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Veilleux Carpentier A, Okun MS. Surgical Treatments of Parkinson's Disease. Neurol Clin 2025; 43:383-397. [PMID: 40185527 DOI: 10.1016/j.ncl.2024.12.012] [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] [Indexed: 04/07/2025]
Abstract
Surgical interventions have become an integral part of the treatment armamentarium for Parkinson's disease in cases where medication management alone has proven inadequate. Ablative techniques, deep brain stimulation, levodopa-carbidopa intestinal gel infusion, and subcutaneous pump systems offer unique advantages and disadvantages, and the choice of surgical therapy should be individualized. As newer techniques and technologies emerge, the landscape for surgical therapies continues to evolve. A multidisciplinary approach is necessary to establish appropriate candidacy and to determine the most appropriate surgical intervention for each patient. Regular follow-up is essential to assess efficacy, manage complications, and to adjust and optimize treatment.
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Affiliation(s)
| | - Michael S Okun
- Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, USA; Department of Neurology, University of Florida, Gainesville, FL, USA
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Miyaue N, Yamamoto H, Liu S, Ito Y, Yamanishi Y, Ando R, Suzuki Y, Mogi M, Nagai M. Association of Enterococcus faecalis and tyrosine decarboxylase gene levels with levodopa pharmacokinetics in Parkinson's disease. NPJ Parkinsons Dis 2025; 11:49. [PMID: 40102479 PMCID: PMC11920041 DOI: 10.1038/s41531-025-00903-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 03/06/2025] [Indexed: 03/20/2025] Open
Abstract
Multiple factors affect the absorption of orally administered levodopa, the gold standard for the treatment of Parkinson's disease (PD). Enterococcus faecalis (E. faecalis) expresses the enzyme tyrosine decarboxylase (tyrDC), which metabolizes levodopa into dopamine and thereby may influence its absorption in patients with PD. This study investigated the association between fecal E. faecalis and tyrDC gene levels and the pharmacokinetics of orally administered levodopa in 21 patients with PD. Our results revealed a significant association between elevated fecal levels of E. faecalis and tyrDC gene levels and reduced peak plasma levodopa concentrations. Additionally, among patients receiving levodopa-carbidopa intestinal gel treatment, strong positive correlations were observed between E. faecalis and tyrDC gene levels in fecal samples and those from the tip of the jejunal tube. Further prospective studies are required to explore the potential role of gut microbiota as a therapeutic target in patients with PD.
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Affiliation(s)
- Noriyuki Miyaue
- Department of Clinical Pharmacology and Therapeutics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
| | - Haruto Yamamoto
- Department of Clinical Pharmacology and Therapeutics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Shuang Liu
- Department of Pharmacology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Yuko Ito
- Department of Clinical Pharmacology and Therapeutics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Yuki Yamanishi
- Department of Clinical Pharmacology and Therapeutics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Rina Ando
- Department of Clinical Pharmacology and Therapeutics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Yasuyuki Suzuki
- Department of Pharmacology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
- Department of Anesthesiology, Saiseikai Matsuyama Hospital, Matsuyama, Ehime, Japan
- Research Division, Saiseikai Research Institute of Health Care and Welfare, Tokyo, Japan
| | - Masaki Mogi
- Department of Pharmacology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
| | - Masahiro Nagai
- Department of Clinical Pharmacology and Therapeutics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
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de Jong L, Luinstra M, Aalbers AF, Wijma-Vos AJ, D’Angremont E, van der Meulen AAE, Rutgers AWF, Steenhuis L, Hagedoorn P, van Laar T, Frijlink HW. Therapeutic effect of an inhaled levodopa dry powder formulation on off episodes in patients with Parkinson's disease. Ther Adv Neurol Disord 2024; 17:17562864241289207. [PMID: 39483816 PMCID: PMC11526263 DOI: 10.1177/17562864241289207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Accepted: 09/16/2024] [Indexed: 11/03/2024] Open
Abstract
Background Limited treatment options with a rapid onset of action are available to treat off episodes in Parkinson's disease (PD) patients. Therefore, the development of rapid onset formulations, for instance with levodopa, is warranted, which was the reason to investigate an inhalable formulation of levodopa. Objectives The primary objective was to determine the duration until maximum effect is reached of inhaled levodopa on the improvement of motor function of PD patients. The secondary objective was to compare the time until maximal effect and the maximal effect of inhaled levodopa versus oral levodopa. Design Open-label randomized two-way one-period crossover trial. Methods Nine PD patients in the 'off state' received one dose of inhaled levodopa (90 mg) from Cyclops® and one dose of levodopa orodispersible tablet (100 mg) on two consecutive days in a randomized order. A timed tapping test, Timed Up and Go test (TUG test) and Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III score were performed pre-dose and on set time points up to 90 min post-dose as measure for motor function. In addition, blood samples were taken for a pharmacokinetic evaluation (T max, C max and area under the concentration time curve (AUC) 0-3 h). Results The maximal effect of inhaled levodopa was reached at 30 min (tapping test), at 75 min (TUG test) and at 60 min (UPDRS III). The positive effect on the UPDRS was statistically significant within 20 min after inhalation. After oral administration, C max and AUC 0-3 h were found to be significant higher (p = 0.028 and p = 0.028, respectively) than after pulmonary administration. T max was achieved significantly (p = 0.028) faster after inhalation. The motor function examinations showed a similar maximum clinical improvement after pulmonary and oral administration and although not significant, inhaled levodopa results in a shorter median duration to maximum clinical effect for the TUG and timed finger-tapping test compared with oral administration (TUG: inhalation 55.0 and oral 67.5 min, timed finger-tapping test: inhalation 35.0 and oral 57.5 min). After the levodopa inhalation, there were no adverse events observed and no significant differences found in long-function parameters. Conclusion Inhaled levodopa from Cyclops® shows promising data as a rescue therapy for PD patients with off episodes, not responsive to the current oral therapies. Trial registration The study protocol was approved by the local ethics board 'Regionale toetsingscommissie patiëntgebonden onderzoek' (RTPO) in Leeuwarden, The Netherlands (approval number RTPO1019). The study was registered in in the Dutch trial register (LTR) with identification number NL6876. From 5 March 2024 on, the research data on onderzoekmetmensen.nl are known as 'Overview of Medical Research in the Netherlands' (OMON). This means the use of the name LTR has thus been dropped. Now, it is registered in the OMON with the same identification number (NL6876, Effectiveness of inhaled levodopa in PD | Research with human participants (onderzoekmetmensen.nl)). All patients provided written informed consent.
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Affiliation(s)
- Lara de Jong
- Department of Clinical Pharmacy, Martini Hospital Groningen, Van Swietenplein 1, Groningen 9728 NT, The Netherlands
- Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands
| | - Marianne Luinstra
- Department of Clinical Pharmacy, Martini Hospital Groningen, Groningen, The Netherlands
| | | | | | - Emile D’Angremont
- Department of Psychiatry, University Medical Centre Groningen, Groningen, The Netherlands
| | | | | | - Luc Steenhuis
- Department of Pulmonary Diseases, Martini Hospital Groningen, Groningen, The Netherlands
| | - Paul Hagedoorn
- Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands
| | - Teus van Laar
- Department of Neurology, University Medical Centre Groningen, Groningen, The Netherlands
| | - Hendrik Willem Frijlink
- Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands
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Miyaue N, Yabe H, Nagai M. Effect of concomitant use of esomeprazole on levodopa pharmacokinetics and clinical symptoms in patients with Parkinson's disease. J Neurol Sci 2024; 465:123202. [PMID: 39213821 DOI: 10.1016/j.jns.2024.123202] [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: 04/26/2024] [Revised: 07/08/2024] [Accepted: 08/25/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND Proton pump inhibitors (PPIs), which inhibit gastric acid secretion, are frequently prescribed to patients with Parkinson's disease (PD). Levodopa, the gold-standard treatment for PD, demonstrates enhanced solubility in acidic environments. Although PPIs increase gastric pH and may affect levodopa absorption, the effect of concomitant PPI use on levodopa pharmacokinetics in patients with PD remains unknown. This study aimed to investigate the effect of the concomitant use of esomeprazole, a PPI, on the pharmacokinetics of levodopa and carbidopa and clinical symptoms in patients with PD. METHODS We prospectively enrolled 40 patients with PD and compared the pharmacokinetics of levodopa and carbidopa and clinical symptoms before and two weeks after the concomitant use of esomeprazole. RESULTS The plasma concentrations of levodopa 30 min after concomitant oral administration of levodopa and esomeprazole were significantly lower (4.92 ± 4.10 μmol/L) than those without concomitant esomeprazole use (6.26 ± 3.75 μmol/L; p = 0.027). The plasma concentrations of carbidopa showed no significant differences with respect to concomitant esomeprazole use. Significant elevation was recorded in all subscores of the Movement Disorder Society-sponsored revision of the Unified Parkinson's disease Rating Scale scores after concomitant use of esomeprazole. No significant differences were observed between Helicobacter pylori-negative and Helicobacter pylori-positive patients. Non-elderly patients (age ≤ 70 years) tended to be more susceptible to the effect of esomeprazole on levodopa pharmacokinetics and clinical symptoms. CONCLUSIONS The unnecessary use of PPIs should be avoided in patients with PD, especially in non-elderly patients, to improve absorption of levodopa.
