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The objective was to design and develop a drug-in-adhesive-type transdermal patch formulation of metoclopramide HCl, which is used as an effective antiemetic, dopaminergic antagonist agent. In DIA patches, drug is directly embedded in the polymeric adhesive layer and permeates through the skin to provide systemic effect, avoiding gastrointestinal tract complications, including the first-pass metabolism. Six different patch formulations were prepared by a solvent evaporation method using varying metoclopramide HCl concentrations using acrylate polymer DURO-TAK® 387/2510 for adhesive support. In vitro permeation profiles and parameters were obtained by using the skin of hairless albino Wistar rats. The influence of drug content on the rate of permeation was investigated, and patch formulation was optimized based on Q12, flux, and lag time. The effect of permeation enhancers (EO and PG) on the permeation rate of metoclopramide HCl was also studied. The skin irritation study was performed to observe the hypersensitivity against the patch component. Stability studies of the optimized formulation of a transdermal patch for three months at three different temperatures were investigated. The transdermal patch formulation containing 10% w/w metoclopramide HCl was capable of effectively delivering metoclopramide HCl for systemic effect without any skin irritation. It has Q12 of 3.892 ± 0.0043 mg/cm2, flux rate of 0.2501 mg/cm2 h, and the coefficient of permeability of 6.25E−02 cm/h with a lag time of 0.442 h. The stability data revealed that the optimized patch formulation could be stored at 4 °C in the refrigerator with a shelf life of 3.53 months. This newly developed metoclopramide transdermal DIA patch is an effective alternative to oral delivery with desirable antiemetic activity. [ABSTRACT FROM AUTHOR]

Hydrogels can maintain a high local drug concentration during treatments and may be useful to local targeting diseased areas. We propose a pH sensitive hydrogel consisting of poly-vinylpyrrolidone (PVP) and chitosan as a new treatment method for KRAS mutant lung cancer. Addition of dopamine improved the drug loading and release effects of this hydrogel. We demonstrate that Tasquinimod-loading of this dopamine-modified pH sensitive hydrogel is more effective than Tasquinimod alone for inhibiting the proliferation of KRAS mutant lung cancer cells. Combination of conventional drugs with hydrogels may thus provide a new treatment modality for lung cancer. [ABSTRACT FROM AUTHOR]

Objective: To identify the impact of a collaborative pharmaceutical care service (CPCS) on medication safety and establish the impact of the CPCS on patient reported outcomes for Parkinson's disease (PD) patients. Methods: Initially, PD outpatients receiving the CPCS between March 2017 and March 2019 were compared with PD patients receiving standard of care to identify differences in management. Pharmacist interventions data were coded and patients with PD receiving the CPCS were compared with those receiving standard of care to determine differences in medicines prescribed and dosage associated with these. Following this, data of patients receiving CPCS at baseline and 3-months follow-up were collected using a questionnaire consisting of validated measures of two patient-reported outcomes [adherence and quality of life (QoL)]. Mean scores for continuous variables were calculated, with descriptive analysis of categorical variables consisting of frequency counts and percentages. Change in adherence score before and after CPCS was investigated using a Wilcoxon sign rank sum test, spearman correlation analysis was used to correlate the changes in QoL before and after CPCS with the number of interventions, and p < 0.05 indicates that the difference is statistically significant. Results: A total of 331 PD outpatients received CPCS over 490 outpatient visits with an average age of 71.83 (±12.54). Five hundred and forty-five drug related problems were recorded as pharmacist interventions, of which most involved change to dosage (n = 226, 41.47%), adverse drug reactions (n = 135, 24.77%), and change in a medication (n = 102, 18.72%). Compared with those receiving standard of care, patients receiving CPCS were significantly less likely to have been prescribed pramipexole (18.52 versus 23.77%, p < 0.001) and more likely to have been prescribed amantadine (5.40 versus 3.70%, p = 0.02) and selegiline (17.36 versus 11.64%, p < 0.001). Lower dosages of levodopa/benserazide (0.51 ± 0.31 g versus 0.84 ± 0.37 g, p < 0.001), levodopa/carbidopa (0.33 ± 0.23 g versus 0.66 ± 0.47 g, p < 0.001), pramipexole (1.14 ± 1.63 mg versus 1.27 ± 0.69 mg, p = 0.01), and entacapone (130.00 ± 79.76 mg versus 173.09 ± 97.86 mg, p < 0.001) were also recorded. At baseline 119 PD outpatients with an average age of 69.98 (±9.90) were recruited for the longitudinal study. At 3-month follow-up, participants reported improvement in bodily pain subscale (baseline versus 3-months follow-up, 30.04 ± 22.21 versus 23.01 ± 20.98, p = 0.037) and medication adherence (6.19 ± 1.50 versus 6.72 ± 1.73, p = 0.014). Frequency of CPCS use was related to activity of daily living subscale (p = 0.047), the bodily pain subscale (p = 0.026), and medication adherence (p = 0.011). Total score of PDQ-39 was associated with patient education (p = 0.005) and usage and dosage combined with patient education (p = 0.006), while medication adherence score was associated with usage and dosage (p = 0.005). Conclusion: The CPCS was effective in resolving drug-related problems and in improving patients' medication regimens, medication adherence, and QoL through patient education and dosage adjustments. This is the first step in the development and feasibility testing of pharmacy services for PD patients in China. [ABSTRACT FROM AUTHOR]

OBJECTIVES: We aimed to disclose the relationship between restless leg syndrome (RLS) and antiparkinsonian treatment, and its effect on quality of life (QoL) in patients with Parkinson's disease (PD). BACKGROUND: Previous studies documented the prevalence of RLS among patients with PD to be higher than in the general population, but conclusions regarding the aetiology and impact were contradictory. METHODS: We examined 101 patients with idiopathic PD. All participants completed the five-dimension/five-level-EuroQoL questionnaire (EQ-5D-5L) and the International Restless-Legs-syndrome-study-group rating Scale (IRLS). RESULTS: The prevalence of RLS was 22.77 %. There were no statistically significant differences in levodopa or dopamine agonists (DA) doses between RLS-positive and negative participants. However, the use of levodopa as the last night-time medication was connected with a higher risk of RLS (OR=2.049, p=0.041). There was significantly lower prevalence of RLS in patients after surgical treatment for PD (p=0.024). Participants with RLS were at a greater risk for sleep disturbances (OR=3.866, p=0.023) and excessive daytime sleepiness (OR=7.202, p<0.001). Greater RLS symptoms were associated with worse QoL (higher IRLS score predicted higher EQ5D5L score, p=0.023). CONCLUSION: RLS is prevalent among PD patients and night-time dopaminergic over-excitation with levodopa plays an important role in its pathogenesis. Since the symptoms of RLS are associated with decreased QoL, early accurate diagnosis and appropriate adjustment of dopaminergic therapy can lead to immediate relief from RLS symptoms and to QoL improvement. [ABSTRACT FROM AUTHOR]

Hydrogels can maintain a high local drug concentration during treatments and may be useful to local targeting diseased areas. We propose a pH sensitive hydrogel consisting of poly-vinylpyrrolidone (PVP) and chitosan as a new treatment method for KRAS mutant lung cancer. Addition of dopamine improved the drug loading and release effects of this hydrogel. We demonstrate that Tasquinimod-loading of this dopamine-modified pH sensitive hydrogel is more effective than Tasquinimod alone for inhibiting the proliferation of KRAS mutant lung cancer cells. Combination of conventional drugs with hydrogels may thus provide a new treatment modality for lung cancer. [ABSTRACT FROM AUTHOR]

