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Molecular Psychiatry May 2024The dopamine hypothesis of schizophrenia posits that elevated striatal dopamine functioning underlies the development of psychotic symptoms. Chronic exposure to social...
The dopamine hypothesis of schizophrenia posits that elevated striatal dopamine functioning underlies the development of psychotic symptoms. Chronic exposure to social stressors increases psychosis risk, possibly by upregulating striatal dopamine functioning. Here we systematically review single photon emission computed tomography (SPECT) and positron emission tomography (PET) studies that examined the relationship between chronic social stress exposure and in vivo striatal dopamine functioning in humans. We searched the scientific databases PubMed and PsycINFO from inception to August 2023. The quality of the included studies was evaluated with the ten-item Observational Study Quality Evaluation (PROSPERO: CRD42022308883). Twenty-eight studies were included, which measured different aspects of striatal dopamine functioning including dopamine synthesis capacity (DSC), vesicular monoamine transporter type 2 binding, dopamine release following a pharmacological or behavioral challenge, D receptor binding, and dopamine transporter binding. We observed preliminary evidence of an association between childhood trauma and increased striatal DSC and dopamine release. However, exposure to low socioeconomic status, stressful life events, or other social stressors was not consistently associated with altered striatal dopamine functioning. The quality of available studies was generally low. In conclusion, there is insufficient evidence that chronic social stressors upregulate striatal dopamine functioning in humans. We propose avenues for future research, in particular to improve the measurement of chronic social stressors and the methodological quality of study designs.
PubMed: 38760501
DOI: 10.1038/s41380-024-02581-x -
Neurology Jun 2024
Topics: Humans; Dopamine Plasma Membrane Transport Proteins; Parkinsonian Disorders; Tomography, Emission-Computed, Single-Photon
PubMed: 38759140
DOI: 10.1212/WNL.0000000000209558 -
Neurology Jun 2024Degeneration of the presynaptic nigrostriatal dopaminergic system is one of the main biological features of Parkinson disease (PD), multiple system atrophy (MSA),...
BACKGROUND AND OBJECTIVES
Degeneration of the presynaptic nigrostriatal dopaminergic system is one of the main biological features of Parkinson disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), which can be measured using single-photon emission CT imaging for diagnostic purposes. Despite its widespread use in clinical practice and research, the diagnostic properties of presynaptic nigrostriatal dopaminergic (DAT) imaging in parkinsonism have never been evaluated against the diagnostic gold standard of neuropathology. The aim of this study was to evaluate the diagnostic parameters of DAT imaging compared with pathologic diagnosis in patients with parkinsonism.
METHODS
Retrospective cohort study of patients with DAT imaging for the investigation of a clinically uncertain parkinsonism with brain donation between 2010 and 2021 to the Queen Square Brain Bank (London). Patients with DAT imaging for investigation of pure ataxia or dementia syndromes without parkinsonism were excluded. Those with a pathologic diagnosis of PD, MSA, PSP, or CBD were considered presynaptic dopaminergic parkinsonism, and other pathologies were considered postsynaptic for the analysis. DAT imaging was performed in routine clinical practice and visually classified by hospital nuclear medicine specialists as normal or abnormal. The results were correlated with neuropathologic diagnosis to calculate diagnostic accuracy parameters for the diagnosis of presynaptic dopaminergic parkinsonism.
RESULTS
All of 47 patients with PD, 41 of 42 with MSA, 68 of 73 with PSP, and 6 of 10 with CBD (sensitivity 100%, 97.6%, 93.2%, and 60%, respectively) had abnormal presynaptic dopaminergic imaging. Eight of 17 patients with presumed postsynaptic parkinsonism had abnormal scans (specificity 52.9%).
DISCUSSION
DAT imaging has very high sensitivity and negative predictive value for the diagnosis of presynaptic dopaminergic parkinsonism, particularly for PD. However, patients with CBD, and to a lesser extent PSP (of various phenotypes) and MSA (with predominant ataxia), can show normal DAT imaging. A range of other neurodegenerative disorders may have abnormal DAT scans with low specificity in the differential diagnosis of parkinsonism. DAT imaging is a useful diagnostic tool in the differential diagnosis of parkinsonism, although clinicians should be aware of its diagnostic properties and limitations.
CLASSIFICATION OF EVIDENCE
This study provides Class II evidence that DAT imaging does not accurately distinguish between presynaptic dopaminergic parkinsonism and non-presynaptic dopaminergic parkinsonism.