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Affiliation(s)
- Noriyuki Miyaue
- Department of Clinical Pharmacology and Therapeutics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan; Department of Neurology, Saiseikai Matsuyama Hospital, Matsuyama, 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, Toon, Ehime, 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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Pasricha TS, Guerrero-Lopez IL, Kuo B. Management of Gastrointestinal Symptoms in Parkinson's Disease: A Comprehensive Review of Clinical Presentation, Workup, and Treatment. J Clin Gastroenterol 2024; 58:211-220. [PMID: 38260966 PMCID: PMC10855995 DOI: 10.1097/mcg.0000000000001961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 12/11/2023] [Indexed: 01/24/2024]
Abstract
Gastrointestinal symptoms in Parkinson's disease (PD) are among the most prevalent and debilitating of complications and present unique diagnostic and management challenges. Patients with PD commonly experience dysphagia, nausea, bloating, and constipation related to pathologic involvement of the enteric nervous system. In turn, gastrointestinal complications may impact motor fluctuations and the efficacy of levodopa therapy. This review will explore the common gastrointestinal manifestations of PD with an emphasis on clinical presentation, workup, and treatment strategies.
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Affiliation(s)
- Trisha S. Pasricha
- Division of Gastroenterology, Massachusetts General Hospital
- Harvard Medical School, Boston, MA
| | | | - Braden Kuo
- Division of Gastroenterology, Massachusetts General Hospital
- Harvard Medical School, Boston, MA
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Zou X, Chen X, Wen Y, Jing X, Luo M, Xin F, Tang Y, Hu M, Liu J, Xu F. Gastric-filling ultrasonography to evaluate gastric motility in patients with Parkinson's disease. Front Neurol 2024; 15:1294260. [PMID: 38410194 PMCID: PMC10895041 DOI: 10.3389/fneur.2024.1294260] [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: 09/14/2023] [Accepted: 01/25/2024] [Indexed: 02/28/2024] Open
Abstract
Background Delayed gastric emptying is a common non-motor symptom of Parkinson's disease (PD). However, there is currently no objective evaluation and diagnostic method for this condition. Objectives The purpose of this study was to evaluate the feasibility of gastric-filling ultrasonography for gastric motility in patients with PD and the relationship between gastric dynamics and gastrointestinal symptoms and motor symptoms of PD. Design setting and patients We performed a case-control study with 38 patients with PD and 34 healthy controls. Methods All patients underwent a 120-min ultrasonography examination using a 500-ml semi-liquid test meal. We determined the antral contraction amplitude (ACA), the antrum contraction frequency (ACF), the motility index (MI), and the gastric antral cross-sectional area (CSA). We acquired the CSA at six time points: fasting for 12 h (T0), immediately after drinking the semi-liquid test meal (T1); and at 30 (T30), 60 (T60), 90 (T90), and 120 (T120) min. We calculated the gastric emptying rate (GER) at different time points by using the CSA. We compared the GER between the groups and evaluated the correlation between the GER and gastrointestinal symptoms and motor symptoms of PD. Results The MI and ACF were significantly lower in the PD group compared with the control group (P < 0.05). The GER at T30 and the ACA showed no significant difference between the groups (P > 0.05). At different time points, the GER was significantly different between the PD and control groups (P < 0.001). There was no significant association between the GER and gastrointestinal symptoms; none of them were risk factors for impaired gastric emptying (odds ratio > 1). The GER was negatively correlated with the severity of PD motor symptoms (P < 0.05). Conclusion Patients with PD had significantly delayed gastric emptying, which was negatively correlated with the severity of PD motor symptoms. Measuring gastric emptying by gastric-filling ultrasound had good diagnostic value in clinical screening for delayed gastric motility in patients with PD. Clinical Trial Registration https://www.chictr.org.cn/showproj.html?proj=126304.
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Affiliation(s)
- Xianwei Zou
- Department of Neurology, First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Xiaqing Chen
- Department of Neurology, First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Yanxia Wen
- Department of Neurology, First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Xiaofeng Jing
- Department of Public Health, Chengdu Medical College, Chengdu, Sichuan, China
| | - Man Luo
- Department of Neurology, First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Fengyue Xin
- Department of Ultrasonography, First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Yao Tang
- Department of Neurology, First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Mengfei Hu
- Department of Neurology, First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Jian Liu
- Department of Ultrasonography, First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Fan Xu
- Department of Public Health, Chengdu Medical College, Chengdu, Sichuan, China
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Onoue S. New Drug Delivery Systems for Stable Oral Absorption: Theory, Strategies, and Applications. Biol Pharm Bull 2024; 47:1797-1803. [PMID: 39496383 DOI: 10.1248/bpb.b24-00566] [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] [Indexed: 11/06/2024]
Abstract
The oral dosage route still remains the most common and preferred route for drug administration due to convenient handling, high patient compliance, and cost-effectiveness. However, the oral absorption of drugs can be a complex process depending upon: (i) physicochemical properties of the drug (e.g., pKa, lipophilicity, solubility), (ii) pharmaceutical factors (e.g., dosage form), and (iii) physiological factors (e.g., gastrointestinal pH values, gastric emptying rate, gastric and intestinal pH, metabolism). Oral administration of drugs sometimes leads to poor and/or variable oral bioavailability, possible leading to unstable clinical outcomes. To offer stable and improved pharmacokinetic behavior of drugs, a number of formulation approaches have been developed with a focus on enhancement of the solubility, dissolution rate, and oral bioavailability of drugs. To provide new formulation platforms for better and safe medication, it is considered essential to understand the physicochemical, biochemical, metabolic, and biological barriers which limit overall drug bioavailability in more detail. The review article considers several crucial factors affecting oral absorption of drug substances. This article also describes the recent progress in formulation approaches to achieve stable and improved biopharmaceutical properties of orally-taken drugs.
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Affiliation(s)
- Satomi Onoue
- Laboratory of Biopharmacy, School of Pharmaceutical Sciences, University of Shizuoka
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Demailly A, Moreau C, Devos D. Effectiveness of Continuous Dopaminergic Therapies in Parkinson's Disease: A Review of L-DOPA Pharmacokinetics/Pharmacodynamics. JOURNAL OF PARKINSON'S DISEASE 2024; 14:925-939. [PMID: 38848195 PMCID: PMC11307025 DOI: 10.3233/jpd-230372] [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: 04/24/2024] [Indexed: 06/09/2024]
Abstract
Background Parkinson's disease (PD) is characterized by striatal dopamine deficiency. Since dopamine cannot cross the digestive and blood-brain barriers, its precursor, levodopa (L-DOPA), remains the mainstay of treatment. However, the significant pharmacokinetic (Pk) and pharmacodynamic (Pd) limitations of L-DOPA, combined with the severity of PD, may trigger motor and non-motor complications, for which continuous dopaminergic delivery therapies have been developed. Objective The aim of this study was to review the literature on the Pk/Pd limitations of L-DOPA and how current treatments of continuous dopaminergic administration ameliorate these problems, in order to identify the need for new therapeutic avenues. Methods A comprehensive literature search was carried out using PubMed and 75 articles were initially extracted. Following independent screening by two reviewers and consideration of eligibility, 10 articles were chosen for further analysis. Information concerning the Pk/Pd of L-DOPA was classified for each article. Results Pk/Pd problems notably include: (i) restricted digestive and cerebral absorption; (ii) unnecessary peripheral distribution; (iii) short half-life; (iv) age- and PD-induced decline of central aromatic L-amino acid decarboxylase; (v) misdistribution in many cells; and (vii) pulsatile stimulation of dopaminergic receptors. Current treatments only slightly ameliorate some of these problems. Conclusions Many Pk/Pd constraints are not resolved by existing continuous dopaminergic delivery therapies. This highlights the significant gap between these treatments and the ideal of continuous dopaminergic stimulation.