The main challenge war focused on the detection of dopamine drug using a type of AlN nanotube sensor through density functional theory (DFT) calculations. The interaction behavior of dopamine (DA) and aluminum nitride single-wall nanotube (AlNNT) was investigated by using DFT calculation. For the most stable complex, the energy of adsorption of DA on the aluminum nitride single-wall nanotube's surface was − 17.31 kcal/mol. DA adsorbs through an electrostatic mechanism on the AlNNT. The electrical conductivity of the nanotube has improved significantly by around 28.78 percent through the DA molecules' absorption on the surface of nanotube. This increase can be used as a signal to detect a drug. Therefore, after DA drug adsorption, the AlNNT work function is reduced from 4.56 to 3.25 eV. Thus, the AlNNT can be both the electronic and work function-type sensor for DA detection. Compared with the gas phase, AlNNT-DA has more stability in aqueous media according to polarizable continuum model (PCM). Eventually, our results also uncovered that, in the presence of environmental contaminants, the AlNNT can selectively recognize the DA molecule. [ABSTRACT FROM AUTHOR]

Objective: Chronic METH use results in neurodegenerative alternations in the human brain. The present study aimed to assess the long-term METH impact on brain metabolite concentrations in cases meeting the DSM-5 criteria regarding METH use. Method: We recruited 42 METH users meeting the DSM-5 criteria and 21 healthy controls. Psychotic signs were measured using the Positive and Negative Syndrome Scale (PANSS). Proton magnetic resonance spectroscopy (1HMRS) evaluating Myo-inositol (Ml), Choline (Cho), Glutamine plus Glutamate (Glx), N-acetyl aspartate (NAA), and Creatine (Cre) were obtained in the dopaminergic pathway (Frontal Cortex, Substantia nigra, Ventral Tegmental Area (VTA), Nucleus Accumbens (NAc), Hippocampus, Striatum,) the subjects. All participants collected urine specimens for 24 hours to measure presence of specific metabolites including METH metabolite level, 5-Hydroxy indoleacetic acid metabolite (for serotonin level monitoring), and metanephrine metabolite (for dopamine level monitoring). Results: Dopamine and Serotonin increased in the METH group (P < 0.001). METH caused an increase in the Cre (P < 0.001) and a decline in the Glx (P < 0.001), NAA (P = 0.008), and MI (P < 0.001) metabolite concentrations of dopamine circuits in METH users in comparison with healthy subjects. We found no change in Cho metabolite concentration. Psychological data and the neurometabolite concentrations in the studied area of the brain were significantly correlated. Conclusion: There is an association between METH use and active neurodegeneration in the dopamine circuit, and it causes serious mental illness. 1HMRS can detect patient's deterioration and progression of disease as well as follow-up management in patients with METH use disorder. [ABSTRACT FROM AUTHOR]

Background: Tremor is one of the most prevalent symptoms in Parkinson's Disease (PD). The progression and management of tremor in PD can be challenging, as response to dopaminergic agents might be relatively poor, particularly in patients with tremordominant PD compared to the akinetic/rigid subtype. In this review, we aim to highlight recent advances in the underlying pathogenesis and treatment modalities for tremor in PD. Methods: A structured literature search through Embase was conducted using the terms "Parkinson's Disease" AND "tremor" OR "etiology" OR "management" OR "drug resistance" OR "therapy" OR "rehabilitation" OR "surgery." After initial screening, eligible articles were selected with a focus on published literature in the last 10 years. Discussion: The underlying pathophysiology of tremor in PD remains complex and incompletely understood. Neurodegeneration of dopaminergic neurons in the retrorubral area, in addition to high-power neural oscillations in the cerebello-thalamo-cortical circuit and the basal ganglia, play a major role. Levodopa is the first-line therapeutic option for all motor symptoms, including tremor. The addition of dopamine agonists or anticholinergics can lead to further tremor reduction. Botulinum toxin injection is an effective alternative for patients with pharmacological-resistant tremor who are not seeking advanced therapies. Deep brain stimulation is the most well-established advanced therapy owing to its longterm efficacy, reversibility, and effectiveness in other motor symptoms and fluctuations. Magnetic resonance-guided focused ultrasound is a promising modality, which has the advantage of being incisionless. Cortical and peripheral electrical stimulation are noninvasive innovatory techniques that have demonstrated good efficacy in suppressing intractable tremor. [ABSTRACT FROM AUTHOR]

The article presents the case of a 34-year-old female with congenital human immunodeficiency virus (HIV)/AIDS who was rushed to a clinic due to 10 days of intermittent right arm and leg shaking movements to discuss new onset focal tremor in patient with HIV. She is undergoing antiretroviral therapy (ART). She was eventually diagnosed with progressive multifocal leukoencephalopathy.

Photoreceptor cell degeneration leads to visual impairment and blindness in several types of retinal disease. However, the discovery of safe and effective therapeutic strategies conferring photoreceptor cell protection remains challenging. Targeting distinct cellular pathways with low doses of different drugs that produce a functionally synergistic effect could provide a strategy for preventing or treating retinal dystrophies. We took a systems pharmacology approach to identify potential combination therapies using a mouse model of light-induced retinal degeneration. We showed that a combination of U.S. Food and Drug Administration-approved drugs that act on different G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors (GPCRs) exhibited synergistic activity that protected retinas from light-induced degeneration even when each drug was administered at a low dose. In functional assays, the combined effects of these drugs were stimulation of Gi/o signaling by activating the dopamine receptors D2R and D4R, as well as inhibition of Gs and Gq signaling by antagonizing D1R and the α1A-adrenergic receptor ADRA1A, respectively. Moreover, transcriptome analyses demonstrated that such combined GPCR-targeted treatments preserved patterns of retinal gene expression that were more similar to those of the normal retina than did higher-dose monotherapy. Our study thus supports a systems pharmacology approach to identify treatments for retinopathies, an approach that could extend to other complex disorders.

Elucidating the neurobiological mechanisms underlying individual differences in the extent to which reward cues acquire the ability to act as incentive stimuli may contribute to the development of successful treatments for addiction and related disorders. We used the sign-tracker/goal-tracker animal model to examine the role of dopamine D2 and D3 receptors in the propensity to attribute incentive salience to reward cues. Following Pavlovian training, wherein a discrete lever-cue was paired with food reward, rats were classified as sign- or goal-trackers based on the resultant conditioned response. We examined the effects of D2/D3 agonists, 7-OH-DPAT (0.01-0.32mg/kg) or pramipexole (0.032-0.32mg/kg), the D2/D3 antagonist raclopride (0.1mg/kg), and the selective D3 antagonist, SB-277011A (6 or 24mg/kg), on the expression of sign- and goal-tracking conditioned responses. The lever-cue acquired predictive value and elicited a conditioned response for sign- and goal-trackers, but only for sign-trackers did it also acquire incentive value. Following administration of either 7-OH-DPAT, pramipexole, or raclopride, the performance of the previously acquired conditioned response was attenuated for both sign- and goal-trackers. For sign-trackers, the D2/D3 agonist, 7-OH-DPAT, also attenuated the conditioned reinforcing properties of the lever-cue. The selective D3 antagonist did not affect either conditioned response. Alterations in D2/D3 receptor signaling, but not D3 signaling alone, transiently attenuate a previously acquired Pavlovian conditioned response, regardless of whether the response is a result of incentive motivational processes. These findings suggest activity at the dopamine D2 receptor is critical for a reward cue to maintain either its incentive or predictive qualities.

