Application of the concept of continuous dopaminergic stimulation for the management of Parkinson's disease.
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ABSTRACT:
SUBMITTER: Lv Q
PROVIDER: S-EPMC5561951 | biostudies-other | 2013 Oct
REPOSITORIES: biostudies-other
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Project description:Continuous dopaminergic stimulation in Parkinson's disease (PD) has several advantages over pulsatile, non-continuous, stimulation. These therapies currently consist of pump-based and transcutaneous therapies and are based on a more constant delivery of the dopaminergic drug resulting in continuous dopaminergic stimulation and a more stable treatment effect. Several clinical and experimental observations have shown that continuous stimulation of dopaminergic receptors induces fewer complications, such as dyskinesia, compared to pulsatile stimulation. Currently available non-oral pharmacological continuous therapies in PD include the transdermal Rotigotine (RTG) patch, infusion therapies with Apomorphine and Intrajejunal Levodopa (IJLI) and the Rivastigmine patch. Here we aim to provide a concise review of these current therapies and discuss ongoing and future developments of continuous non-oral pharmacological dopaminergic therapies in PD.
| S-EPMC6311379 | biostudies-literature
Project description:BackgroundIn patients with Parkinson's disease, stimulation above the subthalamic nucleus (STN) may engage the pallidofugal fibers and directly suppress dyskinesia.ObjectivesThe objective of this study was to evaluate the effect of interleaving stimulation through a dorsal deep brain stimulation contact above the STN in a cohort of PD patients and to define the volume of tissue activated with antidyskinesia effects.MethodsWe analyzed the Core Assessment Program for Surgical Interventional Therapies dyskinesia scale, Unified Parkinson's Disease Rating Scale parts III and IV, and other endpoints in 20 patients with interleaving stimulation for management of dyskinesia. Individual models of volume of tissue activated and heat maps were used to identify stimulation sites with antidyskinesia effects.ResultsThe Core Assessment Program for Surgical Interventional Therapies dyskinesia score in the on medication phase improved 70.9 ± 20.6% from baseline with noninterleaved settings (P < 0.003). With interleaved settings, dyskinesia improved 82.0 ± 27.3% from baseline (P < 0.001) and 61.6 ± 39.3% from the noninterleaved phase (P = 0.006). The heat map showed a concentration of volume of tissue activated dorsally to the STN during the interleaved setting with an antidyskinesia effect.ConclusionInterleaved deep brain stimulation using the dorsal contacts can directly suppress dyskinesia, probably because of the involvement of the pallidofugal tract, allowing more conservative medication reduction. © 2019 International Parkinson and Movement Disorder Society.
| S-EPMC10957149 | biostudies-literature
Project description:Background:Spinal cord stimulation (SCS) exerts neuroprotective effects in animal models of Parkinson's disease (PD). Conventional stimulation techniques entail limited stimulation time and restricted movement of animals, warranting the need for optimizing the SCS regimen to address the progressive nature of the disease and to improve its clinical translation to PD patients. Objective:Recognizing the limitations of conventional stimulation, we now investigated the effects of continuous SCS in freely moving parkinsonian rats. Methods:We developed a small device that could deliver continuous SCS. At the start of the experiment, thirty female Sprague-Dawley rats received the dopamine (DA)-depleting neurotoxin, 6-hydroxydopamine, into the right striatum. The SCS device was fixed below the shoulder area of the back of the animal, and a line from this device was passed under the skin to an electrode that was then implanted epidurally over the dorsal column. The rats were divided into three groups: control, 8-h stimulation, and 24-h stimulation, and behaviorally tested then euthanized for immunohistochemical analysis. Results:The 8- and 24-h stimulation groups displayed significant behavioral improvement compared to the control group. Both SCS-stimulated groups exhibited significantly preserved tyrosine hydroxylase (TH)-positive fibers and neurons in the striatum and substantia nigra pars compacta (SNc), respectively, compared to the control group. Notably, the 24-h stimulation group showed significantly pronounced preservation of the striatal TH-positive fibers compared to the 8-h stimulation group. Moreover, the 24-h group demonstrated significantly reduced number of microglia in the striatum and SNc and increased laminin-positive area of the cerebral cortex compared to the control group. Conclusions:This study demonstrated the behavioral and histological benefits of continuous SCS in a time-dependent manner in freely moving PD animals, possibly mediated by anti-inflammatory and angiogenic mechanisms.