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Affiliation(s)
| | - Caroline Moreau
- Université Lille, Lille, France
- Neurology Department & Parkinson’s Disease Centre of Excellence, INSERM, CHU Lille, U1172 - Degenerative & Vascular Cognitive Disorders, LilNCog, Lille Neuroscience & Cognition, LICEND, NS-Park Network, Lille, France
| | - David Devos
- Université Lille, Lille, France
- Neurology Department & Parkinson’s Disease Centre of Excellence, INSERM, CHU Lille, U1172 - Degenerative & Vascular Cognitive Disorders, LilNCog, Lille Neuroscience & Cognition, LICEND, NS-Park Network, Lille, France
- Medical Pharmacology Department, CHU Lille, Lille, France
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Chaudhuri KR, Batzu L. Can Continuous Levodopa Delivery Be Achieved in the Absence of Intrajejunal Levodopa Infusion? Implications for India and Underserved Countries. Mov Disord Clin Pract 2024; 11:21-29. [PMID: 38291849 PMCID: PMC10828610 DOI: 10.1002/mdc3.13915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 08/24/2023] [Accepted: 10/12/2023] [Indexed: 02/01/2024] Open
Affiliation(s)
- K. Ray Chaudhuri
- Department of Basic and Clinical NeuroscienceInstitute of Psychiatry, Psychology, and Neuroscience, King's College LondonLondonUK
- Parkinson's Foundation Centre of Excellence, King's College HospitalLondonUK
| | - Lucia Batzu
- Department of Basic and Clinical NeuroscienceInstitute of Psychiatry, Psychology, and Neuroscience, King's College LondonLondonUK
- Parkinson's Foundation Centre of Excellence, King's College HospitalLondonUK
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Nishikawa N, Iwaki H, Mukai Y, Takahashi Y. Classification of l-DOPA pharmacokinetics shapes and creating a predictive model. Parkinsonism Relat Disord 2023; 114:105798. [PMID: 37556972 DOI: 10.1016/j.parkreldis.2023.105798] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 07/28/2023] [Accepted: 08/04/2023] [Indexed: 08/11/2023]
Abstract
BACKGROUND It is known that the pharmacokinetics (PK) of levodopa (LD) varies considerably. Difference in PK shapes is expected to affect drug efficacy and development of dyskinesia. In this study, the authors aimed to explore correlations between PK series data of LD and clinical characteristics and dyskinesia in patients with Parkinson's disease (PD). METHODS We studied 270 PD patients who underwent PK assessment after administration of LD/carbidopa (100/10 mg) in non-compartmental analysis. The patients were grouped according to similarities in time series data of blood LD concentration. Each group was analyzed with respect to clinical characteristics and PK parameters. We created a model to predict PK patterns based on these findings. RESULTS PD patients were divided into three groups by clustering analysis: blood LD concentration of the patients in Groups 1 (n = 129), 3 (n = 44) and 2 (n = 97) rose rapidly, relatively slowly and at an intermediate rate, respectively. There were no statistically significant differences in patient characteristics except age among the three groups (one-way ANOVA). Multivariate analysis showed that frequency of dyskinesias in Group 1 was significantly higher than that in Group 2. We successfully created a PK pattern prediction model based on body weight and blood LD concentration at 15 and 30 min after administration. CONCLUSIONS The PK series data of LD was classified into three patterns. The rapid absorption was associated with dyskinesias. Patients' PK patterns were successfully predicted based on their body weight and two-point LD concentration.
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Affiliation(s)
- Noriko Nishikawa
- Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan; Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.
| | | | - Yohei Mukai
- Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan
| | - Yuji Takahashi
- Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan
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12
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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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13
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Acosta-Mejia MT, Villalobos N. Neurophysiology of Brain Networks Underlies Symptoms of Parkinson's Disease: A Basis for Diagnosis and Management. Diagnostics (Basel) 2023; 13:2394. [PMID: 37510138 PMCID: PMC10377975 DOI: 10.3390/diagnostics13142394] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 07/04/2023] [Accepted: 07/13/2023] [Indexed: 07/30/2023] Open
Abstract
Parkinson's disease (PD) is one of the leading neurodegenerative disorders. It is considered a movement disorder, although it is accepted that many nonmotor symptoms accompany the classic motor symptoms. PD exhibits heterogeneous and overlaying clinical symptoms, and the overlap of motor and nonmotor symptoms complicates the clinical diagnosis and management. Loss of modulation secondary to the absence of dopamine due to degeneration of the substantia nigra compacta produces changes in firing rates and patterns, oscillatory activity, and higher interneuronal synchronization in the basal ganglia-thalamus-cortex and nigrovagal network involvement in motor and nonmotor symptoms. These neurophysiological changes can be monitored by electrophysiological assessment. The purpose of this review was to summarize the results of neurophysiological changes, especially in the network oscillation in the beta-band level associated with parkinsonism, and to discuss the use of these methods to optimize the diagnosis and management of PD.
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Affiliation(s)
- Martha Teresa Acosta-Mejia
- Área Académica de Nutrición, Área Académica de Farmacia, Instituto de Ciencias de la Salud, Universidad Autónoma del Estado de Hidalgo, Ex-Hacienda La Concepción, Sn Agustin Tlaxiaca, Estado de Hidalgo 42160, Mexico
| | - Nelson Villalobos
- Academia de Fisiología, Escuela Superior de Medicina, Instituto Politécnico, Nacional, Plan de San Luis y Díaz Mirón, Colonia Casco de Santo Tomás, Ciudad de Mexico 11340, Mexico
- Sección de Estudios de Posgrado e Investigación de la Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, Colonia Casco de Santo Tomás, Ciudad de Mexico 11340, Mexico
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14
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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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15
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LeWitt PA, Stocchi F, Arkadir D, Caraco Y, Adar L, Perlstein I, Case R, Giladi N. The pharmacokinetics of continuous subcutaneous levodopa/carbidopa infusion: Findings from the ND0612 clinical development program. Front Neurol 2022; 13:1036068. [PMID: 36438968 PMCID: PMC9686322 DOI: 10.3389/fneur.2022.1036068] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Accepted: 10/24/2022] [Indexed: 08/29/2023] Open
Abstract
BACKGROUND While treatment with levodopa remains the cornerstone of Parkinson's disease (PD) management, chronic oral therapy is often associated with the development of motor complications, that correlate to fluctuating levodopa plasma concentrations, limiting its clinical utility. Continuous infusion is considered to be the optimal delivery route for treating PD patients with motor fluctuations, but current infusion systems require invasive surgery. Subcutaneous infusion of (SC) levodopa has the potential to provide a better tolerated and more convenient route of continuous levodopa delivery. ND0612 is in development as a combination product providing continuous levodopa/carbidopa via a minimally invasive, subcutaneous delivery system for PD patients experiencing motor response fluctuations. We present pharmacokinetic results from a series of studies that analyzed plasma concentrations after SC levodopa delivery with ND0612 to inform the clinical development program. METHODS We performed a series of six Phase I and II studies to characterize the pharmacokinetics of levodopa and carbidopa derived from ND0612 infusion with/without adjunct oral therapy of the same ingredients. These studies were conducted in healthy volunteers and in PD patients experiencing motor response fluctuations while on their current levodopa therapy regimen. RESULTS Taken together, the results demonstrate dose-proportionality dependent on rate of subcutaneous levodopa infusion leading to stable and sustained plasma concentrations of levodopa. Subcutaneous infusion of ND0612 administered with oral levodopa/carbidopa maintained near-constant, therapeutic levodopa plasma concentrations, thereby avoiding the troughs in levodopa plasma concentrations that are associated with OFF time in PD. The data generated in this series of studies also confirmed that a levodopa/carbidopa dose ratio of 8:1 would be the most reasonable choice for ND0612 development. CONCLUSIONS This series of clinical pharmacokinetic studies have demonstrated that ND0612, administered continuously with a levodopa concentration of 60 mg/ml combined with carbidopa 7.5 mg/ml, and complemented with oral levodopa/carbidopa, is suitable for 24 h continuous administration in patients with PD. The stable plasma concentrations of levodopa achieved predict utility of ND0612 as a parenteral formulation for achieving clinically useful delivery of levodopa for PD patients.
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Affiliation(s)
- Peter A. LeWitt
- Department of Neurology, Wayne State University School of Medicine and Henry Ford Hospital, Detroit, MI, United States
| | - Fabrizio Stocchi
- Department of Neurology, University and Institute for Research and Medical Care Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele, Rome, Italy
| | - David Arkadir
- Department of Neurology, The Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Yoseph Caraco
- Clinical Pharmacology Unit, Division of Medicine, Hadassah Hebrew-University Medical Center, Jerusalem, Israel
| | | | | | | | - Nir Giladi
- Sackler School of Medicine, Tel Aviv Medical Center and Sagol School of Neurosciences, Neurological Institute, Tel-Aviv University, Tel Aviv-Yafo, Israel
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16
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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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17
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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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18
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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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19
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Windolf H, Chamberlain R, Breitkreutz J, Quodbach J. 3D Printed Mini-Floating-Polypill for Parkinson's Disease: Combination of Levodopa, Benserazide, and Pramipexole in Various Dosing for Personalized Therapy. Pharmaceutics 2022; 14:931. [PMID: 35631518 PMCID: PMC9145509 DOI: 10.3390/pharmaceutics14050931] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 04/19/2022] [Accepted: 04/22/2022] [Indexed: 01/27/2023] Open
Abstract
Therapy for Parkinson’s disease is quite challenging. Numerous drugs are available for symptomatic treatment, and levodopa (LD), in combination with a dopa decarboxylase inhibitor (e.g., benserazide (BZ)), has been the drug of choice for years. As the disease progresses, therapy must be supplemented with a dopamine agonist (e.g., pramipexole (PDM)). Side effects increase, as do the required dose and dosing intervals. For these specific requirements of drug therapy, the 3D printing method fused deposition modelling (FDM) was applied in this study for personalized therapy. Hot melt extrusion was utilized to produce two different compositions into filaments: PDM and polyvinyl alcohol for rapid drug release and a fixed combination of LD/BZ (4:1) in an ethylene-vinyl acetate copolymer matrix for prolonged drug release. Since LD is absorbed in the upper gastrointestinal tract, a formulation that floats in gastric fluid was desired to prolong API absorption. Using the FDM 3D printing process, different polypill geometries were printed from both filaments, with variable dosages. Dosage forms with 15−180 mg LD could be printed, showing similar release rates (f2 > 50). In addition, a mini drug delivery dosage form was printed that released 75% LD/BZ within 750 min and could be used as a gastric retentive drug delivery system due to the floating properties of the composition. The floating mini-polypill was designed to accommodate patients’ swallowing difficulties and to allow for individualized dosing with an API release over a longer period of time.
