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Turkish Journal of Medical Sciences Apr 2021The dopamine transporter (DAT) imaging provides an objective tool for the assessment of dopaminergic function of presynaptic terminals which is valuable for the... (Review)
Review
The dopamine transporter (DAT) imaging provides an objective tool for the assessment of dopaminergic function of presynaptic terminals which is valuable for the differential diagnosis of parkinsonian disorders related to a striatal dopaminergic deficiency from movement disorders not related a striatal dopaminergic deficiency. DAT imaging with single-photon emission computed tomography (SPECT) can be used to confirm or exclude a diagnosis of dopamine deficient parkinsonism in cases where the diagnosis is unclear. It can also detect the dopaminergic dysfunction in presymptomatic subjects at risk for Parkinson’s disease (PD) since the reduced radiotracer binding to DATs in striatum is already present in the prodromal stage of PD. This review covers the rationale of using DAT SPECT imaging in the diagnosis of PD and other parkinsonian disorders, specifically focusing on the practical aspects of imaging and routine clinical indications.
Topics: Corpus Striatum; Diagnosis, Differential; Dopamine; Dopamine Plasma Membrane Transport Proteins; Female; Humans; Male; Movement Disorders; Parkinson Disease; Parkinsonian Disorders; Prodromal Symptoms; Protein Binding; Radioisotopes; Tomography, Emission-Computed, Single-Photon
PubMed: 33237660
DOI: 10.3906/sag-2008-253 -
Neuron May 2023Lasker's award-winning drug propofol is widely used in general anesthesia. The recreational use of propofol is reported to produce a well-rested feeling and euphoric...
Lasker's award-winning drug propofol is widely used in general anesthesia. The recreational use of propofol is reported to produce a well-rested feeling and euphoric state; yet, the neural mechanisms underlying such pleasant effects remain unelucidated. Here, we report that propofol actively and directly binds to the dopamine transporter (DAT), but not the serotonin transporter (SERT), which contributes to the rapid relief of anhedonia. Then, we predict the binding mode of propofol by molecular docking and mutation of critical binding residues on the DAT. Fiber photometry recording on awake freely moving mice and [F] FP-CIT-PET scanning further establishes that propofol administration evokes rapid and lasting dopamine accumulation in nucleus accumbens (NAc). The enhanced dopaminergic tone drives biased activation of dopamine-receptor-1-expressing medium spiny neurons (D1-MSNs) in NAc and reverses anhedonia in chronically stressed animals. Collectively, these findings suggest the therapeutic potential of propofol against anhedonia, which warrants future clinical investigations.
Topics: Mice; Animals; Dopamine; Propofol; Dopamine Plasma Membrane Transport Proteins; Molecular Docking Simulation; Receptors, Dopamine D1; Nucleus Accumbens; Anhedonia; Mice, Inbred C57BL
PubMed: 36917979
DOI: 10.1016/j.neuron.2023.02.017 -
Journal of Parkinson's Disease 2020There is a need for reliable and robust Parkinson's disease biomarkers that reflect severity and are sensitive to disease modifying investigational therapeutics.
BACKGROUND
There is a need for reliable and robust Parkinson's disease biomarkers that reflect severity and are sensitive to disease modifying investigational therapeutics.
OBJECTIVE
To demonstrate the utility of EEG as a reliable, quantitative biomarker with potential as a pharmacodynamic endpoint for use in clinical assessments of neuroprotective therapeutics for Parkison's disease.
METHODS
A multi modal study was performed including aquisition of resting state EEG data and dopamine transporter PET imaging from Parkinson's disease patients off medication and compared against age-matched controls.
RESULTS
Qualitative and test/retest analysis of the EEG data demonstrated the reliability of the methods. Source localization using low resolution brain electromagnetic tomography identified significant differences in Parkinson's patients versus control subjects in the anterior cingulate and temporal lobe, areas with established association to Parkinson's disease pathology. Changes in cortico-cortical and cortico-thalamic coupling were observed as excessive EEG beta coherence in Parkinson's disease patients, and correlated with UPDRS scores and dopamine transporter activity, supporting the potential for cortical EEG coherence to serve as a reliable measure of disease severity. Using machine learning approaches, an EEG discriminant function analysis classifier was identified that parallels the loss of dopamine synapses as measured by dopamine transporter PET.