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Project description:(1) Background: Deep brain stimulation (DBS) and continuous intrajejunal levodopa infusion (CLI) are efficacious treatments of medication related motor response fluctuations in advanced Parkinson's disease (PD). Literature regarding the use of both advanced treatments within one patient is scarce. (2) Methods: We present a retrospective single center case series and a review of the literature. Patients with PD who were treated with both DBS and CLI in our tertiary referral center between 2005 and 2020 were identified and medical records were assessed. Additionally, literature on patients treated with both therapies was systematically searched for in Medline and Embase. (3) Results: Nineteen patients were included. Medication related motor response fluctuations were a major indication for the second therapy in all but one. Of nine patients initially treated with DBS, five reported improvement with CLI. Seven of ten patients initially treated with CLI experienced benefits from DBS. The systematic literature search resulted in fifteen previous publications comprising 66 patients. Of the 59 patients, for whom the effect of the second treatment was known, 57 improved. (4) Conclusions: PD patients, who have persisting medication related motor response fluctuations, despite DBS or CLI treatment, may benefit from an additional or alternative treatment with either CLI or DBS.
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Project description:Motor complications are a consequence of the chronic treatment of Parkinson's disease (PD) and include motor fluctuations (wearing-off phenomenon) and levodopa-induced dyskinesia. Both can have a significant impact on functionality and quality of life; thus, proper recognition and management is essential. The phenomenology and temporal relationship of motor complications to the schedule of levodopa dosing can be helpful in characterizing them. There are several therapeutic approaches to motor complications, including pharmacological and surgical options. The authors summarize the different types of motor complications according to phenomenology and the currently available medical treatments, including ongoing trials for the management of this condition.
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Project description:BackgroundThe effects of dopaminergic therapy in parkinson's disease (PD) can vary depending on the class of medication selected.ObjectiveThe aim of this post hoc study was to determine if the class of dopaminergic therapy correlated with disease severity in persons with early, treated PD.MethodsA non-parametric global statistical test (GST) was used to assess the status of participants treated with dopamine agonist (DA) monotherapy, levodopa (LD) monotherapy or combined LD and DA therapy on multiple PD outcomes encompassing motor, cognitive, psychiatric and autonomic function, as well as disability and quality of life.ResultsThe outcomes measured at the beginning of the study showed lower disease burden for participants on initial DA monotherapy compared to those taking combined LD and DA therapy after controlling for age, education, taking cog-meds and amantadine.ConclusionThis observation suggests that clinicians treating early PD patients favor combined LD and DA therapy in patients with more disabling features over DA monotherapy. As such, studies of PD progression in treated PD patients may be affected by the class of symptomatic dopaminergic therapy.
| S-EPMC4340731 | biostudies-literature
Project description:ObjectiveThe nigral lesion and the resulting contralateral motor signs of Parkinson's disease (PD) are remarkably asymmetric. This study investigated the prevalence of patients with "wrong-sided" lesions, that is, patients with symptoms on the side ipsilateral to the predominant dopaminergic nigrostriatal deficit.MethodsThe analyzed sample included 434 early unmedicated PD patients from the Parkinson's Progression Markers Initiative database. Asymmetry indices of motor function and putamen [(123)I]FP-CIT SPECT were calculated from the screening visit data.ResultsIpsilateral deficits were unexpectedly common even when only patients with clear motor and dopaminergic asymmetries were included in the analysis (8.1%, n = 24/295). When patients with any asymmetry were included in the analysis, the prevalence of ipsilateral deficits was 15.4% (n = 65/423). Wrong-sided symptoms were not associated with the PD motor subtype. However, the dataset was heavily biased toward tremor-dominant patients (85% of patients). Right-handed PD patients had predominantly right-sided motor symptoms and left-sided dopamine defects, whereas the effect was opposite in left-handed patients (P = 0.005 and 0.028, respectively).InterpretationThe results indicate that the side of the predominant motor symptoms and the corresponding side of the dopaminergic defects in PD are not random, but are directed by brain lateralization. Importantly, the traditional pathogenetic model of nigral degeneration causing primarily contralateral motor symptoms may be inadequate in many patients.
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Project description:Since the 1960's treatments for Parkinson's disease (PD) have traditionally been directed to restore or replace dopamine, with L-Dopa being the gold standard. However, chronic L-Dopa use is associated with debilitating dyskinesias, limiting its effectiveness. This has resulted in extensive efforts to develop new therapies that work in ways other than restoring or replacing dopamine. Here we describe newly emerging non-dopaminergic therapeutic strategies for PD, including drugs targeting adenosine, glutamate, adrenergic, and serotonin receptors, as well as GLP-1 agonists, calcium channel blockers, iron chelators, anti-inflammatories, neurotrophic factors, and gene therapies. We provide a detailed account of their success in animal models and their translation to human clinical trials. We then consider how advances in understanding the mechanisms of PD, genetics, the possibility that PD may consist of multiple disease states, understanding of the etiology of PD in non-dopaminergic regions as well as advances in clinical trial design will be essential for ongoing advances. We conclude that despite the challenges ahead, patients have much cause for optimism that novel therapeutics that offer better disease management and/or which slow disease progression are inevitable.