Topics: Humans; Female; Aged; Male; Retrospective Studies; Dopamine Plasma Membrane Transport Proteins; Parkinsonian Disorders; Tomography, Emission-Computed, Single-Photon; Middle Aged; Multiple System Atrophy; Supranuclear Palsy, Progressive; Aged, 80 and over; Parkinson Disease; Cohort Studies; Corticobasal Degeneration; Dopamine; Presynaptic Terminals; Sensitivity and Specificity; Dopaminergic Imaging
PubMed: 38759132
DOI: 10.1212/WNL.0000000000209453 -
Journal of Gambling Studies May 2024The role of dopamine in the pathophysiology of gambling disorder (GD) remains incompletely understood, with disparate research findings concerning presynaptic and...
The role of dopamine in the pathophysiology of gambling disorder (GD) remains incompletely understood, with disparate research findings concerning presynaptic and postsynaptic structures and dopaminergic synthesis. The aim of this study was to investigate potential correlations between striatal dopamine transporter (DAT) lateralization and asymmetry index, as assessed by I-FP-CIT SPECT, and temperamental traits, as measured by Cloninger's Temperament and Character Inventory (TCI), in GD subjects. Significant associations were found between DAT binding asymmetries in the caudate and putamen and the temperamental dimensions of harm avoidance and novelty seeking. Specifically, high novelty seeking scores correlated with increased DAT binding in the left caudate relative to the right, whereas higher harm avoidance scores corresponded to increased DAT binding in the right putamen relative to the left. These observations potentially imply that the asymmetry in DAT expression in the basal ganglia could be an outcome of hemispheric asymmetry in emotional processing and behavioural guidance. In summary, our study provides evidence supporting the relationship between DAT asymmetries, temperamental dimensions and GD. Future investigations could be directed towards examining postsynaptic receptors to gain a more comprehensive understanding of dopamine's influence within the basal ganglia circuit in disordered gambling. If confirmed in larger cohorts, these findings could have substantial implications for the tailoring of individualized neuromodulation therapies in the treatment of behavioural addictions.
PubMed: 38755422
DOI: 10.1007/s10899-024-10311-9 -
Clinical Neurology and Neurosurgery Jul 2024Psychosis, especially in delusions, greatly impairs the quality of life of patients with Parkinson's disease (PD) and their caregivers. Few objective risk indicators of...
OBJECTIVES
Psychosis, especially in delusions, greatly impairs the quality of life of patients with Parkinson's disease (PD) and their caregivers. Few objective risk indicators of the association between psychosis and clinical features has been reported. It is unclear whether the reduction in DAT binding represents the underlying mechanism of delusion or its association. There are no long-term data on the objective prognostic value of DAT binding for delusions. We investigated whether DAT binding at baseline can be a prognostic risk factor for future development of PD delusions.
MATERIALS AND METHODS
We reviewed the detailed clinical chart of patients with PD without a history of psychosis who underwent [I]FP-CIT SPECT during the disease. The endpoint was defined as when the delusions occurred during the 5 years after the examination of [I]FP-CIT SPECT. Specific binding ratio (SBR) values were calculated.
RESULTS
Sixty-one patients with PD were included in the analysis, and 11 patients had delusions within 5 years of [I] FP-CIT SPECT. The average (p = 0.004), minimum (p = 0.004), maximum (p = 0.001), right-sided (p = 0.002), and left-sided (p = 0.003) SBRs in the striatum were significantly smaller in patients with delusions than in patients without delusions. Each difference of each SBR was significantly smaller than those without delusions after adjusting after controlling for age, gender, disease severity, timing of [I]FP-CIT SPECT, anti-parkinsonian medications, hospitalization, administering more or newly anti-parkinsonian drugs, and receiving DBS or LCIG.
CONCLUSIONS
PD delusions is still problematic, and lowering DAT binding may be helpful for predicting future delusions, regardless of the timing of [I]FP-CIT SPECT.
Topics: Humans; Male; Female; Delusions; Dopamine Plasma Membrane Transport Proteins; Tomography, Emission-Computed, Single-Photon; Aged; Middle Aged; Parkinson Disease; Tropanes; Retrospective Studies; Aged, 80 and over
PubMed: 38749355
DOI: 10.1016/j.clineuro.2024.108321 -
ACS Chemical Neuroscience Jun 2024Considerable research efforts have been directed toward the symptom relief of Parkinson's disease (PD) by attenuating dopamine (DA) depletion. One common feature of...
(+)-Borneol Protects Dopaminergic Neuronal Loss in Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Induced Parkinson's Disease Mice: A Study of Dopamine Level using In Vivo Brain Microdialysis.
