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Frontiers in Neurology 2024Dopamine transporter single-photon emission computed tomography (DAT-SPECT) is a crucial tool for evaluating patients with Parkinson's disease (PD). However, its...
BACKGROUND
Dopamine transporter single-photon emission computed tomography (DAT-SPECT) is a crucial tool for evaluating patients with Parkinson's disease (PD). However, its implication is limited by inter-site variability in large multisite clinical trials. To overcome the limitation, a conventional prospective correction method employs linear regression with phantom scanning, which is effective yet available only in a prospective manner. An alternative, although relatively underexplored, involves retrospective modeling using a statistical method known as "combatting batch effects when combining batches of gene expression microarray data" (ComBat).
METHODS
We analyzed DAT-SPECT-specific binding ratios (SBRs) derived from 72 healthy older adults and 81 patients with PD registered in four clinical sites. We applied both the prospective correction and the retrospective ComBat correction to the original SBRs. Next, we compared the performance of the original and two corrected SBRs to differentiate the PD patients from the healthy controls. Diagnostic accuracy was assessed using the area under the receiver operating characteristic curve (AUC-ROC).
RESULTS
The original SBRs were 6.13 ± 1.54 (mean ± standard deviation) and 2.03 ± 1.41 in the control and PD groups, respectively. After the prospective correction, the mean SBRs were 6.52 ± 1.06 and 2.40 ± 0.99 in the control and PD groups, respectively. After the retrospective ComBat correction, the SBRs were 5.25 ± 0.89 and 2.01 ± 0.73 in the control and PD groups, respectively, resulting in substantial changes in mean values with fewer variances. The original SBRs demonstrated fair performance in differentiating PD from controls (Hedges's = 2.76; AUC-ROC = 0.936). Both correction methods improved discrimination performance. The ComBat-corrected SBR demonstrated comparable performance ( = 3.99 and AUC-ROC = 0.987) to the prospectively corrected SBR ( = 4.32 and AUC-ROC = 0.992) for discrimination.
CONCLUSION
Although we confirmed that SBRs fairly discriminated PD from healthy older adults without any correction, the correction methods improved their discrimination performance in a multisite setting. Our results support the utility of harmonization methods with ComBat for consolidating SBR-based diagnosis or stratification of PD in multisite studies. Nonetheless, given the substantial changes in the mean values of ComBat-corrected SBRs, caution is advised when interpreting them.
PubMed: 38440115
DOI: 10.3389/fneur.2024.1306546 -
CNS Neuroscience & Therapeutics Mar 2024To investigate the risk factors for early-onset psychosis in Parkinson's disease (PD) in a cohort of patients from the Parkinson's Progression Markers Initiative.
AIMS
To investigate the risk factors for early-onset psychosis in Parkinson's disease (PD) in a cohort of patients from the Parkinson's Progression Markers Initiative.
METHODS
Longitudinal data on motor and non-motor features, dopamine transporter (DAT) imaging, and cerebrospinal fluid (CSF) measurements were collected. The survival probability of psychotic symptoms, potential risk factors for psychosis development over a 5-year follow-up period, and the performance of the prediction model were evaluated.
RESULTS
Among the 338 newly diagnosed patients with PD, 83 developed psychotic symptoms. Gastrointestinal autonomic dysfunction, presence of probable rapid-eye-movement sleep behavior disorder, and the ratio Aβ42: total-tau could independently predict onset of psychosis in PD (hazard ratio (HR) = 1.157, 95% confidence interval (CI) 1.022-1.309, p = 0.021, HR = 2.596, 95% CI 1.287-5.237, p = 0.008, and HR = 0.842, 95% CI 0.723-0.980, p = 0.027, respectively). The combined model integrating baseline clinical predictors, DAT imaging, and CSF measurements achieved better sensitivity than the clinical predictors alone (area under the curve = 0.770 [95% CI 0.672-0.868] vs. 0.714 [95% CI 0.625-0.802], p = 0.098).
CONCLUSION
We identified clinical and CSF predictors of early-onset psychosis in patients with PD. Our study provides evidence and implications for prognostic stratification and therapeutic approaches for PD psychosis.
Topics: Humans; Parkinson Disease; Cohort Studies; Psychotic Disorders; Autonomic Nervous System Diseases; Risk Factors
PubMed: 38432692
DOI: 10.1111/cns.14651 -
Clinical Neurophysiology : Official... May 2024Both blinking and walking are altered in Parkinson's disease and both motor outputs have been shown to be linked in healthy subjects. Additionally, studies suggest an...
