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Movement Disorders : Official Journal... Jun 2024Among the different types of pain related to Parkinson's disease (PD), parkinsonian central pain (PCP) is the most disabling.
BACKGROUND
Among the different types of pain related to Parkinson's disease (PD), parkinsonian central pain (PCP) is the most disabling.
OBJECTIVES
We investigated the analgesic efficacy of two therapeutic strategies (opioid with oxycodone- prolonged-release (PR) and higher dose of levodopa/benserazide) compared with placebo in patients with PCP.
METHODS
OXYDOPA was a randomized, double-blind, double-dummy, placebo-controlled, multicenter parallel-group trial run at 15 centers within the French NS-Park network. PD patients with PCP (≥30 on the Visual Analogue Scale [VAS]) were randomly assigned to receive oxycodone-PR (up to 40 mg/day), levodopa/benserazide (up to 200 mg/day) or matching placebo three times a day (tid) for 8 weeks at a stable dose, in add-on to their current dopaminergic therapy. The primary endpoint was the change in average pain intensity over the previous week rated on VAS from baseline to week-10 based on modified intention-to-treat analyses.
RESULTS
Between May 2016 and August 2020, 66 patients were randomized to oxycodone-PR (n = 23), levodopa/benserazide (n = 20) or placebo (n = 23). The mean change in pain intensity was -17 ± 18.5 on oxycodone-PR, -8.3 ± 11.1 on levodopa/benserazide, and -14.3 ± 18.9 in the placebo groups. The absolute difference versus placebo was -1.54 (97.5% confidence interval [CI], -17.0 to 13.90; P = 0.8) on oxycodone-PR and +7.79 (97.5% CI, -4.99 to 20.58; P = 0.2) on levodopa/benserazide. Similar proportions of patients in each group experienced all-cause adverse events. Those leading to study discontinuation were most frequently observed with oxycodone-PR (39%) than levodopa/benserazide (5%) or placebo (15%).
CONCLUSIONS
The present trial failed to demonstrate the superiority of oxycodone-PR or a higher dose of levodopa in patients with PCP, while oxycodone-PR was poorly tolerated. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
PubMed: 38850081
DOI: 10.1002/mds.29878 -
Journal of Parkinson's Disease May 2024Parkinson's disease (PD) is characterized by striatal dopamine deficiency. Since dopamine cannot cross the digestive and blood-brain barriers, its precursor, levodopa... (Review)
Review
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.
PubMed: 38848195
DOI: 10.3233/JPD-230372 -
Physiology and Molecular Biology of... May 2024Faba bean ( L.) is a winter season grain legume and a rich source of the anti-parkinson drug, L-3,4-dihydroxyphenylalanine (L-DOPA). The biosynthesis of L-DOPA in plants...
UNLABELLED
Faba bean ( L.) is a winter season grain legume and a rich source of the anti-parkinson drug, L-3,4-dihydroxyphenylalanine (L-DOPA). The biosynthesis of L-DOPA in plants is not uniform and remains largely unexplored. While the hydroxylase activities of Tyrosine Hydroxylase (TH), the Cytochrome P450 (CYP450) class of enzymes, and Polyphenol Oxidases (PPOs) on tyrosine substrate have been reported in plants, only the roles of PPOs in L-DOPA biosynthesis have been recently established in velvet bean (). To understand the differential accumulation of L-DOPA in different tissues of faba bean, profiling of L-Tyrosine, L-DOPA, Tyramine, and Dopamine in different tissues was performed. Differential accumulation of L-DOPA depended on tissue type and maturity. Furthermore, dopamine biosynthesis through L-DOPA from L-Tyr was confirmed in faba bean. The expression analysis of PPOs in leaf and flower tissues revealed the selective induction of only four (, , , and ) out of ten genes encoding different PPOs mined from the faba bean genome. Higher accumulation of L-DOPA in young leaves and flower buds than in mature leaves and flowers was accompanied by significantly higher expression of and , respectively. The role of various transcription factors contributing to such metabolite dynamics was also predicted. Further exploration of this mechanism using a multi-omics approach can provide meaningful insight and pave the way for enhancing L-DOPA content in crops.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1007/s12298-024-01449-2.
PubMed: 38846459
DOI: 10.1007/s12298-024-01449-2 -
Parkinson's Disease 2024Patients with Parkinson's disease (PD) experience significantly reduced quality of life when PD is complicated with Pisa syndrome (PS). PS is a postural abnormality...
