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Current Opinion in Neurology Aug 2014Later stage Parkinson's disease, sometimes referred to as advanced disease, has been characterized by motor complication, as well as by the potential emergence of... (Review)
Review
PURPOSE OF REVIEW
Later stage Parkinson's disease, sometimes referred to as advanced disease, has been characterized by motor complication, as well as by the potential emergence of nonlevodopa responsive motor and nonmotor symptoms. The management of advanced stage Parkinson's disease can be complex. This review summarizes the currently available treatment strategies for addressing advanced Parkinson's disease.
RECENT FINDINGS
We will discuss the latest pharmacological strategies (e.g., inhibitors of dopamine-metabolizing enzymes, dopamine agonists, and extended release dopamine formulations) for addressing motor dysfunction. We will summarize the risks and benefits of current invasive treatments. Finally, we will address the current evidence supporting the treatment of nonmotor symptoms in the advanced Parkinson's disease patient. We will conclude by detailing the potential nonpharmacological and multidisciplinary approaches for advanced stage Parkinson's disease.
SUMMARY
The optimization of levodopa is, in most cases, the most powerful therapeutic option available; however, medication optimization requires an advanced understanding of Parkinson's disease. Failure of conventional pharmacotherapy should precipitate a discussion of the potential risks and benefits of more invasive treatments. Currently, there are no comparative studies of invasive treatment. Among the invasive treatments, deep brain stimulation has the largest amount of existing evidence, but also has the highest individual per patient risk. Nonmotor symptoms will affect quality of life more than the motor Parkinson's disease symptoms, and these nonmotor symptoms should be aggressively treated. Many advanced Parkinson's disease patients will likely benefit from multi and interdisciplinary Parkinson's disease teams with multiple professionals collaborating to develop a collective and tailored strategy for an individual patient.
Topics: Antiparkinson Agents; Humans; Levodopa; Parkinson Disease
PubMed: 24978634
DOI: 10.1097/WCO.0000000000000118 -
Biosensors Feb 2022Levodopa (L-Dopa) is considered to be one of the most effective therapies available for Parkinson's disease (PD) treatment. The therapeutic window of L-Dopa is narrow...
Levodopa (L-Dopa) is considered to be one of the most effective therapies available for Parkinson's disease (PD) treatment. The therapeutic window of L-Dopa is narrow due to its short half-life, and long-time L-Dopa treatment will cause some side effects such as dyskinesias, psychosis, and orthostatic hypotension. Therefore, it is of great significance to monitor the dynamic concentration of L-Dopa for PD patients with wearable biosensors to reduce the risk of complications. However, the high concentration of interferents in the body brings great challenges to the in vivo monitoring of L-Dopa. To address this issue, we proposed a minimal-invasive L-Dopa biosensor based on a flexible differential microneedle array (FDMA). One working electrode responded to L-Dopa and interfering substances, while the other working electrode only responded to electroactive interferences. The differential current response of these two electrodes was related to the concentration of L-Dopa by eliminating the common mode interference. The differential structure provided the sensor with excellent anti-interference performance and improved the sensor's accuracy. This novel flexible microneedle sensor exhibited favorable analytical performance of a wide linear dynamic range (0-20 μM), high sensitivity (12.618 nA μM cm) as well as long-term stability (two weeks). Ultimately, the L-Dopa sensor displayed a fast response to in vivo L-Dopa dynamically with considerable anti-interference ability. All these attractive performances indicated the feasibility of this FDMA for minimal invasive and continuous monitoring of L-Dopa dynamic concentration for Parkinson's disease.
