Hypomania and saccadic changes in Parkinson's disease: influence of D2 and D3 dopaminergic signalling.
Ontology highlight
ABSTRACT:
SUBMITTER: Pelzer EA
PROVIDER: S-EPMC6969176 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
Publications
Hypomania and saccadic changes in Parkinson's disease: influence of D2 and D3 dopaminergic signalling.
Pelzer Esther A EA Dillenburger Barbara B Grundmann Sophie S Iliaev Vladimir V Aschenberg Sophie S Melzer Corina C Hess Martin M Fink Gereon R GR Eggers Carsten C Tittgemeyer Marc M Timmermann Lars L
NPJ Parkinson's disease 20200117
In order to understand the influence of two dopaminergic signalling pathways, TaqIA rs1800497 (influencing striatal D2 receptor density) and <i>Ser9Gly</i> rs6280 (influencing the striatal D3 dopamine-binding affinity), on saccade generation and psychiatric comorbidities in Parkinson's disease, this study aimed to investigate the association of saccadic performance in hypomanic or impulsive behaviour in parkinsonian patients; besides we questioned whether variants of D2 (A1+/A1-) and D3 (B1+/B1- ...[more]
Similar Datasets
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.
| S-EPMC6360186 | biostudies-literature
Project description:BackgroundResting-state functional magnetic resonance imaging (fMRI) studies have demonstrated that basal ganglia functional connectivity is altered in Parkinson's disease (PD) as compared to healthy controls. However, such functional connectivity alterations have not been related to the dopaminergic deficits that occurs in PD over time.ObjectivesTo examine whether functional connectivity impairments are correlated with dopaminergic deficits across basal ganglia subdivisions in patients with PD both cross-sectionally and longitudinally.MethodsWe assessed resting-state functional connectivity of basal ganglia subdivisions and dopamine transporter density using 11C-PE2I PET in thirty-four PD patients at baseline. Of these, twenty PD patients were rescanned after 19.9 ± 3.8 months. A seed-based approach was used to analyze resting-state fMRI data. 11C-PE2I binding potential (BPND) was calculated for each participant. PD patients were assessed for disease severity.ResultsAt baseline, PD patients with greater dopaminergic deficits, as measured with 11C-PE2I PET, showed larger decreases in posterior putamen functional connectivity with the midbrain and pallidum. Reduced functional connectivity of the posterior putamen with the thalamus, midbrain, supplementary motor area and sensorimotor cortex over time were significantly associated with changes in DAT density over the same period. Furthermore, increased motor disability was associated with lower intraregional functional connectivity of the posterior putamen.ConclusionsOur findings suggest that basal ganglia functional connectivity is related to integrity of dopaminergic system in patients with PD. Application of resting-state fMRI in a large cohort and longitudinal scanning may be a powerful tool for assessing underlying PD pathology and its progression.
| S-EPMC7490914 | biostudies-literature
Project description:In this study, in vitro and in vivo experiments were carried out with the high-affinity multifunctional D2/D3 agonist D-512 to explore its potential neuroprotective effects in models of Parkinson's disease and the potential mechanism(s) underlying such properties. Pre-treatment with D-512 in vitro was found to rescue rat adrenal Pheochromocytoma PC12 cells from toxicity induced by 6-hydroxydopamine administration in a dose-dependent manner. Neuroprotection was found to coincide with reductions in intracellular reactive oxygen species, lipid peroxidation, and DNA damage. In vivo, pre-treatment with 0.5 mg/kg D-512 was protective against neurodegenerative phenotypes associated with systemic administration of MPTP, including losses in striatal dopamine, reductions in numbers of DAergic neurons in the substantia nigra (SN), and locomotor dysfunction. These observations strongly suggest that the multifunctional drug D-512 may constitute a novel viable therapy for Parkinson's disease.
| S-EPMC4177263 | biostudies-literature
Project description:The effects of dopaminergic therapy for Parkinson's disease (PD) on the brain functional architecture are still unclear. We investigated this topic in 31 PD patients (disease duration: 11.2 ± (SD) 3.6 years) who underwent clinical and MRI assessments under chronic dopaminergic treatment (duration: 8.3 ± (SD) 4.4 years) and after its withdrawal. Thirty healthy controls were also included. Functional and morphological changes were studied, respectively, with eigenvector centrality mapping and seed-based connectivity, and voxel-based morphometry. Patients off medication, compared to controls, showed increased connectivity in cortical sensorimotor areas extending to the cerebello-thalamo-cortical pathway and parietal and frontal brain structures. Dopaminergic therapy normalized this increased connectivity. Notably, patients showed decreased interconnectedness in the medicated compared to the unmedicated condition, encompassing putamen, precuneus, supplementary motor and sensorimotor areas bilaterally. Similarly, lower connectivity was found comparing medicated patients to controls, overlapping with the within-group comparison in the putamen. Seed-based analyses revealed that dopaminergic therapy reduced connectivity in motor and default mode networks. Lower connectivity in the putamen correlated with longer disease duration, medication dose, and motor symptom improvement. Notably, atrophy and connectivity changes were topographically dissociated. After chronic treatment, dopaminergic therapy decreases connectivity of key motor and default mode network structures that are abnormally elevated in PD off condition.
