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NPJ Parkinson's Disease Jun 2024The effects of subthalamic nucleus deep brain stimulation (STN-DBS) on anxiety in Parkinson's disease (PD) are understudied. We identified clinical predictors of STN-DBS...
The effects of subthalamic nucleus deep brain stimulation (STN-DBS) on anxiety in Parkinson's disease (PD) are understudied. We identified clinical predictors of STN-DBS effects on anxiety in this study. In this prospective, open-label, multicentre study, we assessed patients with anxiety undergoing STN-DBS for PD preoperatively and at 6-month follow-up postoperatively. We assessed the Hospital Anxiety and Depression Scale (HADS-anxiety and depression subscales), Unified PD Rating Scale-motor examination, Scales for Outcomes in PD-motor (SCOPA-M)-activities of daily living (ADL) and -motor complications, Non-Motor Symptom Scale (NMSS), PDQuestionnaire-8 (PDQ-8), and levodopa-equivalent daily dose. We tested changes at follow-up with Wilcoxon signed-rank test and corrected for multiple comparisons (Bonferroni method). We identified patients with a clinically relevant anxiety improvement of anxiety based on a designated threshold of ½ standard deviation of baseline HADS-anxiety. Moreover, we investigated predictors of HADS-anxiety changes with correlations and linear regressions. We included 50 patients with clinically relevant baseline anxiety (i.e., HADS-anxiety ≥ 8) aged 63.1 years ± 8.3 with 10.4 years ± 4.5 PD duration. HADS-anxiety improved significantly at 6-month follow-up as 80% of our cohort experienced clinically relevant anxiety improvement. In predictor analyses, worse baseline SCOPA-ADL and NMSS-urinary domain were associated with greater HADS-anxiety improvements. HADS-anxiety and PDQ-8 changes correlated moderately. Worse preoperative ADL and urinary symptoms predicted favourable postoperative anxiety outcome, which in turn was directly proportionate to greater QoL improvement. This study highlights the importance of detailed anxiety assessments alongside other non-motor and motor symptoms when advising and monitoring patients undergoing STN-DBS for PD.
PubMed: 38851717
DOI: 10.1038/s41531-024-00701-6 -
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 -
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 -
Ideggyogyaszati Szemle May 2024
The aim of this study is to comprehensively determine the types of affected fibers in Parkinson’s disease (PD) patients by employing nerve conduction studies...
BACKGROUND AND PURPOSE
The aim of this study is to comprehensively determine the types of affected fibers in Parkinson’s disease (PD) patients by employing nerve conduction studies (NCS), sympathetic skin response (SSR) examinations, and current perception threshold (CPT) testing and to analyze the correlation between levodopa use and nerve involvement.
.METHODS
This retrospective study included 36 clinically diagnosed PD patients who were recruited between January 2018 and April 2019. All patients underwent NCS, SSR testing, and CPT sensory examinations. Additionally, the PD patients were assessed for disease staging using the Hoehn and Yahr (H-Y) scale.
.RESULTS
Fifteen patients were included in the tremor-dominant subtype, ten patients in the rigid-dominant subtype, and eleven patients in the mixed subtype. Eleven patients were using levodopa, while twenty-five patients had never used any anti-Parkinson’s medication. Ten patients (28%) showed abnormal sympathetic skin responses (SSR). The CPT examination revealed sensory abnormalities in twenty-four patients (67%), with eighteen patients (75%) experiencing sensory hypersensitivity and six patients (25%) experiencing sensory hypoesthesia. Twelve patients (33%) had normal CPT results. Among the patients with abnormal CPT findings, seven cases (29%) involved large myelinated fiber damage, twenty-two cases (92%) involved small myelinated fiber damage, and nineteen cases (79%) involved unmyelinated fiber damage. The rate of sensory abnormalities was 64% (7/11) in the levodopa group and 68% (17/25) in the non-levodopa group, with no statistically significant difference between the two groups.
.CONCLUSION
The incidence of abnormal CPT findings in PD patients was higher than that of abnormal SSR responses, suggesting that nerve fiber damage primarily affects small fiber nerves (SFN).