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Affiliation(s)
- Hellen Windolf
- Institute of Pharmaceutics and Biopharmaceutics, Heinrich Heine University, Universitätsstr. 1, 40225 Düsseldorf, Germany; (H.W.); (R.C.); (J.B.)
| | - Rebecca Chamberlain
- Institute of Pharmaceutics and Biopharmaceutics, Heinrich Heine University, Universitätsstr. 1, 40225 Düsseldorf, Germany; (H.W.); (R.C.); (J.B.)
| | - Jörg Breitkreutz
- Institute of Pharmaceutics and Biopharmaceutics, Heinrich Heine University, Universitätsstr. 1, 40225 Düsseldorf, Germany; (H.W.); (R.C.); (J.B.)
| | - Julian Quodbach
- Institute of Pharmaceutics and Biopharmaceutics, Heinrich Heine University, Universitätsstr. 1, 40225 Düsseldorf, Germany; (H.W.); (R.C.); (J.B.)
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands
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20
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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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21
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Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease and affects about 1% of the population over the age of 60 years in industrialised countries. The aim of this review is to examine nutrition in PD across three domains: dietary intake and the development of PD; whole body metabolism in PD and the effects of PD symptoms and treatment on nutritional status. In most cases, PD is believed to be caused by a combination of genetic and environmental factors and although there has been much research in the area, evidence suggests that poor dietary intake is not a risk factor for the development of PD. The evidence about body weight changes in both the prodromal and symptomatic phases of PD is inconclusive and is confounded by many factors. Malnutrition in PD has been documented as has sarcopaenia, although the prevalence of the latter remains uncertain due to a lack of consensus in the definition of sarcopaenia. PD symptoms, including those which are gastrointestinal and non-gastrointestinal, are known to adversely affect nutritional status. Similarly, PD treatments can cause nausea, vomiting and constipation, all of which can adversely affect nutritional status. Given that the prevalence of PD will increase as the population ages, it is important to understand the interplay between PD, comorbidities and nutritional status. Further research may contribute to the development of interventional strategies to improve symptoms, augment care and importantly, enhance the quality of life for patients living with this complex neurodegenerative disease.
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22
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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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23
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Han MN, Finkelstein DI, McQuade RM, Diwakarla S. Gastrointestinal Dysfunction in Parkinson’s Disease: Current and Potential Therapeutics. J Pers Med 2022; 12:jpm12020144. [PMID: 35207632 PMCID: PMC8875119 DOI: 10.3390/jpm12020144] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 01/17/2022] [Accepted: 01/18/2022] [Indexed: 02/04/2023] Open
Abstract
Abnormalities in the gastrointestinal (GI) tract of Parkinson’s disease (PD) sufferers were first reported over 200 years ago; however, the extent and role of GI dysfunction in PD disease progression is still unknown. GI dysfunctions, including dysphagia, gastroparesis, and constipation, are amongst the most prevalent non-motor symptoms in PD. These symptoms not only impact patient quality of life, but also complicate disease management. Conventional treatment pathways for GI dysfunctions (i.e., constipation), such as increasing fibre and fluid intake, and the use of over-the-counter laxatives, are generally ineffective in PD patients, and approved compounds such as guanylate cyclase C agonists and selective 5-hyroxytryptamine 4 receptor agonists have demonstrated limited efficacy. Thus, identification of potential targets for novel therapies to alleviate PD-induced GI dysfunctions are essential to improve clinical outcomes and quality of life in people with PD. Unlike the central nervous system (CNS), where PD pathology and the mechanisms involved in CNS damage are relatively well characterised, the effect of PD at the cellular and tissue level in the enteric nervous system (ENS) remains unclear, making it difficult to alleviate or reverse GI symptoms. However, the resurgence of interest in understanding how the GI tract is involved in various disease states, such as PD, has resulted in the identification of novel therapeutic avenues. This review focuses on common PD-related GI symptoms, and summarizes the current treatments available and their limitations. We propose that by targeting the intestinal barrier, ENS, and/or the gut microbiome, may prove successful in alleviating PD-related GI symptoms, and discuss emerging therapies and potential drugs that could be repurposed to target these areas.
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Affiliation(s)
- Myat Noe Han
- Gut-Axis Injury and Repair Laboratory, Department of Medicine Western Health, University of Melbourne, Melbourne, VIC 3021, Australia; (M.N.H.); (S.D.)
- The Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3010, Australia
- Australian Institute of Musculoskeletal Science (AIMSS), Melbourne, VIC 3021, Australia
| | - David I. Finkelstein
- Parkinson’s Disease Laboratory, The Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3010, Australia;
| | - Rachel M. McQuade
- Gut-Axis Injury and Repair Laboratory, Department of Medicine Western Health, University of Melbourne, Melbourne, VIC 3021, Australia; (M.N.H.); (S.D.)
- The Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3010, Australia
- Australian Institute of Musculoskeletal Science (AIMSS), Melbourne, VIC 3021, Australia
- Correspondence: ; Tel.: +61-3-8395-8114
| | - Shanti Diwakarla
- Gut-Axis Injury and Repair Laboratory, Department of Medicine Western Health, University of Melbourne, Melbourne, VIC 3021, Australia; (M.N.H.); (S.D.)
- The Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3010, Australia
- Australian Institute of Musculoskeletal Science (AIMSS), Melbourne, VIC 3021, Australia
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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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Mylius V, Möller JC, Bohlhalter S, Ciampi de Andrade D, Perez Lloret S. Diagnosis and Management of Pain in Parkinson's Disease: A New Approach. Drugs Aging 2021; 38:559-577. [PMID: 34224103 DOI: 10.1007/s40266-021-00867-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/18/2021] [Indexed: 12/27/2022]
Abstract
Pain is a frequent and disabling non-motor feature of Parkinson's disease (PD). The recently proposed PD Pain Classification System (PD-PCS) allows for an association of pain with PD to be determined before being allocated to the main pain mechanism (i.e. nociceptive, neuropathic, and nociplastic). In this article, previous studies on treatments for pain in PD are summarized according to the pain mechanisms. A mechanistic approach to treatment is discussed. We suggest that the first step should be optimizing dopaminergic therapy before other therapy is started. When these treatments remain unsuccessful, further causes of pain must be considered. The role of drugs, invasive treatments, and physiotherapeutic interventions are discussed with a focus on older PD patients and considering polypharmacy, altered pharmacokinetics, and comorbidities.
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Affiliation(s)
- Veit Mylius
- Department of Neurology, Center for Neurorehabilitation, 7317, Valens, Switzerland. .,Department of Neurology, Philipps University, Marburg, Germany. .,Department of Neurology, Kantonsspital, St. Gallen, Switzerland.
| | - Jens Carsten Möller
- Department of Neurology, Philipps University, Marburg, Germany.,Parkinson Center, Center for Neurological Rehabilitation, Zihlschlacht, Switzerland
| | - Stephan Bohlhalter
- Neurocenter, Luzerner Kantonsspital, Lucerne, Switzerland.,Department of Neurology, University of Zurich, Zurich, Switzerland
| | - Daniel Ciampi de Andrade
- Centro de Dor, Departamento de Neurologia da Faculdade de Medicina da, Universidade de Sao Paulo, Sao Paulo, Brazil.,Instituto do Cancer de Sao Paulo, Octavio Frias de Oliveira, Sao Paulo, Brazil.,Hospital das Clinicas, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Santiago Perez Lloret
- LIM 62, Biomedical Research Center (CAECIHS-UAI), National Research Council (CONICET), Buenos Aires, Argentina.,Facultad de Ciencias Médicas, Pontificia Universidad Católica Argentina, Buenos Aires, Argentina.,Departamento de Fisiología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
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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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Boelens Keun JT, Arnoldussen IA, Vriend C, van de Rest O. Dietary Approaches to Improve Efficacy and Control Side Effects of Levodopa Therapy in Parkinson's Disease: A Systematic Review. Adv Nutr 2021; 12:2265-2287. [PMID: 34113965 PMCID: PMC8634393 DOI: 10.1093/advances/nmab060] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 03/19/2021] [Accepted: 04/20/2021] [Indexed: 12/26/2022] Open
Abstract
Although levodopa remains the most effective drug for symptomatic management of Parkinson's Disease (PD), treatment during advanced disease stages may raise unpredictable motor fluctuations and other complications. Counteracting these complications with other pharmacological therapies may prompt a vicious circle of side effects, and here, nutritional therapy may have great potential. Knowledge about the role of diet in PD is emerging and multiple studies have investigated nutritional support specifically with respect to levodopa therapy. With this systematic review, we aim to give a comprehensive overview of dietary approaches to optimize levodopa treatment in PD. A systematic search was performed using the databases of PubMed and Scopus between January 1985 and September 2020. Nutritional interventions with the rationale to optimize levodopa therapy in human PD patients were eligible for this study and their quality was assessed with the Cochrane risk-of-bias tool. In total, we included 22 papers that addressed the effects of dietary proteins (n = 10), vitamins (n = 7), fiber (n = 2), soybeans (n = 1), caffeine (n = 1), and ketogenic diets (n = 1) on levodopa therapy. Interventions with protein redistribution diets (PRDs), dietary fiber, vitamin C, and caffeine improved levodopa absorption, thereby enhancing clinical response and reducing motor fluctuations. Furthermore, supplementation of vitamin B-12, vitamin B-6, and folic acid successfully reduced high homocysteine concentrations that emerged from levodopa metabolism and promoted many metabolic and clinical complications, such as neuropathology and osteoporosis. In conclusion, dietary interventions have the potential to optimize levodopa efficacy and control side effects. Nutrition that improves levodopa absorption, including PRDs, fiber, vitamin C, and caffeine, is specifically recommended when fluctuating clinical responses appear. Supplements of vitamin B-12, vitamin B-6, and folic acid are advised along with levodopa initiation to attenuate hyperhomocysteinemia, and importantly, their potential to treat consequent metabolic and clinical complications warrants future research.