Amphetamines elevate extracellular dopamine, but the underlying mechanisms remain uncertain. Here we show in rodents that acute pharmacological inhibition of the vesicular monoamine transporter (VMAT) blocks amphetamine-induced locomotion and self-administration without impacting cocaine-induced behaviours. To study VMAT's role in mediating amphetamine action in dopamine neurons, we have used novel genetic, pharmacological and optical approaches in Drosophila melanogaster. In an ex vivo whole-brain preparation, fluorescent reporters of vesicular cargo and of vesicular pH reveal that amphetamine redistributes vesicle contents and diminishes the vesicle pH-gradient responsible for dopamine uptake and retention. This amphetamine-induced deacidification requires VMAT function and results from net H(+) antiport by VMAT out of the vesicle lumen coupled to inward amphetamine transport. Amphetamine-induced vesicle deacidification also requires functional dopamine transporter (DAT) at the plasma membrane. Thus, we find that at pharmacologically relevant concentrations, amphetamines must be actively transported by DAT and VMAT in tandem to produce psychostimulant effects.

Introduction: Organophosphate compound poisoning is one of the most common causes for admission to the Medical Intensive Care Unit. Parkinsonism is a primary neurotoxic manifestation of organophosphate intoxication. In this case report, we present the case of a 26 year old man who had the experience of organothiophosphate poisoning. Case presentation: A 26 year old man was admitted with tremors in upper and lower limbs together with the rigidity of all 4 limbs as well as difficulty in swallowing and in daily activities like walking, rising from chair, and turning on bed. He had consumed organophosphorus compound quinalphos, 15 days before. The basal ganglia changes were documented radiologically by Magnetic Resonance Imaging (MRI). Gradual recovery was observed by treatment with dopaminergic agents and central anticholinergics over few weeks. Only 0.5% of organophosphate poisoning patients develop neurotoxic manifestations in the form of extrapyramidal syndromes such as Parkinsonism. Discussion: The occurrence of Parkinsonism as a complication of organophosphate poisoning raises safety concerns, especially in developing countries. Yet, this study is the first case report on Organothiophospahate induced Parkinsonism. Conclusion: Clinicians should be aware of the possibility of extrapyramidal manifestations following organophosphate poisoning and the patients should be asked for regular follow-ups as the symptoms may appear even 1 month after the poisoning.

• Methamphetamine abuse leads to long lasting pathological manifestations in the brain. • These effects are attributed to the structural similarities of this drug with dopamine. • Methamphetamine-induced changes of the dopamine system impair learning and memory. • Methamphetamine abuse alters dopaminergic transmission and hippocampal integrity. • Abuse of this drug likely predisposes to develop Alzheimer's and Parkinson's diseases. Diverse intellectual functions including memory are some important aspects of cognition. Dopamine is a neurotransmitter of the catecholamine family, which contributes to the experience of pleasure and/or emotional states but also plays crucial roles in learning and memory. Methamphetamine is an illegal drug, the abuse of which leads to long lasting pathological manifestations in the brain. Chronic methamphetamine-induced neurotoxicity results in an alteration of various parts of the memory systems by affecting learning processes, an effect attributed to the structural similarities of this drug with dopamine. An evolving field of research established how cognitive deficits in abusers arise and how they could possibly trigger neurodegenerative disorders. Thus, the drugs-induced tenacious neurophysiological changes of the dopamine system trigger cognitive deficits, thereby affirming the influence of this addictive drug on learning, memory and executive function in human abusers. Here we present an overview of the effects of methamphetamine abuse on cognitive functions, dopaminergic transmission and hippocampal integrity as they have been validated in animals and in humans during the past 20 years. [ABSTRACT FROM AUTHOR]

Purpose: Parkinson's disease (PD) is primarily defined by motor symptoms and is associated with alterations of sensorimotor areas. Evidence for network changes of the sensorimotor network (SMN) in PD is inconsistent and a systematic evaluation of SMN in PD yet missing. We investigate functional connectivity changes of the SMN in PD, both, within the network, and to other large-scale connectivity networks. Methods: Resting-state fMRI was assessed in 38 PD patients under long-term dopaminergic treatment and 43 matched healthy controls (HC). Independent component analysis (ICA) into 20 components was conducted and the SMN was identified within the resulting networks. Functional connectivity within the SMN was analyzed using a dual regression approach. Connectivity between the SMN and the other networks from group ICA was investigated with FSLNets. We investigated for functional connectivity changes between patients and controls as well as between medication states (OFF vs. ON) in PD and for correlations with clinical parameters. Results: There was decreased functional connectivity within the SMN in left inferior parietal and primary somatosensory cortex in PD OFF. Across networks, connectivity between SMN and two motor networks as well as two visual networks was diminished in PD OFF. All connectivity decreases partially normalized in PD ON. Conclusion: PD is accompanied by functional connectivity losses of the SMN, both, within the network and in interaction to other networks. The connectivity changes in short- and long-range connections are probably related to impaired sensory integration for motor function in PD. SMN decoupling can be partially compensated by dopaminergic therapy. [ABSTRACT FROM AUTHOR]

In Parkinson's disease (PD) impairments in decision making can occur, in particular because of the tendency toward risky and rewarding options. The Iowa Gambling Task has been widely used to investigate decision processes involving these options. The task assesses the ability to manage risk and to learn from feedback. The present paper aims at critically examining those studies in which this task has been administered to PD patients, in order to understand possible anomalies in patients' decision processes and which variables are responsible for that. A meta‐analysis has been conducted as well. Features of the task, sociodemographic and clinical aspects (including daily drugs intake), cognitive conditions and emotional disorders of the patients have been taken into account. Neural correlates of decision‐making competences were considered. It emerged that PD patients show a trend of preference toward risky choices, probably due to an impairment in anticipating the unrewarding consequences or to an insensitiveness to punishment. The possible role played by dopamine medications in decision making under uncertain conditions, affecting basal ganglia and structures involved in the limbic loop, was discussed. Attention has been focused on some aspects that need to be investigated in further research, in order to delve into this issue and promote patients' quality of life. [ABSTRACT FROM AUTHOR]

Freezing of gait (FOG) is a common and challenging clinical symptom in Parkinson's disease. In this review, we summarise the recent insights into freezing of gait and highlight the strategies that should be considered to improve future treatment. There is a need to develop individualised and on-demand therapies, through improved detection and wearable technologies. Whilst there already exist a number of pharmacological (e.g., dopaminergic and beyond dopamine), non-pharmacological (physiotherapy and cueing, cognitive training, and non-invasive brain stimulation) and surgical approaches to freezing (i.e., dual-site deep brain stimulation, closed-loop programming), an integrated collaborative approach to future research in this complex area will be necessary to systematically investigate new therapeutic avenues. A review of the literature suggests standardising how gait freezing is measured, enriching patient cohorts for preventative studies, and harnessing the power of existing data, could help lead to more effective treatments for freezing of gait and offer relief to many patients. [ABSTRACT FROM AUTHOR]

In Parkinson's disease, both motor and neuropsychiatric complications unfold as a consequence of both incremental striatal dopaminergic denervation and intensifying long-term dopaminergic treatment. Together, this leads to 'dopaminergic sensitization' steadily increasing motor and behavioral responses to dopaminergic medication that result in the detrimental sequalae of long-term dopaminergic treatment. We review the clinical presentations of 'dopaminergic sensitization', including rebound off and dyskinesia in the motor domain, and neuropsychiatric fluctuations and behavioral addictions with impulse control disorders and dopamine dysregulation syndrome in the neuropsychiatric domain. We summarize state-of-the-art deep brain stimulation, and show that STN-DBS allows dopaminergic medication to be tapered, thus supporting dopaminergic desensitization. In this framework, we develop our integrated debatable viewpoint of "changing gears", that is we suggest rethinking earlier use of subthalamic nucleus deep brain stimulation, when the first clinical signs of dopaminergic motor or neuropsychiatric complications emerge over the steadily progressive disease course. In this sense, subthalamic deep brain stimulation may help reduce longitudinal motor and neuropsychiatric symptom expression - importantly, not by neuroprotection but by supporting dopaminergic desensitization through postoperative medication reduction. Therefore, we suggest considering STN-DBS early enough before patients encounter potentially irreversible psychosocial consequences of dopaminergic complications, but importantly not before a patient shows first clinical signs of dopaminergic complications. We propose to consider neuropsychiatric dopaminergic complications as a new inclusion criterion in addition to established motor criteria, but this concept will require validation in future clinical trials. ANN NEUROL 2021;90:699-710. [ABSTRACT FROM AUTHOR]