OBJECTIVE
Both blinking and walking are altered in Parkinson's disease and both motor outputs have been shown to be linked in healthy subjects. Additionally, studies suggest an involvement of basal ganglia activity and striatal dopamine in blink generation. We investigated the role of the basal ganglia circuitry on spontaneous blinking and if this role is dependent on movement state and striatal dopamine.
METHODS
We analysed subthalamic nucleus (STN) activity in seven chronically implanted patients for deep brain stimulation (DBS) with respect to blinks and movement state (resting state and unperturbed walking). Neurophysiological recordings were combined with individual molecular brain imaging assessing the dopamine reuptake transporter (DAT) density for the left and right striatum separately.
RESULTS
We found a significantly higher blink rate during walking compared to resting. The blink rate during walking positively correlated with the DAT density of the left caudate nucleus. During walking only, spontaneous blinking was followed by an increase in the right STN beta power and a bilateral subthalamic phase reset in the low frequencies. The right STN blink-related beta power modulation correlated negatively with the DAT density of the contralateral putamen. The left STN blink-related beta power correlated with the DAT density of the putamen in the less dopamine-depleted hemisphere. Both correlations were specific to the walking condition and to beta power following a blink.
CONCLUSION
Our findings show that spontaneous blinking is related to striatal dopamine and has a frequency specific deployment in the STN. This correlation depends on the current movement state such as walking.
SIGNIFICANCE
This work indicates that subcortical activity following a motor event as well as the relationship between dopamine and motor events can be dependent on the motor state. Accordingly, disease related changes in brain activity should be assessed during natural movement.
Topics: Humans; Subthalamic Nucleus; Parkinson Disease; Male; Middle Aged; Walking; Female; Blinking; Aged; Deep Brain Stimulation; Beta Rhythm; Dopamine Plasma Membrane Transport Proteins
PubMed: 38432185
DOI: 10.1016/j.clinph.2024.02.019 -
Cell Reports Mar 2024Striatal dopamine axons co-release dopamine and gamma-aminobutyric acid (GABA), using GABA provided by uptake via GABA transporter-1 (GAT1). Functions of GABA co-release...
Striatal dopamine axons co-release dopamine and gamma-aminobutyric acid (GABA), using GABA provided by uptake via GABA transporter-1 (GAT1). Functions of GABA co-release are poorly understood. We asked whether co-released GABA autoinhibits dopamine release via axonal GABA type A receptors (GABARs), complementing established inhibition by dopamine acting at axonal D2 autoreceptors. We show that dopamine axons express α3-GABAR subunits in mouse striatum. Enhanced dopamine release evoked by single-pulse optical stimulation in striatal slices with GABAR antagonism confirms that an endogenous GABA tone limits dopamine release. Strikingly, an additional inhibitory component is seen when multiple pulses are used to mimic phasic axonal activity, revealing the role of GABAR-mediated autoinhibition of dopamine release. This autoregulation is lost in conditional GAT1-knockout mice lacking GABA co-release. Given the faster kinetics of ionotropic GABARs than G-protein-coupled D2 autoreceptors, our data reveal a mechanism whereby co-released GABA acts as a first responder to dampen phasic-to-tonic dopamine signaling.
Topics: Mice; Animals; Dopamine; Autoreceptors; gamma-Aminobutyric Acid; Axons; Corpus Striatum; Receptors, GABA-A; Mice, Knockout; Homeostasis
PubMed: 38431842
DOI: 10.1016/j.celrep.2024.113834 -
JACS Au Feb 2024The dopamine transporter (DAT) is one of the key regulators of dopamine (DA) signaling in the central nervous system (CNS) and in the periphery. Recent reports in a...
The dopamine transporter (DAT) is one of the key regulators of dopamine (DA) signaling in the central nervous system (CNS) and in the periphery. Recent reports in a model of Parkinson's disease (PD) have shown that dopamine neuronal loss in the CNS impacts the expression of DAT in peripheral immune cells. The mechanism underlying this connection is still unclear but could be illuminated with sensitive and high-throughput detection of DAT-expressing immune cells in the circulation. Herein, we have developed fluorescently labeled ligands (FLL) that bind to surface-expressing DAT with high affinity and selectivity. The diSulfoCy5-FLL () was utilized to label DAT in human and mouse peripheral blood mononuclear cells (PBMCs) that were analyzed via flow cytometry. Selective labeling was validated using DAT KO mouse PBMCs. Our studies provide an efficient and highly sensitive method using this novel DAT-selective FLL to advance our fundamental understanding of DAT expression and activity in PBMCs in health and disease and as a potential peripheral biomarker.