| S-EPMC6156510 | biostudies-literature
Project description:Parkinson's disease (PD) is the second most common neurodegenerative disease, characterized by the degeneration of midbrain dopaminergic (mDA) neurons and their axons, and aggregation of ?-synuclein, which leads to motor and late-stage cognitive impairments. As the motor symptoms of PD are caused by the degeneration of a specific population of mDA neurons, PD lends itself to neurotrophic factor therapy. The goal of this therapy is to apply a neurotrophic factor that can slow down, halt or even reverse the progressive degeneration of mDA neurons. While the best known neurotrophic factors are members of the glial cell line-derived neurotrophic factor (GDNF) family, their lack of clinical efficacy to date means that it is important to continue to study other neurotrophic factors. Bone morphogenetic proteins (BMPs) are naturally secreted proteins that play critical roles during nervous system development and in the adult brain. In this review, we provide an overview of the BMP ligands, BMP receptors (BMPRs) and their intracellular signalling effectors, the Smad proteins. We review the available evidence that BMP-Smad signalling pathways play an endogenous role in mDA neuronal survival in vivo, before outlining how exogenous application of BMPs exerts potent effects on mDA neuron survival and axon growth in vitro and in vivo. We discuss the molecular mechanisms that mediate these effects, before highlighting the potential of targeting the downstream effectors of BMP-Smad signalling as a novel neuroprotective approach to slow or stop the degeneration of mDA neurons in PD.
| S-EPMC7373244 | biostudies-literature
Project description:Olfactory and rapid eye movement (REM) sleep deficits are commonly found in untreated subjects with a recent diagnosis of Parkinson's disease (PD). Additionally, different studies report declines in olfactory performance during a short period of sleep deprivation. Mechanisms underlying these clinical manifestations are poorly understood, and impairment of dopamine (DA) neurotransmission in the olfactory bulb and the nigrostriatal pathway may have important roles in olfaction and REM sleep disturbances. Therefore, we hypothesized that modulation of the dopaminergic D2 receptors in the olfactory bulb could provide a more comprehensive understanding of the olfactory deficits in PD and REM sleep deprivation (REMSD). We decided to investigate the olfactory, neurochemical, and histological alterations generated through the administration of piribedil (a selective D2 agonist) or raclopride (a selective D2 antagonist) within the glomerular layer of the olfactory bulb, in rats subjected to intranigral rotenone and REMSD. Our findings provide evidence of the occurrence of a negative correlation (r = -0.52, P = 0.04) between the number of periglomerular TH-ir neurons and the bulbar levels of DA in the rotenone, but not sham, groups. A significant positive correlation (r = 0.34, P = 0.03) was observed between nigrostriatal DA levels and olfactory discrimination index (DI) for the sham groups, indicating that increased DA levels in the substantia nigra pars compacta (SNpc) are associated with enhanced olfactory discrimination performance. Also, increased levels in bulbar and striatal DA were induced by piribedil in the rotenone control and rotenone REMSD groups, consistent with reductions in the DI. The present evidence reinforce the idea that DA produced by periglomerular neurons, particularly the bulbar dopaminergic D2 receptors, is an essential participant in olfactory discrimination processes, as the SNpc, and the striatum.