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Affiliation(s)
- Jikke T Boelens Keun
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Anatomy and Neurosciences, Amsterdam Neuroscience, Amsterdam, The Netherlands
| | - Ilse Ac Arnoldussen
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, The Netherlands,Department of Medical Imaging, Anatomy, Radboud University Medical Center, Nijmegen, The Netherlands,Donders Institute for Brain, Cognition, and Behaviour, Nijmegen, The Netherlands
| | - Chris Vriend
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Anatomy and Neurosciences, Amsterdam Neuroscience, Amsterdam, The Netherlands,Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Psychiatry, Amsterdam Neuroscience, Amsterdam, The Netherlands
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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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Chen X, Liu Y, Pan D, Cao M, Wang X, Wang L, Xu Y, Wang Y, Yan J, Liu J, Yang M. 68Ga-NOTA PET imaging for gastric emptying assessment in mice. BMC Gastroenterol 2021; 21:69. [PMID: 33581729 PMCID: PMC7881688 DOI: 10.1186/s12876-021-01642-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 02/03/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Positron emission tomography (PET) has the potential for visualization and quantification of gastric emptying (GE). The traditional Chinese medicine (TCM) has been recognized promising for constipation. This study aimed to establish a PET imaging method for noninvasive GE measurement and to evaluate the efficacy of a TCM on delayed GE caused by constipation using PET imaging. METHODS [68Ga]Ga-NOTA was synthesized as the tracer and sesame paste with different viscosity were selected as test meals. The dynamic PET scans were performed after [68Ga]Ga-NOTA mixed with test meals were administered to normal mice. Two methods were utilized for the quantification of PET imaging. A constipation mouse model was treated with maren chengqi decoction (MCD), and the established PET imaging scans were performed after the treatment. RESULTS [68Ga]Ga-NOTA was synthesized within 20 min, and its radiochemical purity was > 95%. PET images showed the dynamic process of GE. %ID/g, volume, and total activity correlated well with each other. Among which, the half of GE time derived from %ID/g for 4 test meals were 3.92 ± 0.87 min, 13.1 ± 1.25 min, 17.8 ± 1.31 min, and 59.7 ± 3.11 min, respectively. Constipation mice treated with MCD showed improved body weight and fecal conditions as well as ameliorated GE measured by [68Ga]Ga-NOTA PET. CONCLUSIONS A PET imaging method for noninvasive GE measurement was established with stable radiotracer, high image quality, and reliable quantification methods. The efficacy of MCD on delayed GE was demonstrated using PET.
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Affiliation(s)
- Xueyan Chen
- Department of Veterinary Medicine, Southwest University, Rongchang, Chongqing, 402460, China
| | - Yu Liu
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, Jiangsu, China
| | - Donghui Pan
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, Jiangsu, China
| | - Maoyu Cao
- Department of Veterinary Medicine, Southwest University, Rongchang, Chongqing, 402460, China
| | - Xinyu Wang
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, Jiangsu, China
| | - Lizhen Wang
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, Jiangsu, China
| | - Yuping Xu
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, Jiangsu, China
| | - Yan Wang
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, Jiangsu, China
| | - Junjie Yan
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, Jiangsu, China
| | - Juan Liu
- Department of Veterinary Medicine, Southwest University, Rongchang, Chongqing, 402460, China. .,Immunology Center, Medical Research Institute of Southwest University, Rongchang, Chongqing, 402460, China.
| | - Min Yang
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, Jiangsu, China.
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30
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Gastrointestinal dysfunction in movement disorders. Neurol Sci 2021; 42:1355-1365. [PMID: 33538914 DOI: 10.1007/s10072-021-05041-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 01/04/2021] [Indexed: 12/24/2022]
Abstract
PURPOSE OF REVIEW This article provides an overview of the clinical presentation, investigations, and treatment options for gastrointestinal tract (GIT) dysfunction in patients with Parkinson's disease (PD) and other movement disorders. RECENT FINDINGS GIT dysfunction commonly appears as constipation and fecal incontinence (mostly overflow, accompanied with sphincter failure in multiple system atrophy [MSA]). Bowel dysfunction (underactive) occurs irrespectively from the site of the neurologic lesion, which is in contrast to site-dependent bladder dysfunction (brain, overactive; periphery, underactive). GI emergencies may arise, including intestinal pseudo-obstruction, intussusception, volvulus, and stercoral ulcer (ulcer of the colon due to pressure and irritation resulting from severe, prolonged constipation). Bowel function tests in neurologic patients often show a combination of slow transit and anorectal dysfunction. Management for slow transit constipation includes bulking agents, softening agents, yogurt/probiotics, and prokinetic agents. Suppositories, botulinum toxin injections, and transanal irrigation are options for managing anorectal constipation. CONCLUSIONS Function of the bowel is commonly affected in PD and other movement disorders. Neurologists play an important role in assessing bowel symptoms in their patients and planning treatment strategies, often in collaboration with specialist teams.
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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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Panicker JN, Sakakibara R. Lower Urinary Tract and Bowel Dysfunction in Neurologic Disease. Continuum (Minneap Minn) 2020; 26:178-199. [PMID: 31996628 DOI: 10.1212/con.0000000000000824] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE OF REVIEW This article provides an overview of the clinical presentation, investigations, and treatment options for lower urinary tract and bowel dysfunction in patients with neurologic diseases. RECENT FINDINGS The site of the neurologic lesion influences the pattern of lower urinary tract dysfunction. Antimuscarinic agents are first-line management for urinary incontinence; however, the side effect profile should be considered when prescribing them. β3-Receptor agonists are a promising alternative oral medication. Botulinum toxin injections into the detrusor have revolutionized the management of neurogenic detrusor overactivity.Bowel dysfunction commonly presents as constipation and fecal incontinence. Gastrointestinal emergencies may arise, including intestinal pseudoobstruction, intussusception, volvulus, and stercoral ulcer (ulcer of the colon due to pressure and irritation resulting from severe, prolonged constipation). Bowel function tests in neurologic patients often show a combination of slow transit and anorectal dysfunction. Management for slow transit constipation includes bulking agents, softening agents, yogurt/probiotics, and prokinetic agents. Suppositories, botulinum toxin injections, and transanal irrigation are options for managing anorectal constipation. SUMMARY Functions of the lower urinary tract and bowel are commonly affected in neurologic disease. Neurologists play an important role in assessing lower urinary tract and bowel symptoms in their patients and planning treatment strategies, often in collaboration with specialist teams.
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Schaeffer E, Kluge A, Böttner M, Zunke F, Cossais F, Berg D, Arnold P. Alpha Synuclein Connects the Gut-Brain Axis in Parkinson's Disease Patients - A View on Clinical Aspects, Cellular Pathology and Analytical Methodology. Front Cell Dev Biol 2020; 8:573696. [PMID: 33015066 PMCID: PMC7509446 DOI: 10.3389/fcell.2020.573696] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 08/18/2020] [Indexed: 12/15/2022] Open
Abstract
Parkinson’s disease (PD) is marked by different kinds of pathological features, one hallmark is the aggregation of α-synuclein (aSyn). The development of aSyn pathology in the substantia nigra is associated to the manifestation of motor deficits at the time of diagnosis. However, most of the patients suffer additionally from non-motor symptoms, which may occur already in the prodromal phase of the disease years before PD is diagnosed. Many of these symptoms manifest in the gastrointestinal system (GIT) and some data suggest a potential link to the occurrence of pathological aSyn forms within the GIT. These clinical and pathological findings lead to the idea of a gut-brain route of aSyn pathology in PD. The identification of pathological aSyn in the intestinal system, e.g., by GIT biopsies, is therefore of highest interest for early diagnosis and early intervention in the phase of formation and propagation of aSyn. However, reliable methods to discriminate between physiological and pathological forms of enteral aSyn on the cellular and biochemical level are still missing. Moreover, a better understanding of the physiological function of aSyn within the GIT as well as its structure and pathological aggregation pathways are crucial to understand its role within the enteric nervous system and its spreading from the gut to the brain. In this review, we summarize clinical manifestations of PD in the GIT, and discuss biochemical findings from enteral biopsies. The relevance of pathological aSyn forms, their connection to the gut-brain axis and new developments to identify pathologic forms of aSyn by structural features are critically reviewed.