PubMed: 38425927
DOI: 10.1021/jacsau.3c00719 -
Iranian Journal of Psychiatry Jan 2024This research investigates the alleles of Variable Number of Tandem Repeats (VNTR) intron 8 of the gene SLC6A3 with attention-deficit / hyperactivity disorder (ADHD)...
This research investigates the alleles of Variable Number of Tandem Repeats (VNTR) intron 8 of the gene SLC6A3 with attention-deficit / hyperactivity disorder (ADHD) in children and adolescents. The study's target population consisted of children and adolescents referred to the specialized clinic, as well as students attending school in Rasht city during 2021-2022. A sample of 95 children between the ages of 6 and 10 with ADHD was selected as the ADHD group, and 95 healthy children were selected as the control group using purposive sampling. The subjects completed the Child Symptom Inventory-4 (CSI-4) checklist after a clinical interview, and demographic information was collected. Genetic sampling was carried out through hair follicles. The sequence of interest was proliferated using the Polymerase Chain Reaction technique )PCR(; afterward, the samples were used for genotype identification on polyacrylamide gel electrophoresis. The chi-square test results indicated that the 5R / 5R genotype (P = 0.026, χ2 = 7.26) and the 5R allele (P = 0.002, χ2 = 9.35) had a higher frequency compared to the control group. Additionally, the odds ratio test indicated that, compared to other genotypes and alleles, the 5R / 5R genotype (OR = 2.75, 95% CI = 1.29-5.82, P = 0.01) and the 5R allele (OR = 2.02, 95% CI = 1.28-3.19, P = 0.002) increase the odds of developing ADHD by 2.7 and 2 times higher, respectively. The present study successfully showed the association between intron 8 gene polymorphism, which is responsible for encoding the dopamine transporter as well as ADHD in children and adolescents in Iran.
PubMed: 38420272
DOI: 10.18502/ijps.v19i1.14345 -
Neuroscience and Biobehavioral Reviews Apr 2024All individuals on planet earth are sensitive to the environment, but some more than others. These individual differences in sensitivity to environments are seen across... (Review)
Review
All individuals on planet earth are sensitive to the environment, but some more than others. These individual differences in sensitivity to environments are seen across many animal species including humans, and can influence personalities as well as vulnerability and resilience to mental disorders. Yet, little is known about the underlying brain mechanisms. Key genes that contribute to individual differences in environmental sensitivity are the serotonin transporter, dopamine D4 receptor and brain-derived neurotrophic factor genes. By synthesizing neurodevelopmental findings of these genetic factors, and discussing them through the lens of mechanisms related to sensitive periods, which are phases of heightened neuronal plasticity during which a certain network is being finetuned by experiences, we propose that these genetic factors delay but extend postnatal sensitive periods. This may explain why sensitive individuals show behavioral features that are characteristic of a young brain state at the level of sensory information processing, such as reduced filtering or blockade of irrelevant information, resulting in a sensory processing system that 'keeps all options open'.
Topics: Humans; Animals; Mental Disorders; Brain; Resilience, Psychological; Sensation
PubMed: 38417743
DOI: 10.1016/j.neubiorev.2024.105605 -
Frontiers in Cellular Neuroscience 2024The dopaminergic system is susceptible to dysfunction in numerous neurological diseases, including Parkinson's disease (PD). In addition to motor symptoms, some PD...
The dopaminergic system is susceptible to dysfunction in numerous neurological diseases, including Parkinson's disease (PD). In addition to motor symptoms, some PD patients may experience non-motor symptoms, including cognitive and memory deficits. A possible explanation for their manifestation is a disturbed pattern of dopamine release in brain regions involved in learning and memory, such as the hippocampus. Therefore, investigating neuropathological alterations in dopamine release prior to neurodegeneration is imperative. This study aimed to characterize evoked hippocampal dopamine release and assess the impact of the neurotoxin MPP using a genetically encoded dopamine sensor and gene expression analysis. Additionally, considering the potential neuroprotective attributes demonstrated by apoptosis signal-regulating kinase 1 () in various animal-disease-like models, the study also aimed to determine whether knockdown restores MPP-altered dopamine release in acute hippocampal slices. We applied variations of low- and high-frequency stimulation to evoke dopamine release within different hippocampal regions and discovered that acute application of MPP reduced the amount of dopamine released and hindered the recovery of dopamine release after repeated stimulation. In addition, we observed that deficiency attenuated the detrimental effects of MPP on the recovery of dopamine release after repeated stimulation. RNA sequencing analysis indicated that genes associated with the synaptic pathways are involved in response to MPP exposure. Notably, deficiency was found to downregulate the expression of , a gene encoding a sodium-dependent high-affinity choline transporter that regulates acetylcholine levels. Respective follow-up experiments indicated that plays a role in deficiency-mediated protection against MPP neurotoxicity. In addition, increasing acetylcholine levels using an acetylcholinesterase inhibitor could exacerbate the toxicity of MPP. In conclusion, our data imply that the modulation of the dopamine-acetylcholine balance may be a crucial mechanism of action underlying the neuroprotective effects of deficiency in PD.