Patients with Parkinson's disease (PD) experience significantly reduced quality of life when PD is complicated with Pisa syndrome (PS). PS is a postural abnormality associated with a lateral bending of the trunk, causing the patient to lean to one side. Microsaccades during fixation are transmitted to the visual cortex, and this gaze movement may be impaired in PD. We aimed to detect presymptomatic signs of PS. We enrolled 50 patients with PD without dementia and investigated the visual systems in patients with concurrent PD and PS based on a Romberg ratio of<1.0. Gaze analysis, pupil diameter, stabilization tests, neuropsychological tests, and cerebral perfusion scintigraphy were reviewed and statistically analyzed. Two years later, we divided the patients into three groups as follows: PISA++ (patients who had PS at enrollment), PISA-+ (patients without PS that developed PS during the 2-year period), and PISA-- (patients without PS that did not develop PS during the 2-year period). The PISA-+ group exhibited a significantly higher daily levodopa dose and longer fixations, as well as lower position discrimination, Wechsler Adult Intelligence Scale-Third Edition blocking, and blood flow in the left supramarginal and orbital gyri than that in the PISA-- group. The PISA++ group showed a significantly longer fixation time and lower Mini-Mental State Examination score, Romberg ratio of area, amplitude, velocity of microsaccades, and blood flow in the left precuneus and cuneus than that in the PISA-+ group. Before the onset of PS, hypoperfusion occurred in the correlative visual cortex and the position discrimination test. Patients with PS have reduced saccades and slow microsaccades.
PubMed: 38846136
DOI: 10.1155/2024/5550362 -
Neural Regeneration Research Jun 2024The globus pallidus plays a pivotal role In the basal ganglia circuit. Parkinson's disease Is characterized by degeneration of dopamine-producing cells in the substantia...
The globus pallidus plays a pivotal role In the basal ganglia circuit. Parkinson's disease Is characterized by degeneration of dopamine-producing cells in the substantia nigra, which leads to dopamine deficiency in the brain that subsequently manifests as various motor and non-motor symptoms. This review aims to summarize the involvement of the globus pallidus in both motor and non-motor manifestations of Parkinson's disease. The firing activities of parvalbumin neurons in the medial globus pallidus, including both the firing rate and pattern, exhibit strong correlations with the bradykinesia and rigidity associated with Parkinson's disease. Increased beta oscillations, which are highly correlated with bradykinesia and rigidity, are regulated by the lateral globus pallidus. Furthermore, bradykinesia and rigidity are strongly linked to the loss of dopaminergic projections within the cortical-basal ganglia-thalamocortical loop. Resting tremors are attributed to the transmission of pathological signals from the basal ganglia through the motor cortex to the cerebellum-ventral intermediate nucleus circuit. The cortico-striato-pallidal loop is responsible for mediating pallidi-associated sleep disorders. Medication and deep brain stimulation are the primary therapeutic strategies addressing the globus pallidus in Parkinson's disease. Medication is the primary treatment for motor symptoms in the early stages of Parkinson's disease, while deep brain stimulation has been clinically proven to be effective in alleviating symptoms in patients with advanced Parkinson's disease, particularly for the movement disorders caused by levodopa. Deep brain stimulation targeting the globus pallidus internus can improve motor function in patients with tremordominant and non-tremor-dominant Parkinson's disease, while deep brain stimulation targeting the globus pallidus externus can alter the temporal pattern of neural activity throughout the basal ganglia-thalamus network. Therefore, the composition of the globus pallidus neurons, the neurotransmitters that act on them, their electrical activity, and the neural circuits they form can guide the search for new multi-target drugs to treat Parkinson's disease in clinical practice. Examining the potential intra-nuclear and neural circuit mechanisms of deep brain stimulation associated with the globus pallidus can facilitate the management of both motor and non-motor symptoms while minimizing the side effects caused by deep brain stimulation.
PubMed: 38845220
DOI: 10.4103/NRR.NRR-D-23-01660 -
Journal of Neuroscience Methods Jun 2024this study was to analyze the brain functional network of end-of-dose wearing-off (EODWO) in patients with Parkinson's disease (PD) using a convolutional neural network...
Adoption of deep learning-based magnetic resonance image information diagnosis in brain function network analysis of Parkinson's disease patients with end-of-dose wearing-off.
OBJECTIVE
this study was to analyze the brain functional network of end-of-dose wearing-off (EODWO) in patients with Parkinson's disease (PD) using a convolutional neural network (CNN)-based functional magnetic resonance imaging (fMRI) data classification model.
METHODS
one hundred PD patients were recruited and assigned to control (Ctrl) group (39 cases without EODWO) and experimental (Exp) group (61 cases with EODWO). The data classification model based on a CNN was employed to assist the analysis of the changes in brain functional network structure in the two groups. The CNN-based fMRI data classification model was primarily based on a CNN architecture, with improvements made to the initialization of convolutional kernel parameters. Firstly, a structure based on restricted Boltzmann machine (RBM) was constructed, followed by the initialization of convolutional kernel parameters. Subsequently, the model underwent training. Utilizing the data analysis module within the GRETNA toolbox, extracted feature sets were analyzed, including local measures such as betweenness centrality (BC) and degree centrality (DC), as well as global measures such as global efficiency (Eg) and local efficiency (Eloc).