Background: Methamphetamine use disorder is an important public health problem, especially in the younger generation, and associated with various psychiatric, cognitive, social, economic, and legal issues. Cabergoline, a drug with dopaminergic properties and long half-life, has been considered for the treatment of stimulant dependence. The systemic use of cabergoline has been shown to increase glial cell-derived neurotrophic factor (GDNF) expression. Objective: In this study, we investigated the effects of cabergoline on the serum level of GDNF and its effect on abstaining from methamphetamine in individuals treated for methamphetamine use disorder. Method: Sixty male subjects with methamphetamine use disorder were randomly assigned to 2 groups receiving cabergoline and placebo, respectively. During a 12-week follow-up, we compared the serum level of GDNF, urine test results for methamphetamine use, and depression scale between the 2 groups. Results: We found that serum GDNF was lower in subjects who used methamphetamine than healthy subjects (p < 0.0001). However, the serum level of GDNF was not associated with cabergoline use. The rising number of cases testing positive in the placebo group showed a trend resulting in no significant difference between cases testing positive and negative (p = 0.585) at the end of week 12. In the verum group, however, the significantly high number of cases who tested negative – sober – for substances observed in early stages (weeks 7–8) continued to remain significantly higher till the end of the study (p = 0.043), resembling an association between treatment with cabergoline and remaining sober. Although reduced during treatment, recovery from depression was not associated with cabergoline treatment. Conclusion: The findings of this study confirmed the effect of cabergoline in reducing methamphetamine use. However, a serum level of the GDNF increase, as seen in animal studies, was not associated with cabergoline treatment of human subjects. This study was registered at the Iranian Registry of Clinical Trials (TRN:IRCT2015050422077N1, October 06, 2015, https://en.irct.ir/trial/19134). [ABSTRACT FROM AUTHOR]

Visuospatial working memory (WM) impairments in Parkinson's disease (PD) are more prominent and evolve earlier than verbal WM deficits, suggesting some differences in underlying pathology. WM is regulated by dopaminergic neurotransmission in the prefrontal cortex, but the effect of dopamine on specific processes supporting visuospatial WM are not well understood. Dopamine therapeutic effects on different WM processes may also differ given the heterogeneity of cognitive changes in PD. The present study examined the effect of dopamine therapy on memory load and distraction during visuospatial WM. Exploratory analyses evaluated whether individual differences in medication effects were associated with a gene, catechol-O-methyltransferase (COMT), which regulates prefrontal cortex dopamine levels. Cognitively normal PD participants (n = 28) and controls (n = 25) performed a visuospatial WM task, which manipulated memory load and the presence/absence of distractors. PD participants performed the task on and off medication. PD COMT groups were comprised of Met homozygote (lower COMT activity) and heterozygote and Val homozygote carriers (higher COMT activity, Het/Val). The results showed that handling higher memory loads and suppressing distraction were impaired in PD off, but not on medication. Medication improved distraction resistance in Met, but not Het/Val group. COMT did not modulate medication effects on memory load. These findings demonstrate that dopaminergic therapy restores visuospatial WM processes in patients without cognitive impairment and suggest that COMT variants may partly explain the mixed effects of medication on specific processes governed by distinct brain systems. Future investigations into gene-modulated effects of medication could lead to individualized strategies for treating cognitive decline. [ABSTRACT FROM AUTHOR]

The effects of psychotropic agents such as fluvoxamine, fluoxetine, paroxetine, milnacipran, and fluphenazine on dopamine formation from p-tyramine catalysed by cytochrome P450 (CYP) 2D6.2 (Arg296Cys;Ser486Thr), CYP2D6.10 (Pro34Ser;Ser486Thr), and CYP2D6.39 (Ser486Thr) were compared with the effects on dopamine formation from p-tyramine by CYP2D6.1. Michaelis constants (Km) and maximal velocity (kcat) values for dopamine formation and inhibition constants (Ki) of the psychotropic agents were determined. For CYP2D6.39, the kcat values for fluvoxamine, fluoxetine, and milnacipran, but not for paroxetine and fluphenazine, gradually increased with increasing concentrations, indicating activation of the catalysed reaction. Fluphenazine competitively inhibited dopamine formation catalysed by all variants, with a higher Ki value for CYP2D6.10. Among the three compounds that have a trifluoromethyl group in their chemical structure, only fluvoxamine and fluoxetine, as well as milnacipran that does not have this group, decreased Km values and/or increased kcat values for dopamine formation, suggesting that the group may not be essential for the activation. These findings indicate that substitution of amino acids at positions 34 and 486 can affect the affinity (Km) and enzymatic activity (kcat), respectively, for milnacipran and that the effect of substitution of arginine to cysteine at the 296th position on the activation would be effector dependent. [ABSTRACT FROM AUTHOR]

Background Drug-induced alterations to the dopamine system in stimulant use disorder (SUD) are hypothesized to impair reinforcement learning (RL). Computational modeling enables the investigation of the latent processes of RL in SUD patients, which could elucidate the nature of their impairments. Methods We investigated RL in 44 SUD patients and 41 healthy control participants using a probabilistic RL task that assesses learning from reward and punishment separately. In an independent sample, we determined the modulatory role of dopamine in RL following a single dose of the dopamine D2/3 receptor antagonist amisulpride (400 mg) and the agonist pramipexole (0.5 mg) in a randomised, double-blind, placebo-controlled, crossover design. We analyzed task performance using computational modelling and hypothesized that RL impairments in SUD patients would be differentially modulated by a dopamine D2/3 receptor antagonist and agonist. Results Computational analyses in both samples revealed significantly reduced learning rates from punishment in SUD patients compared with healthy controls, whilst their reward learning rates were not measurably impaired. In addition, the dopaminergic receptor agents modulated RL parameters differentially in both groups. Both amisulpride and pramipexole impaired RL parameters in healthy participants, but ameliorated learning from punishment in SUD patients. Conclusion Our findings suggest that RL impairments seen in SUD patients are associated with altered dopamine function. [ABSTRACT FROM AUTHOR]

Social behavior is a hallmark of complex animal systems; however, some species appear to have secondarily lost this social ability. In these non-social species, whether social abilities are permanently lost or suppressed is unclear. The blind cavefish Astyanax mexicanus is known to be asocial. Here, we reveal that cavefish exhibited social-like interactions in familiar environments but suppressed these interactions in stress-associated unfamiliar environments. Furthermore, the level of suppression in sociality was positively correlated with that of stereotypic repetitive behavior, as seen in mammals. Treatment with a human antipsychotic drug targeting the dopaminergic system induced social-like interactions in cavefish, even in unfamiliar environments, while reducing repetitive behavior. Overall, these results suggest that the antagonistic association between repetitive and social-like behaviors is deeply shared from teleosts through mammals. [ABSTRACT FROM AUTHOR]