PubMed: 38414754
DOI: 10.3389/fncel.2024.1288991 -
Scientific Reports Feb 2024The progression of neuroinflammation after anti-parkinsonian therapy on the Parkinson's disease (PD) brain and in vivo evidence of the therapy purporting neuroprotection... (Randomized Controlled Trial)
Randomized Controlled Trial
The progression of neuroinflammation after anti-parkinsonian therapy on the Parkinson's disease (PD) brain and in vivo evidence of the therapy purporting neuroprotection remain unclear. To elucidate this, we examined changes in microglial activation, nigrostriatal degeneration, and clinical symptoms longitudinally after dopamine replacement therapy in early, optimally-controlled PD patients with and without zonisamide treatment using positron emission tomography (PET). We enrolled sixteen PD patients (Hoehn and Yahr stage 1-2), and age-matched normal subjects. PD patients were randomly divided into two groups: one (zonisamide) that did and one (zonisamide) that did not undergo zonisamide therapy. Annual changes in neuroinflammation ([C]DPA713 PET), dopamine transporter availability ([C]CFT PET) and clinical severity were examined. Voxelwise differentiations in the binding of [C]DPA713 (BP) and [C]CFT (SUVR) were compared with normal data and between the zonisamide and zonisamide PD groups. The cerebral [C]DPA713 BP increased with time predominantly over the parieto-occipital region in PD patients. Comparison of the zonisamide group with the zonisamide group showed lower levels in the cerebral [C]DPA713 BP in the zonisamide group. While the striatal [C]CFT SUVR decreased longitudinally, the [C]CFT SUVR in the nucleus accumbens showed a higher binding in the zonisamide group. A significant annual increase in attention score were found in the zonisamide group. The current results indicate neuroinflammation proceeds to the whole brain even after anti-parkinsonian therapy, but zonisamide coadministration might have the potential to ameliorate proinflammatory responses, exerting a neuroprotective effect in more damaged nigrostriatal regions with enhanced attention in PD.
Topics: Humans; Parkinson Disease; Zonisamide; Neuroinflammatory Diseases; Positron-Emission Tomography; Brain; Dopamine Plasma Membrane Transport Proteins
PubMed: 38409373
DOI: 10.1038/s41598-024-55233-z -
Translational Psychiatry Feb 2024Obsessive Compulsive Disorder (OCD) is listed as one of the top 10 most disabling neuropsychiatric conditions in the world. The neurobiology of OCD has not been...
Obsessive Compulsive Disorder (OCD) is listed as one of the top 10 most disabling neuropsychiatric conditions in the world. The neurobiology of OCD has not been completely understood and efforts are needed in order to develop new treatments. Beside the classical neurotransmitter systems and signalling pathways implicated in OCD, the possible involvement of the endocannabinoid system (ECS) has emerged in pathophysiology of OCD. We report here selective downregulation of the genes coding for enzymes allowing the synthesis of the endocannabinoids. We found reduced DAGLα and NAPE-PLD in blood samples of individuals with OCD (when compared to healthy controls) as well as in the amygdala complex and prefrontal cortex of dopamine transporter (DAT) heterozygous rats, manifesting compulsive behaviours. Also mRNA levels of the genes coding for cannabinoid receptors type 1 and type 2 resulted downregulated, respectively in the rat amygdala and in human blood. Moreover, NAPE-PLD changes in gene expression resulted to be associated with an increase in DNA methylation at gene promoter, and the modulation of this gene in OCD appears to be correlated to the progression of the disease. Finally, the alterations observed in ECS genes expression appears to be correlated with the modulation in oxytocin receptor gene expression, consistently with what recently reported. Overall, we confirm here a role for ECS in OCD at both preclinical and clinical level. Many potential biomarkers are suggested among its components, in particular NAPE-PLD, that might be of help for a prompt and clear diagnosis.
Topics: Humans; Rats; Animals; Endocannabinoids; Obsessive-Compulsive Disorder; Amygdala; Prefrontal Cortex; DNA Methylation
PubMed: 38409080
DOI: 10.1038/s41398-024-02829-8