123 I-N-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)] dopaminergic imaging. RESULTS At least one symptom suggestive of gastroparesis was reported in 48% (n = 23) MCI-LB vs 37% MCI-AD (n = 10) (P = 0.36). Rates of definite symptoms of gastroparesis, as defined by a GCSI total score ≥ 1.90, were rare and rates in MCI-LB were not different from MCI-AD (6% vs 0%, p = 0.55). After adjusting for gender differences between groups, no difference in gastroparesis symptom prevalence (2.27 vs 0.81 P = 0.05) or severity score (0.62 vs 0.28, p = 0.28) was noted between normally and abnormally visually rated FP-CIT SPECT scans. CONCLUSION The GCSI is not a useful tool for differentiating MCI-LB from MCI-AD. A low rate of definite gastroparesis was detected in prodromal DLB. No association was found between gastroparesis symptoms and FP-CIT SPECT findings.
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Affiliation(s)
- Rory Durcan
- Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK
| | - Paul C Donaghy
- Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK
| | - Nicky A Barnett
- Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK
| | - Kirsty Olsen
- Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK
| | - Alison J Yarnall
- Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK
| | - John-Paul Taylor
- Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK
| | - Ian McKeith
- Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK
| | - John T O'Brien
- Department of Psychiatry, University of Cambridge School of Clinical Medicine, Cambridge, UK
| | - Alan J Thomas
- Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK
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