Topics: Biosensing Techniques; Electrodes; Humans; Levodopa; Parkinson Disease; Wearable Electronic Devices
PubMed: 35200363
DOI: 10.3390/bios12020102 -
Movement Disorders : Official Journal... Jan 2015Levodopa (L-dopa) has been at the forefront of antiparkinsonian therapy for a half century. Recent advances in functional brain imaging have contributed substantially to... (Review)
Review
Levodopa (L-dopa) has been at the forefront of antiparkinsonian therapy for a half century. Recent advances in functional brain imaging have contributed substantially to the understanding of the effects of L-dopa and other dopaminergic treatment on the activity of abnormal motor and cognitive brain circuits in Parkinson's disease patients. Progress has also been made in understanding the functional pathology of dyskinesias, a common side effect of l-dopa treatment, at both regional and network levels. Here, we review these studies, focusing mainly on the new mechanistic insights provided by metabolic brain imaging and network analysis.
Topics: Animals; Antiparkinson Agents; Cerebral Cortex; Cognition Disorders; Humans; Levodopa; Neuroimaging; Parkinson Disease; Regional Blood Flow
PubMed: 25296957
DOI: 10.1002/mds.26041 -
Scientific Reports Jun 2015Mucuna pruriens is the best known natural source of L-dopa, the gold standard for treatment of Parkinsonism. M. pruriens varieties are protein rich supplements, and are...
Mucuna pruriens is the best known natural source of L-dopa, the gold standard for treatment of Parkinsonism. M. pruriens varieties are protein rich supplements, and are used as food and fodder worldwide. Here, we report L-dopa contents in seeds of fifty six accessions of four M. pruriens varieties, M. pruriens var. pruriens, M. pruriens var. hirsuta, M. pruriens var. utilis and M. pruriens var. thekkadiensis, quantified by HPTLC-densitometry. L-dopa contents varied between 0.58 to 6.42 (%, dr. wt.). High and low L-dopa yielding genotypes/chemotypes of M. pruriens could be multiplied for medicinal and nutritional purposes, respectively. HPTLC profiles of M. pruriens seeds on repeated extraction (24 h) in 1:1 formic acid-alcohol followed by development in butanol:acetic acid:water (4:1:1, v/v) showed consistent degradation of L-dopa (Rf 0.34 ± 0.02) into a second peak (Rf 0.41 ± 0.02). An average of 52.11% degradation of L-dopa was found in seeds of M. pruriens varieties. Since M. pruriens seeds and/or L-dopa are used for treatment of Parkinson's disease and as an aphrodisiac both in modern and/or traditional systems of medicine, the finding of high level of L-dopa degradation (in pure form and in M. pruriens extracts) into damaging quinones and ROS is very significant.
Topics: Biodegradation, Environmental; Chromatography, Thin Layer; Hydrolysis; Levodopa; Mucuna
PubMed: 26058043
DOI: 10.1038/srep11078 -
BMC Medicine Oct 2022Parkinson's disease (PD) is the second most common neurodegenerative disease in middle-aged and elderly populations, whereas there is no cure for PD so far. Novel animal...
BACKGROUND
Parkinson's disease (PD) is the second most common neurodegenerative disease in middle-aged and elderly populations, whereas there is no cure for PD so far. Novel animal models and medications await development to elucidate the aetiology of PD and attenuate the symptoms, respectively.
METHODS
A neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), was used in the current study to establish a PD pathologic model in silkworms. The time required to complete specific behaviours was recorded. Dopamine content was detected by ultra-performance liquid chromatography (UPLC). The activity of insect tyrosine hydroxylase (TH) was determined using a double-antibody sandwich method. Oxidative stress was assessed by changes in antioxidant enzyme activity and the content of oxidative products.
RESULTS
MPTP-treated silkworms were characterized by impaired motor ability, reduced dopamine content, and elevated oxidative stress level. The expression of TH, a dopamine biosynthetic enzyme within dopaminergic neurons in the brain, was significantly reduced, indicating that dopaminergic neurons were damaged. Moreover, MPTP-induced motility impairment and reduced dopamine level in the silkworm PD model could be rescued after feeding a combination of levodopa (L-dopa [LD]) and carbidopa (CD). MPTP-induced oxidative damage was also alleviated, in ways consistent with other PD animal models. Interestingly, administration of Lycium barbarum polysaccharide (LBP) improved the motor ability, dopamine level, and TH activity, and the oxidative damage was concomitantly reduced in the silkworm PD model.