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Affiliation(s)
- Eva Schaeffer
- Department of Neurology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Annika Kluge
- Department of Neurology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Martina Böttner
- Institute of Anatomy, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Friederike Zunke
- Biochemical Institute, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
| | - Francois Cossais
- Institute of Anatomy, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Daniela Berg
- Department of Neurology, Christian-Albrechts-University of Kiel, Kiel, Germany.,Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
| | - Philipp Arnold
- Institute of Anatomy, Christian-Albrechts-University of Kiel, Kiel, Germany.,MSH Medical School Hamburg, Hamburg, Germany
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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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Fukae J, Fujioka S, Umemoto G, Arahata H, Yanamoto S, Mishima T, Tsuboi Y. Impact of Residual Drug in the Pharynx on the Delayed-On Phenomenon in Parkinson's Disease Patients. Mov Disord Clin Pract 2020; 7:273-278. [PMID: 32258224 DOI: 10.1002/mdc3.12908] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 08/03/2019] [Accepted: 01/18/2020] [Indexed: 11/11/2022] Open
Abstract
Background and Objective The delayed-on phenomenon (DOP) related to levodopa treatment frequently disturbs quality of life in advanced-stage Parkinson's disease (PD) patients. The objective of this study was to explore the impact of swallowing dysfunction on the development of DOP. Methods Swallowing function was investigated by endoscopic evaluation in 11 PD patients with the DOP and 9 PD patients without the DOP during the on phase. Residual drug in the pharynx after taking the drug in tablet, capsule, and powder forms was also observed. Results Residual drug was seen in the pharynx in six cases (30.0%). Pooling of saliva, delayed swallowing reflex, and residual drug were more frequent in the DOP group than in the group without the DOP (P < 0.05). The odds ratios for residual drug in the pharynx, pooling of saliva, and delayed swallowing reflex for the DOP were 42.7 (95% confidence interval, 1.89-962.9), 14.0 (95% confidence interval, 1.25-156.6), and 15.8 (95% confidence interval, 1.75-141.4), respectively. Conclusions These results suggest that swallowing dysfunction leading to residual antiparkinsonian drug in the pharynx has substantial impacts on the DOP in PD patients.
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Affiliation(s)
- Jiro Fukae
- Department of Neurology Fukuoka University School of Medicine Fukuoka Japan.,Department of Neurology Juntendo University Nerima Hospital Tokyo Japan
| | - Shinsuke Fujioka
- Department of Neurology Fukuoka University School of Medicine Fukuoka Japan
| | - George Umemoto
- Department of Oral and Maxillofacial Surgery Fukuoka University Fukuoka Japan
| | - Hajime Arahata
- Department of Neurology National Hospital Organization Omuta National Hospital Omuta Japan
| | - Shosaburo Yanamoto
- Department of Neurology Fukuoka University School of Medicine Fukuoka Japan
| | - Takayasu Mishima
- Department of Neurology Fukuoka University School of Medicine Fukuoka Japan
| | - Yoshio Tsuboi
- Department of Neurology Fukuoka University School of Medicine Fukuoka Japan
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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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Olanow CW, Poewe W, Rascol O, Stocchi F, Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA, Department of Neurology, Innsbruck Medical University, Innsbruck, Austria, Research Network Departments of Clinical Pharmacology and Neuroscience, Toulouse University Hospital, Toulouse, France, Department of Neurology, IRCCS San Raffaele Pisana, Rome, Italy. From OFF to ON—Treating OFF Episodes in Parkinson’s Disease. Neurology 2020. [DOI: 10.17925/usn.2020.16.suppl.1.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
In Parkinson’s disease (PD), OFF episodes continue to present a serious burden for patients, and their effective management remains a substantial unmet clinical need. Understanding of the pathophysiology of OFF episodes has advanced in recent years, providing valuable insights for improved treatments. OFF episodes generally appear 3–5 years after starting levodopa treatment, but can begin much earlier. They are characterized by motor symptoms (including tremor, rigidity, slowness, incoordination, and weakness) and are almost always associated with some non-motor symptoms (including psychological symptoms, pain, urinary problems, swallowing difficulties, and shortness of breath). In PD, higher doses of levodopa are associated with increased risk of motor and non-motor complications, which are notable limitations for longterm therapy. Their occurrence is associated with intermittent levodopa delivery and consequent fluctuating plasma levels. These issues can be offset using lower levodopa doses where possible, incremental dose increases, and combinations of levodopa with other pharmacological agents. OFF episodes in PD can be caused by gastroparesis and/or by Helicobacter pylori infection, which delays delivery of levodopa. These issues can be addressed using new formulations for continuous intrajejunal administration. In addition, pen injector, intranasal, and inhaled dosing systems have been studied and may provide relief via non-intestinal routes. Other approaches include deep-brain stimulation, which is effective but is restricted by costs and potential adverse events. This report presents the highlights of a satellite symposium held at the 14th International Conference on Alzheimer’s & Parkinson’s Diseases (AD/PD™ 2019), Lisbon, Portugal, which discussed the nature of OFF episodes in PD, associated risk factors and the potential of current and future treatments to effectively manage them and increase ON time.
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Cabreira V, Soares-da-Silva P, Massano J. Contemporary Options for the Management of Motor Complications in Parkinson's Disease: Updated Clinical Review. Drugs 2019; 79:593-608. [PMID: 30905034 DOI: 10.1007/s40265-019-01098-w] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Parkinson's disease (PD) is a chronic, progressive condition affecting around 1% of the population older than 60 years. Upon long-term treatment with levodopa, the mainstay of treatment in PD, most patients, especially younger ones exposed to higher doses, will experience symptoms related to end-of-dose deterioration, peak-dose dyskinesias, and other motor fluctuations. Therapeutic strategies are grounded on modification of oral levodopa pharmacokinetics to extend levodopa benefit and development of new routes of drug delivery (e.g., levodopa/carbidopa intestinal gel infusion) or long-acting formulations of existing dopaminergic drugs to prolong the duration of striatal dopamine receptors stimulation. As our understanding of the pathophysiology of motor complications evolves, our therapeutic armamentarium is actively expanding and the focus of research is now actively pointing to the new non-dopaminergic agents acting both within the basal ganglia and in other brain regions (e.g., drugs acting on glutamate, GABA, serotonin, and calcium channels). Despite the fact that trials comparing the different therapeutic strategies are lacking, we aimed at devising practical evidence- and experience-guided suggestions for the clinical management of motor complications, emphasizing that this should always be an individualized endeavor. This review summarizes the pharmacological management of motor complications in PD, including new formulations and routes of delivery, and the newer released drugs such as istradefylline, opicapone, safinamide, and zonisamide. Advanced therapeutic strategies for selected cases such as treatment with apomorphine and surgical techniques (deep brain stimulation) are also discussed. A comprehensive knowledge of the available options and evidence is fundamental for the successful management of these challenging complications.
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Affiliation(s)
- Verónica Cabreira
- Department of Neurology, Centro Hospitalar Universitário de S. João, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal.,Department of Clinical Neurosciences and Mental Health, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Patrício Soares-da-Silva
- Department of Biomedicine, Pharmacology and Therapeutics Unit, Faculty of Medicine, University of Porto, Porto, Portugal.,MedInUP, Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal.,Department of Research and Development, BIAL, Portela & Cª S.A., S. Mamede do Coronado, Portugal
| | - João Massano
- Department of Neurology, Centro Hospitalar Universitário de S. João, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal. .,Department of Clinical Neurosciences and Mental Health, Faculty of Medicine, University of Porto, Porto, Portugal.
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Gazerani P. Probiotics for Parkinson's Disease. Int J Mol Sci 2019; 20:E4121. [PMID: 31450864 PMCID: PMC6747430 DOI: 10.3390/ijms20174121] [Citation(s) in RCA: 99] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 08/14/2019] [Accepted: 08/21/2019] [Indexed: 02/08/2023] Open
Abstract
Parkinson's disease (PD) is a complex neurological disorder classically characterized by impairments in motor system function associated with loss of dopaminergic neurons in the substantia nigra. After almost 200 years since the first description of PD by James Parkinson, unraveling the complexity of PD continues to evolve. It is now recognized that an interplay between genetic and environmental factors influences a diverse range of cellular processes, reflecting on other clinical features including non-motor symptoms. This has consequently highlighted the extensive value of early clinical diagnosis to reduce difficulties of later stage management of PD. Advancement in understanding of PD has made remarkable progress in introducing new tools and strategies such as stem cell therapy and deep brain stimulation. A link between alterations in gut microbiota and PD has also opened a new line. Evidence exists of a bidirectional pathway between the gastrointestinal tract and the central nervous system. Probiotics, prebiotics and synbiotics are being examined that might influence gut-brain axis by altering gut microbiota composition, enteric nervous system, and CNS. This review provides status on use of probiotics for PD. Limitations and future directions will also be addressed to promote further research considering use of probiotics for PD.
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Affiliation(s)
- Parisa Gazerani
- Biomedicine: Department of Health Science and Technology, Faculty of Medicine, Aalborg University，Frederik Bajers Vej 3B, 9220 Aalborg East, Denmark.