RESULTS
as sparsity increased, there was a gradual upward trend observed in Eg; however, the values of Eg in both brain functional networks remained relatively stable within the range of 0.2-0.5. The Eg value of the Ctrl group's whole-brain functional network was 0.17 ± 0.02, while that of the Exp group's whole-brain functional network was 0.17 ± 0.03, with no significant difference between them (P>0.05). The functional DC value of the superior frontal gyrus in the Exp group (8.71 ± 2.56) was significantly lower than that of the Ctrl group (13.32 ± 3.22), whereas the functional DC value of the anterior cingulate gyrus in the Exp group (19.33 ± 4.78) was significantly higher than that of the Ctrl group (15.21 ± 4.02) (P<0.05). There was no significant correlation observed between the functional DC value and levodopa or dopamine agonist therapy (DDT) in the Exp group, whereas the Ctrl group exhibited a significant positive correlation.
CONCLUSION
analysis conducted via a CNN-based fMRI data classification model revealed a correlation between the occurrence of EODWO in PD patients and functional impairments in the left precuneus. Additionally, the occurrence of EODWO may potentially diminish the plasticity of the central prefrontal dopamine.
PubMed: 38838748
DOI: 10.1016/j.jneumeth.2024.110184 -
ACS Applied Bio Materials Jun 2024One of the crucial requirements of quantum dots for biological applications is their surface modification for very specific and enhanced biological recognition and...
One of the crucial requirements of quantum dots for biological applications is their surface modification for very specific and enhanced biological recognition and uptake. Toward this end, we present the green synthesis of bright, red-emitting carbon quantum dots derived from mango leaf extract (mQDs). These mQDs are conjugated electrostatically with dopamine to form mQDs-dopamine (mQDs:DOPA) bioconjugates. Bright-red fluorescence of mQDs was used for bioimaging and uptake in cancerous and noncancerous cell lines, tissues, and models like zebrafish. mQDs exhibited the highest uptake in brain tissue compared to the heart, kidney, and liver. mQD:DOPA conjugates killed breast cancer cells and increased uptake in epithelial RPE-1 cells and zebrafish. Additionally, mQDs:DOPA promoted neuronal differentiation of SH-SY5Y cells to differentiated neurons. Both mQDs and mQDs:DOPA exhibited the potential for higher collective cell migrations, implicating their future potential as next-generation tools for advanced biological and biomedical applications.
Topics: Quantum Dots; Humans; Carbon; Dopamine; Animals; Zebrafish; Cell Differentiation; Neurons; Biocompatible Materials; Particle Size; Materials Testing; Antineoplastic Agents; Optical Imaging; Cell Survival; Cell Line, Tumor
PubMed: 38836645
DOI: 10.1021/acsabm.4c00249 -
Cureus May 2024Progressive supranuclear palsy (PSP) is characterized by parkinsonism, downward gaze disorder, and a tendency to fall due to degeneration of the basal ganglia, the brain...
Progressive supranuclear palsy (PSP) is characterized by parkinsonism, downward gaze disorder, and a tendency to fall due to degeneration of the basal ganglia, the brain stem, and the cerebellum. We report a case of PSP that was diagnosed following a traumatic hemopneumothorax caused by a fall while descending stairs. A 79-year-old man experienced lightheadedness and frequent falls for two years. He fell on stairs at home and was transferred to our hospital due to mobility issues. He was hospitalized and treated for traumatic hemopneumothorax. Neurological examination revealed vertical ocular motility disorder, positive Myerson's sign, increased muscle stiffness, and increased limb tendon reflexes. Brain MRI showed a hummingbird sign. In this case, a midbrain area of 58.1 mm was consistent with PSP. He had no medication history that could have caused falls. He was diagnosed with PSP based on clinical and imaging findings, and treatment with levodopa was initiated. Two months later, walking showed limited improvement, and living at home became difficult. He was discharged to a care facility. PSP is a risk factor for frequent falls in the elderly. PSP usually requires three to four years for diagnosis, although falls appear earlier than in other forms of degenerative parkinsonism. Additionally, PSP often results in repeated dynamic falls due to a decreased perception of danger associated with reduced frontal lobe function. As a result, the severity of trauma from falls in PSP tends to be higher than in other neurodegenerative diseases. Therefore, early diagnosis of PSP may help improve patients' quality of life and prevent trauma. Despite frequent falls over two years, the cause was not thoroughly investigated until the patient experienced severe trauma. The lesson from this case is the importance of a thorough neurological examination and sagittal MRI for elderly patients experiencing repeated falls, to consider the possibility of PSP. Furthermore, quantitative evaluation of MRI enhances the diagnostic accuracy of PSP.