Considerable research efforts have been directed toward the symptom relief of Parkinson's disease (PD) by attenuating dopamine (DA) depletion. One common feature of these existing therapies is their unavailability of preventing the neurodegenerative process of dopaminergic neurons. (+)-Borneol, a natural highly lipid-soluble bicyclic monoterpene, has been reported to regulate the levels of monoamine neurotransmitters in the central nervous system and exhibit neuroprotective effects. However, the effect of (+)-borneol on the dopaminergic neuronal loss of methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice is not defined. Herein, we first report that 30 mg/kg (+)-borneol significantly attenuated the motor deficits of PD mice, which benefits from markedly increasing the level of DA and decreasing the metabolic rate of DA in the striatum of conscious and freely moving mouse detected by ultraperformance liquid chromatography tandem mass spectrometry online combined with in vivo brain microdialysis sampling. It is worth noting that the enhanced level of DA by (+)-borneol was enabled by the reduction in loss of tyrosine hydroxylase-immunoreactive dopaminergic neurons in the substantia nigra and striatum and promotion of reserpine- or nomifensine-induced DA release in PD mice. Interestingly, (+)-borneol evidently inhibited the decreased expression levels of DA transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) on the MPTP mouse model of PD. Moreover, (+)-borneol suppressed the neuroinflammation by inhibiting the production of IL-1β, IL-6, and TNF-α and attenuated oxidative stress by decreasing the level of MDA and increasing the activities of SOD and GSH-px in PD mice. These findings demonstrate that (+)-borneol protects DA neurons by inhibiting neuroinflammation and oxidative stress. Further research work for the neuroprotection mechanism of (+)-borneol will focus on reactive oxygen species-mediated apoptosis. Therefore, (+)-borneol is a potential therapeutic candidate for retarding the neurodegenerative process of PD.
Topics: Animals; Dopamine; Dopaminergic Neurons; Male; Mice; Neuroprotective Agents; Microdialysis; Camphanes; Mice, Inbred C57BL; Corpus Striatum; Oxidative Stress; Disease Models, Animal; Brain
PubMed: 38747405
DOI: 10.1021/acschemneuro.4c00139 -
Journal of Alzheimer's Disease Reports 2024Identifying the coexistence of Lewy body (LB) pathology with Alzheimer's disease (AD) in clinical practice is important in the era of anti-amyloid-β antibody therapy....
Identifying the coexistence of Lewy body (LB) pathology with Alzheimer's disease (AD) in clinical practice is important in the era of anti-amyloid-β antibody therapy. However, few studies have predicted the presence of comorbid LB pathology with AD using indicative biomarkers of dementia with Lewy bodies or by collecting detailed clinical symptoms. We report the clinical progression of a 67-year-old patient diagnosed with AD who developed rapid eye movement sleep disorder-like symptoms and transient visual hallucinations 10 years after AD onset and was considered to have comorbid LB pathology based on imaging indicative biomarkers of dementia with Lewy bodies.
PubMed: 38746644
DOI: 10.3233/ADR-240019 -
European Journal of Nuclear Medicine... May 2024[I]I-FP-CIT SPECT is an imaging tool to support the diagnosis of parkinsonian syndromes characterized by nigrostriatal dopaminergic degeneration. After intravenous...
PURPOSE
[I]I-FP-CIT SPECT is an imaging tool to support the diagnosis of parkinsonian syndromes characterized by nigrostriatal dopaminergic degeneration. After intravenous injection, [I]I-FP-CIT is metabolized for a small part by the enzyme CYP3A4, leading to the formation of [I]I-nor-β-CIT. [I]I-nor-β-CIT passes the blood-brain barrier and has a very high affinity for the serotonin transporter (SERT). The SERT is expressed in the striatum and cortical areas. So, at least theoretical, the use of frequently used CYP3A4 inhibitors (like amiodarone) may influence the specific to non-specific striatal [I]I-FP-CIT ratio. Here we tested this novel hypothesis.
METHODS
Using a retrospective design, we determined the specific to non-specific striatal [I]I-FP-CIT ratio (using BRASS software) in 6 subjects that were using an CYP3A4 inhibitor and 18 matched controls. Only subjects were included with a normal rated [I]I-FP-CIT SPECT scan, and all participants were scanned on the same brain-dedicated SPECT system.
RESULTS
The specific to non-specific (assessed in the occipital cortex) striatal [I]I-FP-CIT binding ratio was significantly higher in CYP3A4 users than in the control group (3.52 ± 0.33 vs. 2.90 ± 0.78, p < 0.001).
CONCLUSION
Our preliminary data suggest that the use of CYP3A4 inhibitors may influence striatal [I]I-FP-CIT binding ratios. This information, when reproduced in larger studies, may be relevant for studies in which quantification of [I]I-FP-CIT SPECT imaging is used for diagnostic or research purposes.