.Topics: Humans; Levodopa; Parkinson Disease; Middle Aged; Female; Aged; Retrospective Studies; Male; Neural Conduction; Nerve Fibers; Antiparkinson Agents; Peripheral Nerves
PubMed: 38829252
DOI: 10.18071/isz.77.0161 -
Bioorganic & Medicinal Chemistry Letters Sep 2024The tyrosinase (TYR) enzyme catalyses sequential reactions in the melanogenesis pathway: l-tyrosine is oxidised to yield L-3,4-dihydroxyphenylalanine (l-dopa), which in...
The tyrosinase (TYR) enzyme catalyses sequential reactions in the melanogenesis pathway: l-tyrosine is oxidised to yield L-3,4-dihydroxyphenylalanine (l-dopa), which in turn is converted to dopaquinone. These two reactions are the first two steps of melanin biosynthesis and are rate limiting. The accumulation or overproduction of melanin may cause skin hyperpigmentation and inhibitors of TYR are thus of interest to the cosmeceutical industry. Several TYR inhibitors are used to treat skin hyperpigmentation, however, some are ineffective and possess questionable safety profiles. This emphasises the need to develop novel TYR inhibitors with better safety and efficacy profiles. The small molecule, 3-hydroxycoumarin, has been reported to be a good potency TYR inhibitor (IC = 2.49 µM), and based on this, a series of eight structurally related 3-hydroxyquinolin-2(1H)-one derivatives were synthesised with the aim to discover novel TYR inhibitors. The results showed that four of the derivatives inhibited TYR from the champignon mushroom Agaricus bisporus (abTYR) with IC < 6.11 µM. The most potent inhibitor displayed an IC value of 2.52 μM. Under the same conditions, the reference inhibitors, thiamidol and kojic acid, inhibited abTYR with IC values of 0.130 and 26.4 μM, respectively. Based on the small molecular structures of the active 3-hydroxyquinolin-2(1H)-one inhibitors which are amenable to structure optimisation, it may be concluded that this class of compounds are good leads for the design of TYR inhibitors for cosmeceutical applications.
Topics: Monophenol Monooxygenase; Enzyme Inhibitors; Structure-Activity Relationship; Molecular Structure; Agaricus; Dose-Response Relationship, Drug
PubMed: 38823727
DOI: 10.1016/j.bmcl.2024.129823 -
Scientific Reports May 2024Voriconazole is a second-generation azole used to treat serious fungal infections. Visual hallucinations constitute a representative adverse event caused by...
Association between voriconazole-induced visual hallucination and dopamine in an analysis of the food and drug administration (FDA) adverse event reporting system database.
Voriconazole is a second-generation azole used to treat serious fungal infections. Visual hallucinations constitute a representative adverse event caused by voriconazole. However, its mechanism of action remains unclear. In patients with schizophrenia or Parkinson's disease, the frequency of visual hallucinations is associated with brain dopamine levels. This study investigated the frequency of visual hallucinations in patients treated with voriconazole alone or in combination with dopaminergic medicines or dopamine antagonists, using data collected from the Food and Drug Administration Adverse event Reporting System (FAERS). The frequency of visual hallucinations with voriconazole alone and in combination with a dopaminergic medicine (levodopa) or dopamine antagonists (risperidone and chlorpromazine) was compared using data from the FAERS between 2004 and 2023, using the reporting odds ratio (ROR) with relevant 95% confidence intervals (CI). The reference group comprised patients who had been administered voriconazole without dopaminergic medication or dopamine antagonists. Of the patients, 22,839, 90,810, 109,757, 6,435, 20, 83, and 26, respectively were treated with voriconazole, levodopa, risperidone, chlorpromazine, voriconazole plus levodopa, voriconazole plus risperidone, and voriconazole plus chlorpromazine. The occurrence of visual hallucinations increased when used in combination with levodopa (ROR = 12.302, 95% CI = 3.587-42.183). No increase in incidence was associated with the concomitant use of dopamine antagonists (risperidone, ROR = 1.721, 95% CI = 0.421-7.030; chlorpromazine, ROR = none, 95% CI = none). Dopaminergic medicine may increase the risk of visual hallucinations in patients treated with voriconazole. Whether voriconazole positively modulates dopamine production warrants further investigation using a translational research approach.