CONCLUSION
Our results support the utility of EEG in characterizing alterations in neurophysiological oscillatory activity associated with Parkinson's disease and highlight potential as a reliable method for monitoring disease progression and as a pharmacodynamic endpoint for Parkinson's disease modification therapy.
Topics: Aged; Beta Rhythm; Biomarkers; Dopamine Plasma Membrane Transport Proteins; Electroencephalography; Electroencephalography Phase Synchronization; Female; Humans; Machine Learning; Male; Middle Aged; Outcome Assessment, Health Care; Parkinson Disease; Positron-Emission Tomography
PubMed: 32116262
DOI: 10.3233/JPD-191844 -
Continuum (Minneapolis, Minn.) Jun 2022This article discusses neuroimaging in dementia diagnosis, with a focus on new applications of MRI and positron emission tomography (PET). (Review)
Review
PURPOSE OF REVIEW
This article discusses neuroimaging in dementia diagnosis, with a focus on new applications of MRI and positron emission tomography (PET).
RECENT FINDINGS
Although the historical use of MRI in dementia diagnosis has been supportive to exclude structural etiologies, recent innovations allow for quantification of atrophy patterns that improve sensitivity for supporting the diagnosis of dementia causes. Neuronuclear approaches allow for localization of specific amyloid and tau neuropathology on PET and are available for clinical use, in addition to dopamine transporter scans in dementia with Lewy bodies and metabolic studies with fludeoxyglucose PET (FDG-PET).
SUMMARY
Using computerized software programs for MRI analysis and cross-sectional and longitudinal evaluations of hippocampal, ventricular, and lobar volumes improves sensitivity in support of the diagnosis of Alzheimer disease and frontotemporal dementia. MRI protocol requirements for such quantification are three-dimensional T1-weighted volumetric imaging protocols, which may need to be specifically requested. Fluid-attenuated inversion recovery (FLAIR) and 3.0T susceptibility-weighted imaging (SWI) sequences are useful for the detection of white matter hyperintensities as well as microhemorrhages in vascular dementia and cerebral amyloid angiopathy. PET studies for amyloid and/or tau pathology can add additional specificity to the diagnosis but currently remain largely inaccessible outside of research settings because of prohibitive cost constraints in most of the world. Dopamine transporter PET scans can help identify Lewy body dementia and are thus of potential clinical value.
Topics: Alzheimer Disease; Cross-Sectional Studies; Dopamine Plasma Membrane Transport Proteins; Humans; Lewy Body Disease; Magnetic Resonance Imaging; Neuroimaging; Positron-Emission Tomography
PubMed: 35678403
DOI: 10.1212/CON.0000000000001133 -
JCI Insight Oct 2022BackgroundAlcohol use disorder (AUD) is a chronic, relapsing brain disorder that accounts for 5% of deaths annually, and there is an urgent need to develop new targets... (Randomized Controlled Trial)
Randomized Controlled Trial
BackgroundAlcohol use disorder (AUD) is a chronic, relapsing brain disorder that accounts for 5% of deaths annually, and there is an urgent need to develop new targets for therapeutic intervention. The glucagon-like peptide-1 (GLP-1) receptor agonist exenatide reduces alcohol consumption in rodents and nonhuman primates, but its efficacy in patients with AUD is unknown.MethodsIn a randomized, double-blinded, placebo-controlled clinical trial, treatment-seeking AUD patients were assigned to receive exenatide (2 mg subcutaneously) or placebo once weekly for 26 weeks, in addition to standard cognitive-behavioral therapy. The primary outcome was reduction in number of heavy drinking days. A subgroup also completed functional MRI (fMRI) and single-photon emission CT (SPECT) brain scans.ResultsA total of 127 patients were enrolled. Our data revealed that although exenatide did not significantly reduce the number of heavy drinking days compared with placebo, it significantly attenuated fMRI alcohol cue reactivity in the ventral striatum and septal area, which are crucial brain areas for drug reward and addiction. In addition, dopamine transporter availability was lower in the exenatide group compared with the placebo group. Exploratory analyses revealed that exenatide significantly reduced heavy drinking days and total alcohol intake in a subgroup of obese patients (BMI > 30 kg/m2). Adverse events were mainly gastrointestinal.ConclusionThis randomized controlled trial on the effects of a GLP-1 receptor agonist in AUD patients provides new important knowledge on the effects of GLP-1 receptor agonists as a novel treatment target in addiction.Trial registrationEudraCT: 2016-003343-11. ClinicalTrials.gov (NCT03232112).FundingNovavi Foundation; Research Foundation, Mental Health Services, Capital Region of Denmark; Research Foundation, Capital Region of Denmark; Ivan Nielsen Foundation; A.P. Moeller Foundation; Augustinus Foundation; Woerzner Foundation; Grosserer L.F. Foghts Foundation; Hartmann Foundation; Aase and Ejnar Danielsen Foundation; P.A. Messerschmidt and Wife Foundation; and Lundbeck Foundation.