Purpose: The dopamine transporter (DAT) is a marker of the occurrence and development of Parkinson's disease (PD) and other diseases with nigrostriatal degeneration. 2β-Carbomethoxy-3β-(4-chlorophenyl)-8-(2-[18F]-fluoroethyl)nortropane ([18F]FECNT), an 18F-labelled tropane derivative, was reported to be a useful positron-emitting probe for DAT. However, the rapid formation of brain-penetrating radioactive metabolites is an impediment to the proper quantitation of DAT in PET studies with [18F]FECNT. Deuterium-substituted analogues have presented better in vivo stability to reduce metabolites. This study aimed to synthesize a deuterium-substituted DAT radiotracer, [18F]FECNT-d4, and to make a preliminary investigation of its properties as a DAT tracer in vivo. Procedures: The ligand [18F]FECNT-d4 was obtained by one-step radiolabelling reaction. The lipophilicity was measured by the shake-flask method. Binding properties of [18F]FECNT-d4 were estimated by in vitro binding assay, biodistribution, and microPET imaging in rats. In vivo stability of [18F]FECNT-d4 was estimated by radio-HPLC. Results: [18F]FECNT-d4 was synthesized at an average activity yield of 46 ± 17 % (n = 15) and the molar activity was 67 ± 12 GBq/μmol. The deuterated tracer showed suitable lipophilicity and the ability to penetrate the blood-brain barrier (brain uptake of 1.72 % ID at 5 min). [18F]FECNT-d4 displayed a high binding affinity for DAT comparable to that of [18F]FECNT in rat striatum homogenates. Biodistribution results in normal rats showed that [18F]FECNT-d4 exhibited a higher ratio of the target to non-target (striatum/cerebellum) at 15 min post administration (5.00 ± 0.44 vs 3.84 ± 0.24 for [18F]FECNT-d4 vs [18F]FECNT). MicroPET imaging studies of [18F]FECNT-d4 in normal rats showed that the ligand selectively localized to DAT-rich striatal regions and the accumulation could be blocked with DAT inhibitor. Furthermore, in the unilateral PD model rat, a significant reduction of the signal was found in the lesioned side relative to the unlesioned side. Striatal standardized uptake value of [18F]FECNT-d4 remained ~4.02 in the striatum between 5 and 20 min, whereas that of [18F]FECNT fell rapidly from 4.11 to 2.95. Radio-HPLC analysis of the plasma demonstrated better in vivo stability of [18F]FECNT-d4 than [18F]FECNT. Conclusion: The deuterated compound [18F]FECNT-d4 may serve as a promising PET imaging agent to assess DAT-related disorders. [ABSTRACT FROM AUTHOR]

Background: Maintaining and manipulating sequences online is essential for language and memory. In Parkinson's disease (PD), poor performance in sequencing tasks has been associated with basal ganglia dysfunction, especially subthalamic hyperactivity. Objective: This study is aimed to investigate the impact of high-frequency subthalamic nucleus (STN) deep brain stimulation (DBS) on sequence processing in PD. Methods: Twenty-nine patients with PD (17 women) completed a 'before/after' sentence task and a digit ordering task with STN DBS ON and OFF. In the sentence task, patients read a sequence of events expressed in the actual order of occurrence ('after' sentences) or reversed order ('before' sentences) for comprehension. In the digit task, patients recalled a sequence of ordered digits (ordered trials) or reordered and recalled random digits in ascending order (random trials). Volumes of tissue activated (VTAs) were estimated for the motor and associative STN. Results: Patients were slower with STN DBS ON versus OFF in both tasks, although their motor symptoms were significantly improved under DBS. In the sentence task, patients showed higher ordering-related reaction time costs ('before' > 'after') with DBS ON versus OFF. Moreover, patients with larger left associative VTAs, smaller total motor VTAs, and more daily exposure to dopaminergic drugs tended to show larger reaction time cost increases under DBS. In the digit ordering task, patients with too large or too small right associative VTAs tended to show larger reaction time cost increases under DBS. Conclusion: Stimulating the STN, especially its associative part, might impair sequence processing in language and memory. [ABSTRACT FROM AUTHOR]

Purpose: This article discusses the modulatory effects of the serotonergic system on the behavioral and neurochemical effects exerted by psychostimulants, mainly cocaine. Views: The mesocorticolimbic dopaminergic system plays an important role in the rewarding effects of psychostimulants and the long-lasting neuroadaptive changes underlying the development of addiction. Dopaminergic brain regions such as the ventral tegmental area (VTA) and substantia nigra (SN) and their projection fields (prefrontal cortex - PFC, nucleus accumbens - Acb, dorsal striatum) are innervated by serotonergic neurons that can modulate this system. Pharmacological manipulation of the activity of the serotonergic system in rats has shown that lowering or elevating its activity increases and decreases, respectively, most behavioral responses to cocaine. Studies on the role of serotonin receptors have shown that the serotonin 5-HT1B receptor agonists administered to the Acb during self-administration increase the reinforcing effects of cocaine, whereas when administered during abstinence they decrease cocaine seeking. Distinct populations of 5-HT2AR and 5-HT2CR in the PFC, Acb, and VTA differentially affect the output of the mesocorticolimbic dopaminergic pathway. 5-HT2B receptors exert independent control over the activity of the three ascending dopamine (DA) pathways through specific tonic excitatory and inhibitory control of DA efflux from the Acb and PFC and do not affect striatal activity. Conclusions: The serotonergic system exerts modulatory effects on the behavioral and neurochemical effects of psychostimulants. The pharmacological manipulation of serotonergic system activity makes it possible to attenuate the effects of psychostimulants, which gives hope for the development of effective pharmacotherapy. Currently, the main obstacle to this is the excessive side effects shown by potential drugs. [ABSTRACT FROM AUTHOR]

Tardive dyskinesia (TD) is a hyperkinetic movement disorder caused by the use of dopamine receptor-blocking agents (DRBAs), a category of medications that includes first- and second-generation antipsychotics (APs) and agents such as metoclopramide that are used for the treatment of nausea and gastrointestinal dysmotility. While TD can affect people of all ages, older age is associated with increased risk of TD and also with the emergence of TD occurring after shorter treatment durations and lower dosages of DRBAs. TD is characterized by involuntary movements that include the face, limbs, and trunk, and is associated with increased comorbidities, social stigmatization, and impaired physical and mental health. Once present, TD tends to persist despite AP dose adjustment or discontinuation. Even with the use of US Food and Drug Administration (FDA)-approved medications for TD, symptoms may persist. Because the leading hypothesis for the pathophysiology of TD has been dysregulation of dopamine transmission due to treatment with DRBAs, APs that avoid postsynaptic dopamine receptor blockade may provide an alternative therapeutic approach for patients who require an AP. In this review, we discuss the risks, burdens, prevention, and management of TD, with a focus on older people. [ABSTRACT FROM AUTHOR]

Tourette's syndrome (TS) is a pediatric onset of neuropsychiatric disorder characterized by motor and vocal tics. First line medication is dopaminergic blocking agents. Yet, these drugs are not effective in all patients and sometimes the side effects are intolerance. Cannabis and its derivatives are to use as an adjuvant treatment. They are used to improve tics in TS patients who failed from the first line treatment. The aim of the present report was to describe the clinical course after using the Government Pharmaceutical Organization (GPO) medical cannabis extraction product as an adjuvant treatment in TS patient. Here, the researchers reported a case of a 26-year-old female patient who had TS. She had received sublingual medical cannabis product. The clinical course and disease severity were recorded before and during the administration of the medical cannabis extraction product using several standards severity score: The Yale Global Tic Severity Scale (YGTSS), Tourette's Syndrome Severity Scale (TSSS), Tourette's Disorder Scale (TODS), and quality of life using a standardized measure of health-related quality of life developed by the Euro Quality of life group (EQ-5D-5L). The researchers' observation showed that sublingual administration of medical cannabis extraction product [tetrahydrocannabinol (THC):cannabidiol (CBD) 1:1 and THC enriched] improved both motor and vocal tics without significant adverse effect that came out to be improving the patient's quality of life as a whole. [ABSTRACT FROM AUTHOR]