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Project description:Dopaminergic pathway is the most disrupted pathway in the pathogenesis of Parkinson's disease. Several studies reported associations of dopaminergic genes with the occurrence of adverse events of dopaminergic treatment. However, none of these studies adopted a pathway based approach. The aim of this study was to comprehensively evaluate the influence of selected single nucleotide polymorphisms of key dopaminergic pathway genes on the occurrence of motor and non-motor adverse events of dopaminergic treatment in Parkinson's disease. In total, 231 Parkinson's disease patients were enrolled. Demographic and clinical data were collected. Genotyping was performed for 16 single nucleotide polymorphisms from key dopaminergic pathway genes. Logistic and Cox regression analyses were used for evaluation. Results were adjusted for significant clinical data. We observed that carriers of at least one COMT rs165815 C allele had lower odds for developing visual hallucinations (OR = 0.34; 95% CI = 0.16-0.72; p = 0.004), while carriers of at least one DRD3 rs6280 C allele and CC homozygotes had higher odds for this adverse event (OR = 1.88; 95% CI = 1.00-3.54; p = 0.049 and OR = 3.31; 95% CI = 1.37-8.03; p = 0.008, respectively). Carriers of at least one DDC rs921451 C allele and CT heterozygotes had higher odds for orthostatic hypotension (OR = 1.86; 95% CI = 1.07-3.23; p = 0.028 and OR = 2.30; 95% CI = 1.26-4.20; p = 0.007, respectively). Heterozygotes for DDC rs3837091 and SLC22A1 rs628031 AA carriers also had higher odds for orthostatic hypotension (OR = 1.94; 95% CI = 1.07-3.51; p = 0.028 and OR = 2.57; 95% CI = 1.11-5.95; p = 0.028, respectively). Carriers of the SLC22A1 rs628031 AA genotype had higher odds for peripheral edema and impulse control disorders (OR = 4.00; 95% CI = 1.62-9.88; p = 0.003 and OR = 3.16; 95% CI = 1.03-9.72; p = 0.045, respectively). Finally, heterozygotes for SLC22A1 rs628031 and carriers of at least one SLC22A1 rs628031 A allele had lower odds for dyskinesia (OR = 0.48; 95% CI = 0.24-0.98, p = 0.043 and OR = 0.48; 95% CI = 0.25-0.92; p = 0.027, respectively). Gene-gene interactions, more specifically DDC-COMT, SLC18A2-SV2C, and SLC18A2-SLC6A3, also significantly influenced the occurrence of some adverse events. Additionally, haplotypes of COMT and SLC6A3 were associated with the occurrence of visual hallucinations (AT vs. GC: OR = 0.34; 95% CI = 0.16-0.72; p = 0.005) and orthostatic hypotension (ATG vs. ACG: OR = 2.48; 95% CI: 1.01-6.07; p = 0.047), respectively. Pathway based approach allowed us to identify new potential candidates for predictive biomarkers of adverse events of dopaminergic treatment in Parkinson's disease, which could contribute to treatment personalization.
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Project description:Parkinson's disease (PD) is traditionally regarded as a neurodegenerative movement disorder, however, nigrostriatal dopaminergic degeneration is also thought to disrupt non-motor loops connecting basal ganglia to areas in frontal cortex involved in cognition and emotion processing. PD patients are impaired on tests of emotion recognition, but it is difficult to disentangle this deficit from the more general cognitive dysfunction that frequently accompanies disease progression. Testing for emotion recognition deficits early in the disease course, prior to cognitive decline, better assesses the sensitivity of these non-motor corticobasal ganglia-thalamocortical loops involved in emotion processing to early degenerative change in basal ganglia circuits. In addition, contrasting this with a group of healthy aging individuals demonstrates changes in emotion processing specific to the degeneration of basal ganglia circuitry in PD. Early PD patients (EPD) were recruited from a randomized clinical trial testing the safety and tolerability of deep brain stimulation (DBS) of the subthalamic nucleus (STN-DBS) in early-staged PD. EPD patients were previously randomized to receive optimal drug therapy only (ODT), or drug therapy plus STN-DBS (ODT + DBS). Matched healthy elderly controls (HEC) and young controls (HYC) also participated in this study. Participants completed two control tasks and three emotion recognition tests that varied in stimulus domain. EPD patients were impaired on all emotion recognition tasks compared to HEC. Neither therapy type (ODT or ODT + DBS) nor therapy state (ON/OFF) altered emotion recognition performance in this study. Finally, HEC were impaired on vocal emotion recognition relative to HYC, suggesting a decline related to healthy aging. This study supports the existence of impaired emotion recognition early in the PD course, implicating an early disruption of fronto-striatal loops mediating emotional function.
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