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Luinstra M, Rutgers W, van Laar T, Grasmeijer F, Begeman A, Isufi V, Steenhuis L, Hagedoorn P, de Boer A, Frijlink HW. Pharmacokinetics and tolerability of inhaled levodopa from a new dry-powder inhaler in patients with Parkinson's disease. Ther Adv Chronic Dis 2019; 10:2040622319857617. [PMID: 31258882 PMCID: PMC6589987 DOI: 10.1177/2040622319857617] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 05/23/2019] [Indexed: 11/15/2022] Open
Abstract
Background Inhaled levodopa may quickly resolve off periods in Parkinson's disease. Our aim was to determine the pharmacokinetics and tolerability of a new levodopa dry-powder inhaler. Methods A single-centre, single-ascending, single-dose-response study was performed. Over three visits, eight Parkinson's disease patients (not in the 'off state') received by inhalation 30 mg or 60 mg levodopa, or their regular oral levodopa. Maximum levodopa plasma concentration (C max), time to maximum plasma concentration (Tmax) and area under the concentration time curve 0-180 min were determined. Spirometry was performed three times at each visit. Results After inhalation, levodopa T max occurred within 15 min in all participants, whereas after oral administration, T max ranged from 20 min to 90 min. The bioavailability of inhaled levodopa without carboxylase inhibitor was 53% relative to oral levodopa with carboxylase inhibitor. No change in lung-function parameters was observed and none of the patients experienced cough or dyspnoea. No correlation was observed between inhalation parameters and levodopa pharmacokinetic parameters. Conclusion Inhaled levodopa is well tolerated, absorbed faster than oral levodopa, and can be robustly administered over a range of inhalation flow profiles. It therefore appears suitable for the treatment of off periods in Parkinson's disease.
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Affiliation(s)
- Marianne Luinstra
- Department of Clinical Pharmacy, Martini Hospital Groningen, Groningen, The Netherlands
| | - Wijnand Rutgers
- Department of Neurology and Clinical Neurophysiology, Martini Hospital Groningen, Groningen, The Netherlands
| | - Teus van Laar
- Department of Neurology, University Medical Centre Groningen, Groningen, The Netherlands
| | - Floris Grasmeijer
- Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Antonius Deusinglaan 1, Groningen 9713 AV, The Netherlands
| | - Anja Begeman
- Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands
| | - Valmira Isufi
- Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands
| | - Luc Steenhuis
- Department of Pulmonary Diseases, Martini Hospital Groningen, Groningen, The Netherlands
| | - Paul Hagedoorn
- Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands
| | - Anne de Boer
- Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands
| | - Henderik W Frijlink
- Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands
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Chiang HL, Lin CH. Altered Gut Microbiome and Intestinal Pathology in Parkinson's Disease. J Mov Disord 2019; 12:67-83. [PMID: 31158941 PMCID: PMC6547039 DOI: 10.14802/jmd.18067] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Accepted: 02/20/2019] [Indexed: 12/12/2022] Open
Abstract
Parkinson's disease (PD) is a common neurodegenerative disorder arising from an interplay between genetic and environmental risk factors. Studies have suggested that the pathological hallmarks of intraneuronal α-synuclein aggregations may start from the olfactory bulb and the enteric nervous system of the gut and later propagate to the brain via the olfactory tract and the vagus nerve. This hypothesis correlates well with clinical symptoms, such as constipation, that may develop up to 20 years before the onset of PD motor symptoms. Recent interest in the gut-brain axis has led to vigorous research into the gastrointestinal pathology and gut microbiota changes in patients with PD. In this review, we provide current clinical and pathological evidence of gut involvement in PD by summarizing the changes in gut microbiota composition and gut inflammation associated with its pathogenesis.
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Affiliation(s)
- Han-Lin Chiang
- Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chin-Hsien Lin
- Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
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Quantitative MRI evaluation of gastric motility in patients with Parkinson's disease: Correlation of dyspeptic symptoms with volumetry and motility indices. PLoS One 2019; 14:e0216396. [PMID: 31050679 PMCID: PMC6499432 DOI: 10.1371/journal.pone.0216396] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Accepted: 04/20/2019] [Indexed: 12/12/2022] Open
Abstract
Objective To investigate the correlation between dyspeptic symptoms and gastric motility parameters measured by magnetic resonance imaging (MRI) using volumetry and motility indices in patients with Parkinson’s disease (PD). Materials and methods In this IRB-approved study, MRI datasets obtained from August 2014 to May 2016 in 38 PD patients were retrospectively analyzed. Patients underwent a 120-minute-long MRI study using a liquid test meal and 8 sets of scans. Gastric content volume (GCV) and total volume (TGV), gastric half emptying time (T1/2), motility index (GMI), accommodation (GA), and emptying (GE) values were acquired. These measurements were compared between patients according to the presence of gastric symptoms: early satiety (n = 25), epigastric pain (n = 13), and dyspepsia (n = 28). Results Patients with early satiety showed significantly decreased GE of GCV and TGV (p < 0.001 and p = 0.017). Dyspeptic patients had significantly decreased GE of GCV and GMI (p = 0.001 and p = 0.029). GE of GCV at 90 and 120 minutes were significantly lower in patients with early satiety (p = 0.001 and p = 0.002). GE of GCV and GMI at 90 minutes were significantly decreased in patients with dyspepsia (p = 0.004 and p = 0.002). T1/2 of GCV was prolonged in patients with early satiety, epigastric pain, and dyspepsia (p = 0.004, p = 0.041, and p = 0.023). T1/2 of TGV also delayed in patients with early satiety (p = 0.023). GMI at 90 minutes was significantly correlated with dyspepsia on multivariable analysis (p = 0.028). Conclusions Gastric motility can be quantitatively assessed by MRI, showing decreased GMI, delayed GE, and prolonged T1/2 in PD patients with early satiety or dyspepsia.
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Safety and Tolerability of Pharmacotherapies for Parkinson’s Disease in Geriatric Patients. Drugs Aging 2019; 36:511-530. [DOI: 10.1007/s40266-019-00654-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Doi H, Sakakibara R, Masuda M, Tateno F, Aiba Y, Kishi M, Yamanishi T, Yamamoto T, Matsuoka K. Gastrointestinal function in dementia with Lewy bodies: a comparison with Parkinson disease. Clin Auton Res 2019; 29:633-638. [PMID: 30741396 DOI: 10.1007/s10286-019-00597-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Accepted: 02/04/2019] [Indexed: 12/13/2022]
Abstract
PURPOSE To investigate gastrointestinal function in dementia with Lewy bodies and Parkinson disease. METHODS We examined gastric emptying and colonic transit time in 19 dementia with Lewy bodies and 46 Parkinson disease patients. RESULTS Gastric emptying was longer in dementia with Lewy bodies than in Parkinson disease (p = 0.014). Colonic transit time tended to be longer in dementia with Lewy bodies than in Parkinson disease. There was no relationship between gastric emptying and colonic transit time, nor between gastric emptying, colonic transit time and age. CONCLUSION Gastric emptying was prolonged in dementia with Lewy bodies compared to Parkinson disease.
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Affiliation(s)
- Hirokazu Doi
- Pharmaceutical Unit, Sakura Medical Center, Toho University, Sakura, Japan
| | - Ryuji Sakakibara
- Neurology, Internal Medicine, Sakura Medical Center, Toho University, 564-1 Shimoshizu, Sakura, 285-8741, Japan.
| | - Masayuki Masuda
- Pharmaceutical Unit, Sakura Medical Center, Toho University, Sakura, Japan
| | - Fuyuki Tateno
- Neurology, Internal Medicine, Sakura Medical Center, Toho University, 564-1 Shimoshizu, Sakura, 285-8741, Japan
| | - Yosuke Aiba
- Neurology, Internal Medicine, Sakura Medical Center, Toho University, 564-1 Shimoshizu, Sakura, 285-8741, Japan
| | - Masahiko Kishi
- Neurology, Internal Medicine, Sakura Medical Center, Toho University, 564-1 Shimoshizu, Sakura, 285-8741, Japan
| | | | | | - Katsuyoshi Matsuoka
- Gastroenterology, Internal Medicine, Sakura Medical Center, Toho University, Sakura, Japan
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Iwaki H, Sogo H, Morita H, Nishikawa N, Ando R, Miyaue N, Tada S, Yabe H, Nagai M, Nomoto M. Using Spontaneous Eye-blink Rates to Predict the Motor Status of Patients with Parkinson's Disease. Intern Med 2019; 58:1417-1421. [PMID: 31092772 PMCID: PMC6548932 DOI: 10.2169/internalmedicine.1960-18] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Objective Assessing daily motor fluctuations is an important part of the disease management for patients with Parkinson's disease (PD). However, the frequent recording of subjective and/or objective assessments is not always feasible, and easier monitoring methods have been sought. Previous studies have reported that the spontaneous eye-blink rate (EBR) is correlated with the dopamine levels in the brain. Thus, the continuous monitoring of the EBR may be useful for predicting the motor status in patients with PD. Methods Electrooculograms (EOGs) were recorded for up to 7.5 hours from three PD patients using a wearable device that resembled ordinary glasses. An receiver operating characteristic (ROC) analysis was performed to compare the ability of the EBR estimates at each time-point (Blink Index) and the plasma levodopa levels to predict the motor status. Results The Blink Index was correlated with the plasma levodopa levels. When an indicator for the first hour of the observation period was included in the model, the Blink Index discerned wearing-off and dyskinesia as accurately as the plasma levodopa level. Conclusion Our study provides preliminary evidence regarding the utility of continuous EBR monitoring for the non-invasive evaluation of the motor status in patients with PD.