Background: Depression is the strongest predictor of quality of life for Parkinson's disease (PD). Presentation of Case: A 56 years old man came with the main complaint of difficulty sleeping due to thinking about tremors in his left hand since 6 months. Complaints are accompanied by feelings of sadness, lack of enthusiasm, and decreased appetite accompanied by weight loss. The patient had been diagnosed with PD 8 years previously and was on medication. One month before the visit, the patient underwent a thalamotomy operation. After surgery, the patient received therapy in the form of a combination tablet of levodopa/carbidopa/entacapaone (100/25/200 mg) 4×1 tablet and 1×2 mg of ropirinole. On the Beck Depression Inventory (BDI) examination, a score of 23 was obtained and on the Montgomery Asberg Depression Rating Scale (MADRS) examination a score of 31 was obtained, both of which correspond to major depression. The patient was diagnosed with a major depressive episode without psychotic symptoms and was given escitalopram therapy 1×10 mg and lorazepam 1×2 mg. Patients also received biofeedback therapy with family psychoeducation and supportive psychotherapy. At the time of control, the patient admitted to feeling calmer and able to sleep after receiving therapy. Conclusion: Escitalopram has good efficacy for the management of depression in PD patients. [ABSTRACT FROM AUTHOR]

Freezing of gait (FOG) is a common and challenging clinical symptom in Parkinson’s disease. In this review, we summarise the recent insights into freezing of gait and highlight the strategies that should be considered to improve future treatment. There is a need to develop individualised and on-demand therapies, through improved detection and wearable technologies. Whilst there already exist a number of pharmacological (e.g., dopaminergic and beyond dopamine), non-pharmacological (physiotherapy and cueing, cognitive training, and non-invasive brain stimulation) and surgical approaches to freezing (i.e., dual-site deep brain stimulation, closed-loop programming), an integrated collaborative approach to future research in this complex area will be necessary to systematically investigate new therapeutic avenues. A review of the literature suggests standardising how gait freezing is measured, enriching patient cohorts for preventative studies, and harnessing the power of existing data, could help lead to more effective treatments for freezing of gait and offer relief to many patients.

Parkinson's disease (PD) often shows disrupted brain connectivity and autonomic dysfunctions, progressing alongside with motor and cognitive decline. Recently, PD has been linked to a reduced sensitivity to cardiac inputs, that is, cardiac interoception. Altogether, those signs suggest that PD causes an altered brain-heart connection whose mechanisms remain unclear. Our study aimed to explore the large-scale network disruptions and the neurophysiology of disrupted interoceptive mechanisms in PD. We focused on examining the alterations in brain-heart coupling in PD and their potential connection to motor symptoms. We developed a proof-of-concept method to quantify relationships between the co-fluctuations of brain connectivity and cardiac sympathetic and parasympathetic activities. We quantified the brain-heart couplings from electroencephalogram and electrocardiogram recordings from PD patients on and off dopaminergic medication, as well as in healthy individuals at rest. Our results show that the couplings of fluctuating alpha and gamma connectivity with cardiac sympathetic dynamics are reduced in PD patients, as compared to healthy individuals. Furthermore, we show that PD patients under dopamine medication recover part of the brain-heart coupling, in proportion with the reduced motor symptoms. Our proposal offers a promising approach to unveil the physiopathology of PD and promoting the development of new evaluation methods for the early stages of the disease., (© 2024 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Previous literature supports antipsychotics' (AP) efficacy in acute first-episode psychosis (FEP) in terms of symptomatology and functioning but also a cognitive detrimental effect. However, regarding functional recovery in stabilised patients, these effects are not clear. Therefore, the main aim of this study is to investigate dopaminergic/anticholinergic burden of (AP) on psychosocial functioning in FEP. We also examined whether cognitive impairment may mediate these effects on functioning. Methods: A total of 157 FEP participants were assessed at study entry, and at 2 months and 2 years after remission of the acute episode. The primary outcomes were social functioning as measured by the functioning assessment short test (FAST). Cognitive domains were assessed as potential mediators. Dopaminergic and anticholinergic AP burden on 2-year psychosocial functioning [measured with chlorpromazine (CPZ) and drug burden index] were independent variables. Secondary outcomes were clinical and socio-demographic variables. Results: Mediation analysis found a statistical but not meaningful contribution of dopaminergic receptor blockade burden to worse functioning mediated by cognition (for every 600 CPZ equivalent points, 2-year FAST score increased 1.38 points). Regarding verbal memory and attention, there was an indirect effect of CPZ burden on FAST (b = 0.0045, 95% CI 0.0011–0.0091) and (b = 0.0026, 95% CI 0.0001–0.0006) respectively. However, only verbal memory post hoc analyses showed a significant indirect effect (b = 0.009, 95% CI 0.033–0.0151) adding premorbid IQ as covariate. We did not find significant results for anticholinergic burden. Conclusion: CPZ dose effect over functioning is mediated by verbal memory but this association appears barely relevant. [ABSTRACT FROM AUTHOR]

Background: Work in humans has shown that impulsivity can be advantageous in certain settings. However, evidence for so-called functional impulsivity is lacking in experimental animals. Aims: This study investigated the contexts in which high impulsive (HI) rats show an advantage in performance compared with mid- (MI) and low impulsive (LI) rats. We also assessed the effects of dopaminergic and noradrenergic agents to investigate underlying neurotransmitter mechanisms. Methods: We tested rats on a variable inter-trial interval (ITI) version of the 5-choice serial reaction time task (5CSRTT). Rats received systemic injections of methylphenidate (MPH, 1 mg/kg and 3 mg/kg), atomoxetine (ATO, 0.3 mg/kg and 1 mg/kg), amphetamine (AMPH, 0.2 mg/kg), the alpha-2a adrenoceptor antagonist atipamezole (ATI, 0.3 mg/kg) and the alpha-1 adrenoceptor agonist phenylephrine (PHEN, 1 mg/kg) prior to behavioural testing. Results: Unlike LI rats, HI rats exhibited superior performance, earning more reinforcers, on short ITI trials, when the task required rapid responding. MPH, AMPH and ATI improved performance on short ITI trials and increased impulsivity in long ITI trials, recapitulating the behavioural profile of HI. In contrast, ATO and PHEN impaired performance on short ITI trials and decreased impulsivity, thus mimicking the behavioural profile of LI rats. The effects of ATO were greater on MI rats and LI rats. Conclusions: These findings indicate that impulsivity can be advantageous when rapid focusing and actions are required, an effect that may depend on increased dopamine neurotransmission. Conversely, activation of the noradrenergic system, with ATO and PHEN, led to a general inhibition of responding. [ABSTRACT FROM AUTHOR]

Background and Objectives: Quality of life (QoL) in Parkinson's disease (PD) depends on multiple factors. Due to PD treatment and accompanying, age-related or independent comorbidities, pill burden is often high. The relation of QoL and pharmacotherapy for comorbidities in PD has not been widely studied. This study investigated if and to what extent non-dopaminergic drugs are related to QoL in PD. Second, the impact of demographics and non-motor symptoms were evaluated. A better understanding of the impact of different non-dopaminergic drugs and polypharmacy on QoL will have added value in selecting appropriate (medication) interventions. Methods: In a cross-sectional analysis, medication prescription data of 209 PD patients were analyzed and grouped according to the Rx-Risk comorbidity index. QoL was measured using the PDQ-39 questionnaire. Non-motor symptoms were analyzed with the Non-Motor Symptoms questionnaire. Independent factors associated with a reduced QoL were identified with a multivariate linear regression analysis. Results: Non-dopaminergic drugs, subdivided into Rx-Risk comorbidity categories, were not associated with reduced QoL, except for the use of anti-epileptic drugs. However, using more daily non-dopaminergic drugs was also negatively associated with QoL, as well as female sex, increased PD severity, and more non-motor symptoms. Contraindicated non-dopaminergic medication was barely prescribed (0.4%). Conclusion: Non-dopaminergic drugs are frequently prescribed, and higher numbers are associated with impaired QoL in PD. However, when divided in drug types, only anti-epileptic drugs were negatively associated with QoL. In these patients, physicians might improve QoL by further optimizing the condition it was prescribed for (e.g., pain or anxiety), or managing of side effects. Trial registration: Netherlands Trial Register; NL4360. [ABSTRACT FROM AUTHOR]