| S-EPMC4249459 | biostudies-literature
Project description:Subthalamic nucleus (STN) deep brain stimulation (DBS) is an effective treatment for the motor impairments of patients with advanced Parkinson's disease. However, mood or behavioral changes, such as mania, hypomania, and impulsive disorders, can occur postoperatively. It has been suggested that these symptoms are associated with the stimulation of the limbic subregion of the STN. Electrophysiological studies demonstrate that the low-frequency activities in ventral STN are modulated during emotional processing. In this study, we report 22 patients with Parkinson's disease who underwent STN DBS for treatment of motor impairment and presented stimulation-induced mood elevation during initial postoperative programming. The contact at which a euphoric state was elicited by stimulation was termed as the hypomania-inducing contact (HIC) and was further correlated with intraoperative local field potential recorded during the descending of DBS electrodes. The power of four frequency bands, namely, θ (4-7 Hz), α (7-10 Hz), β (13-35 Hz), and γ (40-60 Hz), were determined by a non-linear variation of the spectrogram using the concentration of frequency of time (conceFT). The depth of maximum θ power is located approximately 2 mm below HIC on average and has significant correlation with the location of contacts (r = 0.676, p < 0.001), even after partializing the effect of α and β, respectively (r = 0.474, p = 0.022; r = 0.461, p = 0.027). The occurrence of HIC was not associated with patient-specific characteristics such as age, gender, disease duration, motor or non-motor symptoms before the operation, or improvement after stimulation. Taken together, these data suggest that the location of maximum θ power is associated with the stimulation-induced hypomania and the prediction of θ power is frequency specific. Our results provide further information to refine targeting intraoperatively and select stimulation contacts in programming.
| S-EPMC8721814 | biostudies-literature
Project description:ObjectiveDysfunction within corticostriatal dopaminergic neurocircuitry has been implicated in neuropsychiatric symptoms associated with Alzheimer disease (AD). This study aimed to test the hypothesis that the symptom domains delusions and apathy would be associated with striatal dopamine (D2) receptor function in AD.MethodsIn vivo dopamine (D2/D3) receptor availability was determined with [(11)C]raclopride (RAC) PET in 23 patients with mild and moderate probable AD. Behavioral symptoms were measured using the Neuropsychiatric Inventory and the Apathy Inventory. Imaging data were analyzed using a region-of-interest approach. The potential confounding effects of age, sex, and disease stage were explored using a linear mixed model. Correlational and independent samples comparisons were used to examine the relationship between behavioral and binding potential (BP(ND)) measures.ResultsMean [(11)C]RAC BP(ND) was higher in patients with delusions (n = 7; 5 men) than in patients without delusions (n = 16; 6 men) (p = 0.006). When women were excluded from the analysis, [(11)C]RAC BP(ND) was higher in men with delusions than in men without delusions (p = 0.05). Apathy measures showed no association with [(11)C]RAC BP(ND).ConclusionsStriatal dopamine (D2/D3) receptor availability is increased in Alzheimer disease patients with delusions, to an extent comparable to that observed in drug-naive patients with schizophrenia. Whether this represents up-regulation of dopamine (D2) or possibly dopamine (D3) receptors and how this relates to responsivity of the striatal dopaminergic system merit further exploration.
| S-EPMC2818181 | biostudies-literature
Project description:Trans-saccadic memory consists of keeping track of objects' locations and features across saccades; pre-saccadic information is remembered and compared with post-saccadic information. It has been shown to have limited resources and involve attention with respect to the selection of objects and features. In support, a previous study showed that recognition of distinct post-saccadic objects in the visual scene is impaired when pre-saccadic objects are relevant and thus already encoded in memory (Poth, Herwig, Schneider, 2015). Here, we investigated the inverse (i.e. how the memory of pre-saccadic objects is affected by abrupt but irrelevant changes in the post-saccadic visual scene). We also modulated the amount of attention to the relevant pre-saccadic object by having participants either make a saccade to it or elsewhere and observed that pre-saccadic attentional facilitation affected how much post-saccadic changes disrupted trans-saccadic memory of pre-saccadic objects. Participants identified a flashed symbol (d, b, p, or q, among distracters), at one of six placeholders (figures "8") arranged in circle around fixation while planning a saccade to one of them. They reported the identity of the symbol after the saccade. We changed the post-saccadic scene in Experiment one by removing the entire scene, only the placeholder where the pre-saccadic symbol was presented, or all other placeholders except this one. We observed reduced identification performance when only the saccade-target placeholder disappeared after the saccade. In Experiment two, we changed one placeholder location (inward/outward shift or rotation re. saccade vector) after the saccade and observed that identification performance decreased with increased shift/rotation of the saccade-target placeholder. We conclude that pre-saccadic memory is disrupted by abrupt attention-capturing post-saccadic changes of visual scene, particularly when these changes involve the object prioritized by being the goal of a saccade. These findings support the notion that limited trans-saccadic memory resources are disrupted when object correspondence at saccadic goal is broken through removal or location change.
| S-EPMC8340665 | biostudies-literature
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.
| S-EPMC4033125 | biostudies-literature