CONCLUSIONS
This study provides a promising animal model for elucidating the pathogenesis of PD, as well as a relevant preliminary drug screening (e.g., LBP) and evaluation.
Topics: Animals; Mice; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Antioxidants; Disease Models, Animal; Dopamine; Levodopa; Mice, Inbred C57BL; Tyrosine 3-Monooxygenase; Parkinson Disease, Secondary; Drugs, Chinese Herbal
PubMed: 36303171
DOI: 10.1186/s12916-022-02621-9 -
NeuroImage Apr 2023Humans learn through reinforcement, particularly when outcomes are unexpected. Recent research suggests similar mechanisms drive how we learn to benefit other people,... (Randomized Controlled Trial)
Randomized Controlled Trial
Humans learn through reinforcement, particularly when outcomes are unexpected. Recent research suggests similar mechanisms drive how we learn to benefit other people, that is, how we learn to be prosocial. Yet the neurochemical mechanisms underlying such prosocial computations remain poorly understood. Here, we investigated whether pharmacological manipulation of oxytocin and dopamine influence the neurocomputational mechanisms underlying self-benefitting and prosocial reinforcement learning. Using a double-blind placebo-controlled cross-over design, we administered intranasal oxytocin (24 IU), dopamine precursor l-DOPA (100 mg + 25 mg carbidopa), or placebo over three sessions. Participants performed a probabilistic reinforcement learning task with potential rewards for themselves, another participant, or no one, during functional magnetic resonance imaging. Computational models of reinforcement learning were used to calculate prediction errors (PEs) and learning rates. Participants behavior was best explained by a model with different learning rates for each recipient, but these were unaffected by either drug. On the neural level, however, both drugs blunted PE signaling in the ventral striatum and led to negative signaling of PEs in the anterior mid-cingulate cortex, dorsolateral prefrontal cortex, inferior parietal gyrus, and precentral gyrus, compared to placebo, and regardless of recipient. Oxytocin (versus placebo) administration was additionally associated with opposing tracking of self-benefitting versus prosocial PEs in dorsal anterior cingulate cortex, insula and superior temporal gyrus. These findings suggest that both l-DOPA and oxytocin induce a context-independent shift from positive towards negative tracking of PEs during learning. Moreover, oxytocin may have opposing effects on PE signaling when learning to benefit oneself versus another.
Topics: Humans; Dopamine; Learning; Levodopa; Magnetic Resonance Imaging; Oxytocin; Reinforcement, Psychology; Reward
PubMed: 36848972
DOI: 10.1016/j.neuroimage.2023.119983 -
Journal of Nuclear Medicine : Official... Jul 2021Congenital hyperinsulinism is characterized by persistent hypoglycemia due to inappropriate excess secretion of insulin resulting in hyperinsulinemic hypoglycemia. The...
Congenital hyperinsulinism is characterized by persistent hypoglycemia due to inappropriate excess secretion of insulin resulting in hyperinsulinemic hypoglycemia. The clinical course varies from mild to severe, with a significant risk for brain damage. Imaging plays a valuable role in the care of infants and children with severe hypoglycemia unresponsive to medical therapy. F-6-fluoro-l-dopa PET/CT is the method of choice for the detection and localization of a focal lesion of hyperinsulinism. Surgical resection of a focal lesion can lead to a cure with limited pancreatectomy. This article reviews the role of F-6-fluoro-l-dopa PET/CT in the management of this vulnerable population.
Topics: Congenital Hyperinsulinism; Humans; Infant; Levodopa; Positron Emission Tomography Computed Tomography
PubMed: 34230074
DOI: 10.2967/jnumed.120.246033 -
The American Journal of Medicine Jan 2021Age-related macular degeneration (AMD) is a common cause of blindness worldwide. Neovascular AMD (nAMD) is an advanced form of the disease, in which excess vascular...