Atremorine is a novel bioproduct obtained by nondenaturing biotechnological processes from a genetic species of Vicia faba. Atremorine is a potent dopamine (DA) enhancer with powerful effects on the neuronal dopaminergic system, acting as a neuroprotective agent in Parkinson's disease (PD). Over 97% of PD patients respond to a single dose of Atremorine (5 g, p.o.) 1 h after administration. This response is gender‐, time‐, dose‐, and genotype‐dependent, with optimal doses ranging from 5 to 20 g/day, depending upon disease severity and concomitant medication. Drug‐free patients show an increase in DA levels from 12.14 ± 0.34 pg/ml to 6463.21 ± 1306.90 pg/ml; and patients chronically treated with anti‐PD drugs show an increase in DA levels from 1321.53 ± 389.94 pg/ml to 16,028.54 ± 4783.98 pg/ml, indicating that Atremorine potentiates the dopaminergic effects of conventional anti‐PD drugs. Atremorine also influences the levels of other neurotransmitters (adrenaline, noradrenaline) and hormones which are regulated by DA (e.g., prolactin, PRL), with no effect on serotonin or histamine. The variability in Atremorine‐induced DA response is highly attributable to pharmacogenetic factors. Polymorphic variants in pathogenic (SNCA, NUCKS1, ITGA8, GPNMB, GCH1, BCKDK, APOE, LRRK2, ACMSD), mechanistic (DRD2), metabolic (CYP2D6, CYP2C9, CYP2C19, CYP3A4/5, NAT2), transporter (ABCB1, SLC6A2, SLC6A3, SLC6A4) and pleiotropic genes (APOE) influence the DA response to Atremorine and its psychomotor and brain effects. Atremorine enhances DNA methylation and displays epigenetic activity via modulation of the pharmacoepigenetic network. Atremorine is a novel neuroprotective agent for dopaminergic neurons with potential prophylactic and therapeutic activity in PD. [ABSTRACT FROM AUTHOR]

Advanced Parkinson's disease is inconsistently defined, and evidence is lacking in relation to device-aided therapies. To update existing reviews of intrajejunal infusion of levodopa/carbidopa (LCIG), we performed a literature search for relevant articles (to November 3, 2020) using PubMed supplemented by hand searching. Retrieved articles were categorized by relevance to identified research questions, including motor complications and symptoms; nonmotor symptoms; functioning, quality of life, and caregiver burden; optimal timing of treatment initiation and administration duration; discontinuation; and complications. Most eligible studies (n = 56) were open-label, observational studies including relatively small patient numbers. LCIG consistently reduces OFF time and increased ON time without troublesome dyskinesia with varying effects regarding ON time with troublesome dyskinesia and the possibility of diphasic dyskinesia. More recent evidence provides some increased support for the benefits of LCIG in relation to nonmotor symptoms, quality of life, activities of daily living, and reduced caregiver burden. Patient age does not appear to significantly impact the effectiveness of LCIG. Discontinuation rates with LCIG (~17%-26%) commonly relate to device-related issues, although the ability to easily discontinue LCIG may represent a potential benefit. LCIG may be a favorable option for patients with advanced Parkinson's disease who show predominant nonmotor symptoms and vulnerability to complications of other advanced therapy modalities. Larger, well-controlled studies, including precise investigation of cost effectiveness, would further assist treatment selection. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Purpose: Dyskinesia-hyperpyrexia syndrome (DHS) is a rare but life-threatening disease. The clinical manifestations of this syndrome overlap substantially with Parkinson hyperpyrexia syndrome and serotonin syndrome and are often confused by clinicians. The purpose of this review was to enable clinicians to recognize this syndrome and thereby reach a correct diagnosis and provide optimal treatments to improve prognosis in clinical practice. Methods: Using the methodology described in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, we conducted a literature search of the PubMed, Embase, and MEDLINE databases using keywords in titles and abstracts of published literature. Quality assessment was performed using the modified Newcastle-Ottawa scale. Results: A total of 11 patients obtained from nine publications were included in this systematic review. All of the cases occurred in patients with advanced Parkinson's disease (PD) of long disease duration. High ambient temperature was the most common trigger of this syndrome. Hyperpyrexia and dyskinesias were present in all cases. The consciousness disturbances of this syndrome included confusion, hallucination, and lethargy or stupor. Autonomic dysfunction (except for hyperpyrexia) is uncommon in DHS, and only two patients presented with tachycardia. The treatment of this syndrome included supportive interventions (including rehydration, anti-pyretic and anti-infection treatments, and maintaining electrolyte balance), dopaminergic drug reduction and sedation. Two patients died due to DHS. Conclusions: We summarized the triggers, clinical features, and treatments of all reported dyskinesia-hyperpyrexia syndrome cases, proposed guiding diagnostic criteria, and established a flow chart to guide diagnoses to quickly identify these three syndromes in clinical practice. [ABSTRACT FROM AUTHOR]

Aromatic l-amino acid decarboxylase (AADC) deficiency is a complex inherited neurological disorder of monoamine synthesis which results in dopamine and serotonin deficiency. The majority of affected individuals have variable, though often severe cognitive and motor delay, with a complex movement disorder and high risk of premature mortality. For most, standard pharmacological treatment provides only limited clinical benefit. Promising gene therapy approaches are emerging, though may not be either suitable or easily accessible for all patients. To characterize the underlying disease pathophysiology and guide precision therapies, we generated a patient-derived midbrain dopaminergic neuronal model of AADC deficiency from induced pluripotent stem cells. The neuronal model recapitulates key disease features, including absent AADC enzyme activity and dysregulated dopamine metabolism. We observed developmental defects affecting synaptic maturation and neuronal electrical properties, which were improved by lentiviral gene therapy. Bioinformatic and biochemical analyses on recombinant AADC predicted that the activity of one variant could be improved by l-3,4-dihydroxyphenylalanine (l-DOPA) administration; this hypothesis was corroborated in the patient-derived neuronal model, where l-DOPA treatment leads to amelioration of dopamine metabolites. Our study has shown that patient-derived disease modelling provides further insight into the neurodevelopmental sequelae of AADC deficiency, as well as a robust platform to investigate and develop personalized therapeutic approaches. [ABSTRACT FROM AUTHOR]

Human bone marrow mesenchymal stem cells (h-BMSCs) have the potential to differentiate into dopaminergic neuron-like cells to treat Parkinson's disease. The Notch signaling pathway has been implicated in the regulation of cell fate decisions such as differentiation of BMSCs. This study investigated changes in the expression of Notch-related genes in the differentiation of BMSCs in vitro into dopaminergic (DA) neuron-like cells. BMSCs transfected with empty lentiviral vectors served as the control group and those transfected with NTN and Lmx1α recombinant lentiviral vectors served as the experimental group. After induction and culture of NTN and Lmx1α-transfected h-BMSCs for 21 days, the cells exhibited features of dopaminergic neuron-like cells, which were observed by transmission and scanning electron microscopy and verified by immunofluorescence of tyrosine hydroxylase (TH) and dopamine transporter (DAT). These induced cells could secrete dopamine and had basic action potentials. Expression of the neural stem cell (NSC) markers, including octamer-binding protein (Oct4), paired box gene 6 (Pax6), and sex determining region Y-box 1 (SOX1), increased on day 14 of induction and decreased on day 21 of induction during differentiation. The human Notch signaling pathway PCR array showed a differential expression of Notch-related genes during the differentiation of h-BMSCs into DA neuron-like cells in vitro relative to that in the control group. In conclusion, h-BMSCs overexpressing NTN and Lmx1α can successfully be induced to differentiate into dopaminergic neuron-like cells with a neuronal phenotype exhibiting fundamental biological functions in vitro, and NTN and Lmx1α may affect the expression of Notch-related genes during differentiation. [ABSTRACT FROM AUTHOR]