Topics: Alcohol Drinking; Alcoholism; Animals; Dopamine Plasma Membrane Transport Proteins; Double-Blind Method; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Peptides; Venoms
PubMed: 36066977
DOI: 10.1172/jci.insight.159863 -
JAMA Sep 2021Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data.
OBJECTIVE
To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression.
DESIGN, PARTICIPANTS, AND SETTING
Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019.
INTERVENTIONS
Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years.
MAIN OUTCOMES AND MEASURES
The primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity.
RESULTS
Based on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine (MDS-UPDRS score, 11.1 [95% CI, 9.7-12.6] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, -0.59 to 3.11] points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years).
CONCLUSIONS AND RELEVANCE
Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02642393.
Topics: Aged; Biomarkers; Disease Progression; Dopamine Plasma Membrane Transport Proteins; Double-Blind Method; Female; Humans; Inosine; Kidney Calculi; Male; Middle Aged; Parkinson Disease; Severity of Illness Index; Treatment Failure; Uric Acid
PubMed: 34519802
DOI: 10.1001/jama.2021.10207 -
Journal of Neurochemistry May 2021Transporters of the solute carrier 6 (SLC6) family mediate the reuptake of neurotransmitters such as dopamine, norepinephrine, serotonin, GABA, and glycine. SLC6 family... (Review)
Review
Transporters of the solute carrier 6 (SLC6) family mediate the reuptake of neurotransmitters such as dopamine, norepinephrine, serotonin, GABA, and glycine. SLC6 family members are 12 transmembrane helix-spanning proteins that operate using the transmembrane sodium gradient for transport. These transporters assume various quaternary arrangements ranging from monomers to complex stoichiometries with multiple subunits. Dopamine and serotonin transporter oligomerization has been implicated in trafficking of newly formed proteins from the endoplasmic reticulum to the plasma membrane with a pre-fixed assembly. Once at the plasma membrane, oligomers are kept fixed in their quaternary assembly by interaction with phosphoinositides. While it remains unclear how oligomer formation precisely affects physiological transporter function, it has been shown that oligomerization supports the activity of release-type psychostimulants. Most recently, single molecule microscopy experiments unveiled that the stoichiometry differs between individual members of the SLC6 family. The present overview summarizes our understanding of the influence of plasma membrane constituents on transporter oligomerization, describes the known interfaces between protomers and discusses open questions.
Topics: Animals; Humans; Neurotransmitter Transport Proteins
PubMed: 32767560
DOI: 10.1111/jnc.15145 -
Biochemical Pharmacology Sep 2023Post-translational modifications are an important mechanism in the regulation of protein expression, function, and degradation. Well-known post-translational... (Review)
Review
Post-translational modifications are an important mechanism in the regulation of protein expression, function, and degradation. Well-known post-translational modifications are phosphorylation, glycosylation, and ubiquitination. However, lipid modifications, including myristoylation, prenylation, and palmitoylation, are poorly studied. Since the early 2000s, researchers have become more interested in lipid modifications, especially palmitoylation. The number of articles in PubMed increased from about 350 between 2000 and 2005 to more than 600 annually during the past ten years. S-palmitoylation, where the 16-carbon saturated (C16:0) palmitic acid is added to free cysteine residues of proteins, is a reversible protein modification that can affect the expression, membrane localization, and function of the modified proteins. Various diseases like Huntington's and Alzheimer's disease have been linked to changes in protein palmitoylation. In humans, the addition of palmitic acid is mediated by 23 palmitoyl acyltransferases, also called DHHC proteins. The modification can be reversed by a few thioesterases or hydrolases. Numerous soluble and membrane-attached proteins are known to be palmitoylated, but among the approximately 400 solute carriers that are classified in 66 families, only 15 found in 8 families have so far been documented to be palmitoylated. Among the best-characterized transporters are the glucose transporters GLUT1 (SLC2A1) and GLUT4 (SLC2A4), the three monoamine transporters norepinephrine transporter (NET; SLC6A2), dopamine transporter (DAT; SLC6A3), and serotonin transporter (SERT; SLC6A4), and the sodium-calcium exchanger NCX1 (SLC8A1). While there is evidence from recent proteomics experiments that numerous solute carriers are palmitoylated, no details beyond the 15 transporters covered in this review are available.