BACKGROUND
Age-related macular degeneration (AMD) is a common cause of blindness worldwide. Neovascular AMD (nAMD) is an advanced form of the disease, in which excess vascular endothelial growth factor (VEGF) induces growth of new blood vessels that leak fluid, accounting for 90% of vision loss in AMD. Dysfunction of the retinal pigment epithelium likely initiates AMD. Retinal pigment epithelial cells express a G protein-coupled receptor, GPR143, which downregulates VEGF in response to levodopa. Anti-VEGF therapy effectively treats nAMD, suggesting that excessive VEGF activity drives the pathology.
METHODS
In an open-label pilot study, in patients with newly diagnosed nAMD and naïve to anti-VEGF injections (Cohort-1), the effects of carbidopa-levodopa on vision and anatomic outcomes were evaluated for 4 weeks. Then patients were followed 5 months further with ascending levodopa doses. Patients previously treated with anti-VEGF injection therapy (Cohort-2) were also treated with ascending levodopa doses and evaluated for 6 months.
RESULTS
Levodopa was safe, well tolerated, and delayed anti-VEGF injection therapy while improving visual outcomes. In the first month, retinal fluid decreased by 29% (P = .02, n = 12) without anti-VEGF treatment. Through 6 months the decrease in retinal fluid was sustained, with a mean frequency of 0.38 injections/month. At month 6, mean visual acuity improved by 4.7 letters in Cohort-1 (P = .004, n = 15) and by 4.8 letters in Cohort-2 (P = .02, n = 11). Additionally, there was a 52% reduction in the need for anti-VEGF injections in Cohort-2 (P = .002).
CONCLUSIONS
Our findings suggest efficacy and support the pharmacological targeting of GPR143 with levodopa for the treatment of nAMD in future studies.
Topics: Aged; Aged, 80 and over; Carbidopa; Cohort Studies; Dopamine Agents; Drug Combinations; Female; Humans; Levodopa; Macular Degeneration; Male; Middle Aged; Pilot Projects; Treatment Outcome
PubMed: 32628915
DOI: 10.1016/j.amjmed.2020.05.038 -
Cell Metabolism Aug 2019Levodopa (L-dopa) is the primary treatment for Parkinson's disease. The gut microbiome can metabolize levodopa, potentially leading to decreased efficacy and side...
Levodopa (L-dopa) is the primary treatment for Parkinson's disease. The gut microbiome can metabolize levodopa, potentially leading to decreased efficacy and side effects, but responsible bacteria were unknown. Maini Rekdal et al. (2019) characterize enzymes in two gut bacteria that sequentially metabolize L-dopa and identify a novel inhibitor that may improve outcomes.
Topics: Bacteria; Gastrointestinal Microbiome; Humans; Levodopa; Parkinson Disease
PubMed: 31390549
DOI: 10.1016/j.cmet.2019.07.005 -
Brain and Behavior Feb 2018The typical clinical presentation of dopa-responsive dystonia, which is also called Segawa disease, is a young age of onset, with predominance in females, diurnal... (Review)
Review
The typical clinical presentation of dopa-responsive dystonia, which is also called Segawa disease, is a young age of onset, with predominance in females, diurnal fluctuation of lower limb dystonia, and fair response to low-dose levodopa. This disease has both autosomal dominant and autosomal recessive inheritance. Autosomal dominant Segawa disease is caused by mutation on chromosome 14q22.1-q22.2. Here, we report the case of a male patient with genetically confirmed Segawa disease and atypical presentations including no diurnal symptom fluctuation and insufficient response to levodopa. The patient's father who had the same mutation presented parkinsonism in old age. We also review the literature to address the broad clinical heterogeneity of Segawa disease and the influence of onset age on clinical presentation.
Topics: Adult; Age of Onset; Botulinum Toxins, Type A; Dopamine Agents; Drug Resistance; Dystonic Disorders; GTP Cyclohydrolase; Humans; Levodopa; Male; Mutation; Neuromuscular Agents; Parkinson Disease; Pedigree; Taiwan; Treatment Outcome
PubMed: 29484265
DOI: 10.1002/brb3.906