Objective: To clarify whether antiparkinsonian drugs contribute to nocturnal sleep disturbances in patients with Parkinson's disease (PD). Background: Although the major antiparkinsonian drugs L-dopa and dopamine agonists (DAs) have been found to affect sleep, little is known about the effects of specific drugs on sleep in PD patients. Methods: The study participants consisted of 112 PD patients (median age 72.5 years [inter-quartile range: IQR 65–79]; mean disease duration 8.44 years [standard deviation: 7.33]; median Hoehn and Yahr stage 3 [IQR 2–3.75]) taking one of three types of non-ergot extended-release DAs (rotigotine 32; pramipexole 44; ropinirole 36) with or without L-dopa (median daily total dosage of antiparkinsonian drugs 525.5 mg [IQR 376.25–658] levodopa equivalent dose [LED]). Participants were assessed using the PD Sleep Scale-2 (PDSS-2). Results: For the whole PD patient cohort, the PDSS-2 sleep disturbance domain score and the scores for item 1 assessing sleep quality and item 8 assessing nocturia were positively correlated with daily total dosage of antiparkinsonian drugs and dosage of L-dopa, but not with the dosage of DAs. Sub-analysis according to DA treatment revealed that DA dosage was not correlated with item 1 or 8 score in any of the subgroups. The LED ratio of rotigotine to the total dosage of antiparkinsonian drugs was inversely correlated with the item 1 score. Conclusions: These data suggest that antiparkinsonian drugs, in particular L-dopa, adversely affect nocturnal sleep in PD patients, especially in terms of sleep quality and nocturia. Thus, adjusting both the total dosage of antiparkinsonian drugs and the dose-ratio of L-dopa might be key actions for alleviating poor sleep quality in patients with PD. Among DAs, we found a clear positive correlation between the dose-ratio of rotigotine and sleep quality. Thus, partial L-dopa replacement with rotigotine could improve sleep quality in patients with PD. [ABSTRACT FROM AUTHOR]

Identifying the advanced stage in Parkinson's disease (PD) is crucial for shifting from conventional to device-aided therapies. The criteria to define the onset of advanced PD have been based on lengthy and disabling daily off-times, troublesome dyskinesia and complex therapeutic regimes, but have also included invalidating non-dopaminergic symptoms, such as dementia, falls or dysphagia. These last problems usually appear in a much later stage of the advanced PD. The key to the definition of advanced PD should be the lack of adequate PD control of both motor and non-motor dopaminergic symptoms. The patient's judgment about the quality of their response to conventional therapy is also critical to establish the advanced stage. The early identification of this phase allows maintaining the patient's functional state whenever appropriate treatments are applied. We should keep the term advanced stage when the dopaminergic symptoms responsive to device-aided therapy are preponderant. When invalidating non-dopaminergic symptoms dominate the clinical picture, the term post-advanced stage could be more suitable. [ABSTRACT FROM AUTHOR]

Background: The enzyme ATP13A2 holds promise as biomarker in Parkinson's disease (PD). No study has examined the content of ATP13A2 in serum and cerebrospinal fluid (CSF) in idiopathic PD cohorts, or how ATP13A2 relates to the clinical features of the disease.Methods: ATP13A2 concentration was evaluated with ELISA and immunoblotting. Correlations of serum and CSF ATP13A2 with clinical parameters were examined. The antiparkinsonian medication regimen was expressed as levodopa equivalent dose (LED, mg/day).Results: Serum ATP13A2 concentration was similar in patients and controls, and it correlated with LED and MDS-UPDRS part-IV score (p < .0001), a scale which allows evaluating motor complications. LED also correlated with MDS-UPDRS part-IV score (p < .0001). Serum ATP13A2 concentration and LED were higher in patients with motor complications than in patients without motor complications (p < .0001). The ratio of serum ATP13A2 concentration versus LED was calculated, and mean value was similar in patients with or without motor complications. ATP13A2 concentration in the CSF was undetectable in many subjects because the ELISA assay was hampered by its detection limit. Immunoblotting indicated that CSF ATP13A2 content was higher in patients relative to controls (p = .0002), and no clinical correlations were found.Conclusions: Increasing LED enhanced serum ATP13A2 concentration and facilitated the development of motor complications. There is a direct relationship between serum ATP13A2 level and the dose intensity of the antiparkinsonian dopaminergic medication. The associations between serum ATP13A2 and LED suggest that serum ATP13A2 content might be a marker of dopamine replacement therapy. [ABSTRACT FROM AUTHOR]

Parkinson disease (PD) is a complex heterogeneous neurodegenerative disorder. Association studies have revealed numerous genetic risk loci and variants, and about 5-10% suffer from a monogenic form. Because the presentation and course of PD is unique to each patient, personalized symptomatic treatment should ideally be offered to treat the most disabling motor and non-motor symptoms. Indeed, clinical milestones and treatment complications that appear during disease progression are influenced by the genetic imprint. With recent advances in PD, more patients live longer to become eligible for device-aided therapies, such as apomorphine continuous subcutaneous infusion, levodopa duodenal gel infusion, and deep brain stimulation surgery, each with its own inclusion and exclusion criteria, advantages and disadvantages. Because genetic variants influence the expression of particular clinical profiles, factors for better or worse outcomes for device-aided therapies may then be proactively identified. For example, mutations in PRKN, LRRK2 and GBA express phenotypes that favor suitability for different device therapies, although with marked differences in the therapeutic window; whereas multiplications of SNCA express phenotypes that make them less desirable for device therapies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: Presentation of the role of the dopaminergic system and microRNAs in the development of depression after glucocorticoids (GCs) therapy. Views: GCs are steroid hormones secreted by the adrenal glands, and their synthesis is regulated by the hypothalamic-pituitary-adrenal (HPA) axis. The secretion of GCs (cortisol in humans and corticosterone in rodents) is dependent directly on corticotropin, secreted from the pituitary gland and indirectly on the corticotropin-releasing factor, a hormone released from the paraventricular nuclei of the hypothalamus. Prolonged treatment with GCs disrupts the functions of the HPA axis, impairs the dopaminergic system, suppresses hippocampal neurogenesis and sensitizes the amygdala, leading to an increased susceptibility to depression. This is an important problem because GCs are commonly prescribed for a broad range of medical conditions, including inflammatory and autoimmune disorders. The action of GCs may be at least partially regulated by epigenetic mechanisms (microRNAs), in addition to which microRNAs modulate GCs production and cellular response to GCs. Conclusions: The administration of GCs may lead to changes in dopaminergic system activity (e.g. D2 receptors activity), which significantly contribute to the predisposition to depression. Additionally, GCs therapy may cause changes in the activity of micro-RNAs (e.g. miR-124), which exacerbates symptoms of depression. Searching for specific changes in microRNA expression will provide clinically practical and easily applicable biomarkers of depression risk and new forms of pharmacotherapy in GC-induced depression. [ABSTRACT FROM AUTHOR]