Topics: Humans; Palmitic Acid; Lipoylation; Protein Processing, Post-Translational; Phosphorylation; Membrane Proteins; Serotonin Plasma Membrane Transport Proteins
PubMed: 37481134
DOI: 10.1016/j.bcp.2023.115695 -
Science (New York, N.Y.) Sep 2021Compulsive drug use despite adverse consequences defines addiction. While mesolimbic dopamine signaling is sufficient to drive compulsion, psychostimulants such as...
Compulsive drug use despite adverse consequences defines addiction. While mesolimbic dopamine signaling is sufficient to drive compulsion, psychostimulants such as cocaine also boost extracellular serotonin (5-HT) by inhibiting reuptake. We used SERT Met172 knockin (SertKI) mice carrying a transporter that no longer binds cocaine to abolish 5-HT transients during drug self-administration. SertKI mice showed an enhanced transition to compulsion. Conversely, pharmacologically elevating 5-HT reversed the inherently high rate of compulsion transition with optogenetic dopamine self-stimulation. The bidirectional effect on behavior is explained by presynaptic depression of orbitofrontal cortex–to–dorsal striatum synapses induced by 5-HT via 5-HT receptors. Consequently, in projection-specific 5-HT receptor knockout mice, the fraction of individuals compulsively self-administering cocaine was elevated.
Topics: Animals; Cocaine; Cocaine-Related Disorders; Dopamine; Gene Knock-In Techniques; Mice; Mice, Knockout; Optogenetics; Receptor, Serotonin, 5-HT1B; Serotonin; Serotonin Plasma Membrane Transport Proteins; Synaptic Transmission
PubMed: 34516792
DOI: 10.1126/science.abi9086 -
Current Neurology and Neuroscience... Nov 2019Being a disease with heterogeneous presentations and unclear consensus on its diagnostic criteria, it is difficult to differentiate vascular parkinsonism (VaP) from... (Review)
Review
PURPOSE OF REVIEW
Being a disease with heterogeneous presentations and unclear consensus on its diagnostic criteria, it is difficult to differentiate vascular parkinsonism (VaP) from other neurodegenerative parkinsonism variants. Ongoing research on structural and functional neuroimaging targeting dopaminergic pathway provides us more insight into the pathophysiology of VaP to improve diagnostic accuracy. The aim of this article is to review how the emerging imaging modalities help the diagnostic process and treatment decision in VaP.
RECENT FINDINGS
Dopamine transporter imaging is a promising tool in differentiating presynaptic parkinsonism and VaP. It also predicts the levodopa responders in VaP. Advanced MRI techniques including volumetry, diffusion tensor imaging and sequences visualising substantia nigra are under development, and they are complementary to each other in detecting structural and functional changes in VaP, which is crucial to ensure the quality of future therapeutic trials for VaP. Dopamine transporter imaging is recommended to patients with suspected VaP. Multimodal MRI in VaP would be an important area to be investigated in the near future.
Topics: Diffusion Tensor Imaging; Dopamine; Dopamine Plasma Membrane Transport Proteins; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Molecular Imaging; Neuroimaging; Parkinsonian Disorders; Substantia Nigra; Tomography, Emission-Computed, Single-Photon
PubMed: 31773419
DOI: 10.1007/s11910-019-1019-7