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Affiliation(s)
- Hirotaka Iwaki
- Department of Neurology and Clinical Pharmacology, Ehime University Graduate School of Medicine, Japan
| | | | | | - Noriko Nishikawa
- Department of Neurology and Clinical Pharmacology, Ehime University Graduate School of Medicine, Japan
| | - Rina Ando
- Department of Neurology and Clinical Pharmacology, Ehime University Graduate School of Medicine, Japan
| | - Noriyuki Miyaue
- Department of Neurology and Clinical Pharmacology, Ehime University Graduate School of Medicine, Japan
| | - Satoshi Tada
- Department of Neurology and Clinical Pharmacology, Ehime University Graduate School of Medicine, Japan
| | - Hayato Yabe
- Department of Neurology and Clinical Pharmacology, Ehime University Graduate School of Medicine, Japan
| | - Masahiro Nagai
- Department of Neurology and Clinical Pharmacology, Ehime University Graduate School of Medicine, Japan
| | - Masahiro Nomoto
- Department of Neurology and Clinical Pharmacology, Ehime University Graduate School of Medicine, Japan
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Moshiree B, Potter M, Talley NJ. Epidemiology and Pathophysiology of Gastroparesis. Gastrointest Endosc Clin N Am 2019; 29:1-14. [PMID: 30396519 DOI: 10.1016/j.giec.2018.08.010] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Gastroparesis is a complex syndrome with symptoms that include nausea, vomiting, and postprandial abdominal pain, and is frequently accompanied by significant delays in gastric emptying. The pathophysiology of diabetic gastroparesis is fairly well understood; however, idiopathic gastroparesis, which accounts for one-third of all cases, may stem from infections, or autoimmune or neurologic disorders, among other causes. To date, few population-based studies have estimated the true prevalence and incidence of gastroparesis. Nonetheless, its prevalence appears to be rising, as does its incidence among minority populations, documented via hospitalizations, which can impose significant economic burdens on patients.
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Affiliation(s)
- Baha Moshiree
- Division of Gastroenterology, University of North Carolina, 1025 Morehead Medical Drive Suite 300, Charlotte, NC 28204, USA; Atrium Health, Carolinas HealthCare System, Digestive Health-Morehead Medical Plaza, 1025 Morehead Medical Drive, Suite 300, Charlotte, NC 28204, USA.
| | - Michael Potter
- Department of Gastroenterology, University of Newcastle, HMRI Building, Kookaburra Circuit, New Lambton Heights, New South Wales 2305, Australia; Department of Gastroenterology, John Hunter Hospital, Lookout Road, New Lambton Heights, New South Wales 2305, Australia
| | - Nicholas J Talley
- Global Research, Digestive and Health Neurogastroenterology, New Lambton, NSW 2305, Australia
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Fang X. Microbial treatment: the potential application for Parkinson's disease. Neurol Sci 2018; 40:51-58. [PMID: 30415447 DOI: 10.1007/s10072-018-3641-6] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 11/07/2018] [Indexed: 02/07/2023]
Abstract
Alterations in the composition of the intestinal flora are associated with the pathophysiology of Parkinson's disease (PD). More importantly, the possible cause-effect links between gut flora and PD pathogenesis have been identified using PD animal models. Recent studies have found that probiotics improve the symptoms associated with constipation in PD patients. In addition, fecal microbiota transplantation (FMT) was recently shown to provide a protective effect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in mice. Effective microbial therapy for PD includes probiotics and FMT. Therefore, microbial therapy may be a useful and novel approach for treatment of PD. In this review, I discuss the use of microbial treatment in PD.
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Affiliation(s)
- Xin Fang
- Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China.
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Parkinson's Disease and Current Treatments for Its Gastrointestinal Neurogastromotility Effects. ACTA ACUST UNITED AC 2018; 16:489-510. [PMID: 30361854 DOI: 10.1007/s11938-018-0201-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE OF REVIEW Gastrointestinal disturbances are seen in nearly all patients with Parkinson's disease and lead to impaired quality of life, affect drug pharmacodynamics, and potentially worsen patient's existing motor fluctuations, leading to further disability. Recent evidence links abnormal accumulations of α-synuclein aggregates in the periphery (gut) as seen in the cortex which causes dysfunctions impacting every level of the gastrointestinal tract from the esophagus, to the stomach, small bowel, colon, and rectum and can even predate the onset of the central neurologic disorder itself. Many treatments exist for the clinical phenotypes that result from the autonomic dysfunction and neuropathy involved in this neurodegenerative disorder. The treatments for the gut dysfunction seen in Parkinson's disease (PD) depend on the specific area of the gastrointestinal tract affected. For dysphagia, behavioral therapies with speech pathology, neuromuscular electrical stimulation, or botulinum toxin injection may be helpful. For gastroparesis, domperidone may serve as an antiemetic while also blunting the hypotensive potential of Levodopa while new treatments such as ghrelin agonists may prove beneficial to help appetite, satiety, gastric emptying in those with constipation, and even improve constipation. Antibiotics such as rifaximin with poor systemic absorption may be used to treat small bacterial overgrowth also found in those with PD while the benefits of probiotics is yet to be determined. Finally, constipation in PD can be a reflection of pelvic floor dyssynergia, slow transit constipation, or both, thus treatments targeting the specific anorectal dysfunction is necessary for better outcomes.
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Perez-Pardo P, Broersen LM, Kliest T, van Wijk N, Attali A, Garssen J, Kraneveld AD. Additive Effects of Levodopa and a Neurorestorative Diet in a Mouse Model of Parkinson's Disease. Front Aging Neurosci 2018; 10:237. [PMID: 30127735 PMCID: PMC6088190 DOI: 10.3389/fnagi.2018.00237] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Accepted: 07/19/2018] [Indexed: 12/03/2022] Open
Abstract
Though Parkinson’s disease (PD) clinical picture is generally dominated by motor impairment, non-motor symptoms, such as cognitive decline and gastrointestinal dysfunctions, may develop before motor symptoms and have major effects on quality of life. L-3,4-di-hydroxy-phenylalanine (Levodopa) is the most commonly used treatment of motor symptoms but has serious side-effects with prolonged use and does not stop the degenerative process. Moreover, gastrointestinal dysfunctions interfere with the absorption of levodopa and modify its effectiveness. Since most patients are on levodopa treatment, there is a need for combinational therapies that allow for an effective reduction of both motor and non-motor symptoms. We have recently shown that a diet containing precursors and cofactors required for membrane phospholipid synthesis, as well as prebiotic fibers, had therapeutic effects in a PD mouse model. We now investigate the effects of combined administration of the same diet together with levodopa in the rotenone model of PD. Mice were injected with rotenone or vehicle in the striatum. The dietary intervention started after full induction of motor symptoms. The effects of dietary intervention and oral treatment with different doses of levodopa were assessed weekly. Motor and cognitive functions were tested, intestinal transit was analyzed and histological examination of the brain and the colon was assessed. Our results confirm our previous findings that rotenone-induced motor and non-motor problems were alleviated by the Active diet (AD). Levodopa showed an additive beneficial effect on rotarod performance in rotenone-treated animals fed with the AD. No negative interaction effects were found between the AD and levodopa. Our findings suggest that the dietary intervention might confer additional clinical benefits on patients receiving levodopa treatment.
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Affiliation(s)
- Paula Perez-Pardo
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands
| | - Laus M Broersen
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands.,Nutricia Research, Utrecht, Netherlands
| | - Tessa Kliest
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands
| | | | | | - Johan Garssen
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands.,Nutricia Research, Utrecht, Netherlands
| | - Aletta D Kraneveld
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands
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Knudsen K, Szwebs M, Hansen AK, Borghammer P. Gastric emptying in Parkinson's disease - A mini-review. Parkinsonism Relat Disord 2018; 55:18-25. [PMID: 29891432 DOI: 10.1016/j.parkreldis.2018.06.003] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 04/30/2018] [Accepted: 06/03/2018] [Indexed: 02/06/2023]
Abstract
Patients with Parkinson's disease (PD) experience a range of non-motor symptoms, including constipation and other gastrointestinal problems. These symptoms are sometimes present in the prodromal disease phase. An improved understanding of the underlying pathophysiology is needed considering that PD has been hypothesized to originate in the gut. Delayed gastric emptying time (GET) is often listed as a prevalent gastrointestinal symptom in PD, but the true prevalence is controversial. The aim of this short review was to investigate if GET in PD is dependent on the applied measuring methodology. A systemic search of Pubmed identified 15 relevant studies, including six using gold standard method gastric scintigraphy and nine using 13C-octanoate breath tests. Overall, gastric scintigraphy studies showed a non-significant GET delay (standardized mean difference (SMD) 0.42) in PD patients. After exclusion of one outlier study, GET was significantly increased (SMD 0.59). In contrast, highly significant GET delay (SMD 1.70) was seen in breath test studies. A limitation of the meta-analyses was reuse of the same control group in some studies. In summary, the marked GET delay observed in breath test studies is not confirmed by gold standard gastric scintigraphy studies. This discrepancy can perhaps be explained by breath test being an indirect GET measure, depending not only on mechanic stomach emptying but also intestinal absorption and liver metabolism. Thus, multi-modality studies under standardized conditions are needed to elucidate the prevalence and severity of gastric dysmotility in PD, along with contributions from other factors including intestinal absorption and permeability.
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Affiliation(s)
- Karoline Knudsen
- Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark.
| | - Martha Szwebs
- Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark
| | - Allan K Hansen
- Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark
| | - Per Borghammer
- Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark
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