Topics: Humans; Voriconazole; Hallucinations; United States; United States Food and Drug Administration; Male; Female; Aged; Middle Aged; Dopamine; Levodopa; Adult; Antifungal Agents; Adverse Drug Reaction Reporting Systems; Chlorpromazine; Risperidone; Dopamine Antagonists; Parkinson Disease; Young Adult; Adolescent; Databases, Factual
PubMed: 38822123
DOI: 10.1038/s41598-024-63504-y -
Communications Biology May 2024Parkinson's disease is managed using levodopa; however, as Parkinson's disease progresses, patients require increased doses of levodopa, which can cause undesirable side...
Parkinson's disease is managed using levodopa; however, as Parkinson's disease progresses, patients require increased doses of levodopa, which can cause undesirable side effects. Additionally, the oral bioavailability of levodopa decreases in Parkinson's disease patients due to the increased metabolism of levodopa to dopamine by gut bacteria, Enterococcus faecalis, resulting in decreased neuronal uptake and dopamine formation. Parkinson's disease patients have varying levels of these bacteria. Thus, decreasing bacterial metabolism is a promising therapeutic approach to enhance the bioavailability of levodopa in the brain. In this work, we show that Mito-ortho-HNK, formed by modification of a naturally occurring molecule, honokiol, conjugated to a triphenylphosphonium moiety, mitigates the metabolism of levodopa-alone or combined with carbidopa-to dopamine. Mito-ortho-HNK suppresses the growth of E. faecalis, decreases dopamine levels in the gut, and increases dopamine levels in the brain. Mitigating the gut bacterial metabolism of levodopa as shown here could enhance its efficacy.
Topics: Levodopa; Gastrointestinal Microbiome; Dopamine; Parkinson Disease; Brain; Animals; Enterococcus faecalis; Male; Antiparkinson Agents; Carbidopa; Humans; Biphenyl Compounds; Mice; Organophosphorus Compounds; Mice, Inbred C57BL
PubMed: 38816577
DOI: 10.1038/s42003-024-06330-2 -
Nature Communications May 2024Circadian rhythms have been shown in the subthalamic nucleus (STN) in Parkinson's disease (PD), but only a few studies have focused on the globus pallidus internus...
Circadian rhythms have been shown in the subthalamic nucleus (STN) in Parkinson's disease (PD), but only a few studies have focused on the globus pallidus internus (GPi). This retrospective study investigates GPi circadian rhythms in a large cohort of subjects with PD (130 recordings from 93 subjects) with GPi activity chronically recorded in their home environment. We found a significant change in GPi activity between daytime and nighttime in most subjects (82.4%), with a reduction in GPi activity at nighttime in 56.2% of recordings and an increase in activity in 26.2%. GPi activity in higher frequency bands ( > 20 Hz) was more likely to decrease at night and in patients taking extended-release levodopa medication. Our results suggest that circadian fluctuations in the GPi vary across individuals and that increased power at night might be due to the reemergence of pathological neural activity. These findings should be considered to ensure successful implementation of adaptive neurostimulation paradigms in the real-world.
Topics: Humans; Globus Pallidus; Parkinson Disease; Circadian Rhythm; Male; Female; Middle Aged; Retrospective Studies; Aged; Deep Brain Stimulation; Levodopa; Subthalamic Nucleus
PubMed: 38816390
DOI: 10.1038/s41467-024-48732-0 -
British Journal of Neuroscience Nursing Aug 2023Advanced Parkinson's disease affects patients with existing Parkinson's disease by further deteriorating their physical and cognitive functions. In this commentary we...
Advanced Parkinson's disease affects patients with existing Parkinson's disease by further deteriorating their physical and cognitive functions. In this commentary we critically assess an economic evaluation which compared the cost-effectiveness of levodopa/carbidopa intestinal gel against standard of care in treating patients with Advanced Parkinson's disease. While the economic evaluation indicated that levodopa/carbidopa intestinal gel could be cost-effective within the UK parameters, we highlight important limitations related to its design, modelling and analysis. Future research should consider the incorporation of a separate arm dedicated to the re-infusion of apomorphine on eligible Advanced Parkinson's disease patients, a wider set of levodopa/carbidopa intestinal gel adverse events and related costs, and a sub-group analysis on different socio-economic strata.
PubMed: 38813118
DOI: 10.12968/bjnn.2023.19.4.140