Gastrointestinal dysfunction in Parkinson's disease

Pfeiffer, Ronald F.

doi:10.1016/s1474-4422(03)00307-7

Cited by 680 publications

(354 citation statements)

References 115 publications

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“…Weight loss is a common feature among PD patients (6,7). Although the cause is still debated, gastrointestinal dysfunction had been suggested due to the often-occurring degeneration of the enteric nervous system during disease progression (30). It is plausible, however, that the diminished DA innervation to the CPu is the cause for the weight loss, because patients with subthalamic deep-brain stimulation gain weight after onset of treatment (31,32).…”

Section: Molecular Changes In Basal Ganglia Of En Ht Micementioning

confidence: 99%

Slow progressive degeneration of nigral dopaminergic neurons in postnatal Engrailed mutant mice

Sgadò

Albèri

Gherbassi

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

133

132

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The homeobox transcription factors Engrailed-1 and Engrailed-2 are required for the survival of mesencephalic dopaminergic neurons in a cell-autonomous and gene-dose-dependent manner. Because of this requirement, the cells die by apoptosis when all four alleles of the Engrailed genes are genetically ablated (En1؊͞؊; En2؊͞؊). In the present study, we show that viable and fertile mice, heterozygous null for Engrailed-1 and homozygous null for Engrailed-2 (En1؉͞؊;En2؊͞؊), have an adult phenotype that resembles key pathological features of Parkinson's disease. Specifically, postnatal mutant mice exhibit a progressive degeneration of dopaminergic neurons in the substantia nigra during the first 3 mo of their lives, leading to diminished storage and release of dopamine in the caudate putamen, motor deficits similar to akinesia and bradykinesia, and a lower body weight. This genetic model may provide access to the molecular etiology for Parkinson's disease and could assist in the development of novel treatments for this neurodegenerative disorder.dopamine ͉ midbrain ͉ mouse mutant ͉ neurodegenerative disease ͉ substantia nigra M esencephalic dopaminergic (mesDA) neurons are the main source of dopamine in the mammalian central nervous system (1). They are located in three distinct nuclei, the substantia nigra pars compacta (SN), the ventral tegmentum (VTA), and the retrorubral field (RRF). Their main innervation targets are the basal ganglia, where they play a major role in controlling emotion, motivation, and motor behavior (2, 3), recognized by their involvement in schizophrenia, addiction, and most prominently in Parkinson's disease (PD; ref. 4). PD is a multisystemic degenerative disorder of the central and peripheral nervous systems. Its hallmark is the progressive degeneration of DA neurons in the SN. The clinical symptoms are resting tremor; muscular rigidity; postural instability; hyposomia; a positive response to the application of L-3,4-dihydroxyphenylalanine (L-DOPA); and the presence of cytoplasmatic inclusions (Lewy bodies) in postmortem brains (5). Additionally, PD patients are often characterized by weight loss starting before diagnosis and continuing with disease progression (6, 7).The homeodomain transcription factors Engrailed-1 and -2 (En1 and En2) are expressed by all mesDA neurons soon after differentiation and then continuously into adulthood. They are cell-autonomously and in a gene-dose-dependent manner required for the survival of this neuronal population, leading to the complete loss of the cells in mutant mice homozygous null for both genes (En1Ϫ͞Ϫ;En2Ϫ͞Ϫ; refs. 8 and 9). In their function as survival factors for mesDA neurons, the two genes are redundant and can compensate for each other (9, 10). The single-null mutants for either En1 (En1Ϫ͞Ϫ) or En2 (En2Ϫ͞Ϫ) show no significant alterations in the organization of the mesDA system at birth, but the mice with genotypes intermediate to the single and double mutants are distinctively different from each other. Whereas En1Ϫ͞Ϫ;En2ϩ͞Ϫ mice die at po...

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Section: Molecular Changes In Basal Ganglia Of En Ht Micementioning

confidence: 99%

Slow progressive degeneration of nigral dopaminergic neurons in postnatal Engrailed mutant mice

Sgadò

Albèri

Gherbassi

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

133

132

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“…Except for motor features of PD subjects, the non-motor symptoms, in some cases, can dominate the clinical picture. Among the most seen non-motor feature is gastrointestinal dysfunction which manifests in many ways and pose many problems [21]. PD patients due to their disease tend to have lower levels of body weight, fat mass and circumferential measures than the matched control subjects.…”