PubMed: 38832160
DOI: 10.7759/cureus.59643 -
Neurology Jun 2024A robust understanding of the natural history of apathy in Parkinson disease (PD) is foundational for developing effective clinical management tools. However, large...
BACKGROUND AND OBJECTIVES
A robust understanding of the natural history of apathy in Parkinson disease (PD) is foundational for developing effective clinical management tools. However, large longitudinal studies are lacking while the literature is inconsistent about even cross-sectional associations. We aimed to determine the longitudinal predictors of apathy development in a large cohort of people with PD and its cross-sectional associations and trajectories over time, using sophisticated Bayesian modeling techniques.
METHODS
People with PD followed up in the longitudinal New Zealand Parkinson's progression project were included. Apathy was defined using the neuropsychiatric inventory subscale ≥4, and analyses were also repeated using a less stringent cutoff of ≥1. Both MoCA and comprehensive neuropsychological testing were used as appropriate to the model. Depression was assessed using the hospital anxiety and depression scale. Cross-sectional Bayesian regressions were conducted, and a multistate predictive model was used to identify factors that predict the initial onset of apathy in nonapathetic PD, while also accounting for the competing risk of death. The relationship between apathy presence and mortality was also investigated.
RESULTS
Three hundred forty-six people with PD followed up for up to 14 years across a total of 1,392 sessions were included. Apathy occurrence did not vary significantly across the disease course (disease duration odds ratio [OR] = 0.55, [95% CI 0.28-1.12], affecting approximately 11% or 22% of people at any time depending on the NPI cutoff used. Its presence was associated with a significantly higher risk of death after controlling for all other factors (hazard ratio [HR] = 2.92 [1.50-5.66]). Lower cognition, higher depression levels, and greater motor severity predicted apathy development in those without motivational deficits (HR [cognition] = 0.66 [0.48-0.90], HR [depression] = 1.45 [1.04-2.02], HR [motor severity] = 1.37 [1.01-1.86]). Cognition and depression were also associated with apathy cross-sectionally, along with male sex and possibly lower dopaminergic therapy level, but apathy still occurred across the full spectrum of each variable (OR [cognition] = 0.58 [0.44-0.76], OR [depression] = 1.43 [1.04-1.97], OR [female sex] = 0.45 [0.22-0.92], and OR [levodopa equivalent dose] = 0.78 [0.59-1.04].
DISCUSSION
Apathy occurs across the PD time course and is associated with higher mortality. Depressive symptoms and cognitive impairment in particular predict its future development in those with normal motivation.
Topics: Humans; Apathy; Parkinson Disease; Male; Female; Cross-Sectional Studies; Aged; Middle Aged; Longitudinal Studies; Bayes Theorem; Depression; Neuropsychological Tests; Disease Progression; New Zealand; Aged, 80 and over
PubMed: 38830182
DOI: 10.1212/WNL.0000000000209301 -
Plant Physiology Jun 2024A unique family of decarboxylated betalains derived from dopamine has recently been discovered. Due to the lack of chemical standards, the existence and distribution of...
A unique family of decarboxylated betalains derived from dopamine has recently been discovered. Due to the lack of chemical standards, the existence and distribution of decarboxylated betalains in nature remains unknown. Traditional betalains contain L-DOPA as the starting point of the biosynthetic pathway and betalamic acid as a structural and functional unit, while the recently discovered betalains rely on dopamine. Here, 30 dopamine-derived betalains were biotechnologically produced, purified, and characterized, creating an unprecedented library to explore their properties and presence in nature. The maximum absorbance wavelengths for the pigments ranged between 461nm and 485 nm. HPLC analysis showed retention times between 0.6-2.2 min higher than traditional betalains due to their higher hydrophobicity. The presence of decarboxybetalains in nature was screened using HPLC-ESI-Q-TOF mass spectrometry in various species of the Amaranthaceae family: beetroot (Beta vulgaris subsp. vulgaris), Swiss chard (B. vulgaris var. cicla), celosia (Celosia argentea var. plumosa) and quinoa (Chenopodium quinoa). The latter species had the highest content of decarboxybetalains (28 compounds in its POEQ-143 variety). 29 pigments were found distributed among the different analyzed plant sources. The abundance of decarboxybetalains demonstrated in this work highlights these pigments as an important family of phytochemicals in the order Caryophyllales.
PubMed: 38829803
DOI: 10.1093/plphys/kiae312