Section: Discussionmentioning

confidence: 99%

Bioelectrical Impedance Vector Analysis (BIVA) in Slovak population: application in a clinical sample

et al. 2013

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The purpose of this study is to provide new data on body composition in the Slovak population, particularly impedance vector components according to sex and age, relevant for bioelectrical impedance vector analysis (BIVA) in a clinical sample. The reference sample consisted of 1543 apparently healthy individuals (1007 females and 536 males), aged from 18 to 92 years and of 60 patients with Parkinson’s disease (PD) (26 females and 34 males), aged from 40 to 81 years. Bioelectrical parameters of resistance (R) and reactance (Xc) were measured with a monofrequency analyser (BIA 101). BIVA was used to analyse tissue electric properties in control subjects and patients with PD. The mean vector position differed significantly between PD patients and healthy controls in males of age subgroups 60–69 years and 70–79 years, respectively. These results were conterminous with significant Hotelling’s T2-test; 60–69 y T2=7.8, P=0.024 and 70–79 y T2=7.6, P=0.026. In the RXc-score graph three patients had values outside the 95% ellipse. Altered tissue electric properties were present in 23.5% of males and 15.4% of females. Distribution of impedance vector components in different age categories of healthy Slovak subjects are relevant to comparative population studies and to clinical practice.

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“…27 Gastroparesis (delayed emptying of the stomach) is a common GI problem in patients with PD at both early and late disease stages and may be one of the underlying causes of delayed TTO. 27,28 Impaired intestinal absorption may also be a contributing factor as amino acids in dietary proteins can compete with levodopa for intestinal absorption and transport across the blood-brain barrier, thus limiting its efficacy. 29 However, since protein is not typically present on awakening, morning akinesia is most probably due to gastroparesis resulting in delayed gastric emptying of the dose of levodopa.…”

Section: Professor Isaacson Went On To Consider the Reasons Underlyinmentioning

confidence: 99%

Twenty Years of Apomorphine Therapy – How Does it Compare with Levodopa?

Lees¹,

Isaacson²

2015

European Neurological Review

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Apomorphine administered subcutaneously has provided clinicians with an effective option for the rapid resolution of the symptoms of Parkinson's disease (PD) for over a quarter of a century. It is available for use either as an intermittent injection or a continuous infusion, depending on the severity of the patient's symptoms. This satellite symposium, held during the 18th International Congress of Parkinson's Disease and Movement Disorders in Stockholm, Sweden, from 8-12 June 2014, and chaired by Professor Andrew Lees, set out to review the extensive clinical experience of subcutaneous apomorphine in the management of PD accumulated over the past 25 years. It also aimed to explore why it continues to play such a valuable therapeutic role in this setting. The presenters highlighted key clinical data demonstrating why apomorphine is an effective choice for the management of both motor and non-motor symptoms in PD. Results from the limited number of comparative studies of apomorphine continuous infusion with other therapies for complex PD suggest that it has a robust motor effect, resulting in a reduction of OFF periods comparable to that achieved with more invasive options such as intrajejunal levodopa infusion or deep brain stimulation. In a large European study, apomorphine infusion has been shown to provide similar improvements in health-related quality of life to intrajejunal levodopa infusion but with a superior side-effect profile. In addition, apomorphine infusion has demonstrated beneficial non-motor effects in PD patients and reports suggest it is associated with low rates of impulse control disorders (ICDs). The motor fluctuations that occur over time in PD patients treated with oral levodopa present a management challenge as the disease progresses. Many PD patients experience these OFF periods despite optimised oral therapy and the use of multiple medications. They are due to both end-of-dose wearing OFF and delayed time to ON (TTO). A prolonged TTO is common in PD patients who have gastroparesis (delayed gastric emptying) whereby the levodopa dose is delayed exiting the stomach and is slow in reaching its site of absorption in the small intestine. Alternative non-oral formulations that avoid the gastrointestinal route, such as subcutaneous apomorphine intermittent injection, have therefore been investigated for the relief of motor fluctuations in this setting. Interim results from the ongoing Apokyn for Motor IMProvement of Morning AKinesia Trial (AM IMPAKT) study have shown that subcutaneous apomorphine injection is a valuable treatment option in PD patients with morning akinesia. This is due to a delayed onset of levodopa dose as it produces a rapid and reliable TTO, with 95 % of patients achieving at least a 20-minute reduction in TTO and an average reduction of 40 minutes. Patients also experienced improvements in Unified Parkinson's Disease Rating Scale (UPDRS) motor score and Hoehn and Yahr stage, as well as measures of quality of life and global impression of severity.

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Gastrointestinal dysfunction in Parkinson's disease

Cited by 680 publications

References 115 publications

Slow progressive degeneration of nigral dopaminergic neurons in postnatal Engrailed mutant mice

Slow progressive degeneration of nigral dopaminergic neurons in postnatal Engrailed mutant mice

Bioelectrical Impedance Vector Analysis (BIVA) in Slovak population: application in a clinical sample

Twenty Years of Apomorphine Therapy – How Does it Compare with Levodopa?

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