PubMed: 38730086
DOI: 10.1007/s00259-024-06748-0 -
Neurology and Therapy Jun 2024This pragmatic review synthesises the current understanding of prodromal dementia with Lewy bodies (pDLB) and prodromal Alzheimer's disease (pAD), including clinical...
This pragmatic review synthesises the current understanding of prodromal dementia with Lewy bodies (pDLB) and prodromal Alzheimer's disease (pAD), including clinical presentations, neuropsychological profiles, neuropsychiatric symptoms, biomarkers, and indications for disease management. The core clinical features of dementia with Lewy bodies (DLB)-parkinsonism, complex visual hallucinations, cognitive fluctuations, and REM sleep behaviour disorder are common prodromal symptoms. Supportive clinical features of pDLB include severe neuroleptic sensitivity, as well as autonomic and neuropsychiatric symptoms. The neuropsychological profile in mild cognitive impairment attributable to Lewy body pathology (MCI-LB) tends to include impairment in visuospatial skills and executive functioning, distinguishing it from MCI due to AD, which typically presents with impairment in memory. pDLB may present with cognitive impairment, psychiatric symptoms, and/or recurrent episodes of delirium, indicating that it is not necessarily synonymous with MCI-LB. Imaging, fluid and other biomarkers may play a crucial role in differentiating pDLB from pAD. The current MCI-LB criteria recognise low dopamine transporter uptake using positron emission tomography or single photon emission computed tomography (SPECT), loss of REM atonia on polysomnography, and sympathetic cardiac denervation using meta-iodobenzylguanidine SPECT as indicative biomarkers with slowing of dominant frequency on EEG among others as supportive biomarkers. This review also highlights the emergence of fluid and skin-based biomarkers. There is little research evidence for the treatment of pDLB, but pharmacological and non-pharmacological treatments for DLB may be discussed with patients. Non-pharmacological interventions such as diet, exercise, and cognitive stimulation may provide benefit, while evaluation and management of contributing factors like medications and sleep disturbances are vital. There is a need to expand research across diverse patient populations to address existing disparities in clinical trial participation. In conclusion, an early and accurate diagnosis of pDLB or pAD presents an opportunity for tailored interventions, improved healthcare outcomes, and enhanced quality of life for patients and care partners.
PubMed: 38720013
DOI: 10.1007/s40120-024-00620-x -
Food & Function May 2024Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder and dopaminergic dysfunction in the prefrontal cortex (PFC) may play a role. Our previous...
Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder and dopaminergic dysfunction in the prefrontal cortex (PFC) may play a role. Our previous research indicated that theobromine (TB), a methylxanthine, enhances cognitive function in rodents the PFC. This study investigates TB's effects on hyperactivity and cognitive function in stroke-prone spontaneously hypertensive rats (SHR), an ADHD animal model. Male SHRs (6-week old) received a diet containing 0.05% TB for 40 days, while control rats received normal diets. Age-matched male Wistar-Kyoto rats (WKY) served as genetic controls. During the TB administration period, we conducted open-field tests and Y-maze tasks to evaluate hyperactivity and cognitive function, then assessed dopamine concentrations and tyrosine hydroxylase (TH), dopamine receptor D1-5 (DRD1-5), dopamine transporter (DAT), vesicular monoamine transporter-2 (VMAT-2), synaptosome-associated protein-25 (SNAP-25), and brain-derived neurotrophic factor (BDNF) expressions in the PFC. Additionally, the binding affinity of TB for the adenosine receptors (ARs) was evaluated. Compared to WKY, SHR exhibited hyperactivity, inattention and working memory deficits. However, chronic TB administration significantly improved these ADHD-like behaviors in SHR. TB administration also normalized dopamine concentrations and expression levels of TH, DRD2, DRD4, SNAP-25, and BDNF in the PFC of SHR. No changes were observed in DRD1, DRD3, DRD5, DAT, and VMAT-2 expression between SHR and WKY rats, and TB intake had minimal effects. TB was found to have affinity binding to ARs. These results indicate that long-term TB supplementation mitigates hyperactivity, inattention and cognitive deficits in SHR by modulating dopaminergic nervous function and BDNF levels in the PFC, representing a potential adjunctive treatment for ADHD.
Topics: Animals; Rats, Inbred SHR; Male; Rats; Rats, Inbred WKY; Theobromine; Attention Deficit Disorder with Hyperactivity; Memory, Short-Term; Dopamine; Brain-Derived Neurotrophic Factor; Dopamine Plasma Membrane Transport Proteins; Frontal Lobe; Prefrontal Cortex; Tyrosine 3-Monooxygenase; Disease Models, Animal; Synaptosomal-Associated Protein 25
PubMed: 38713055
DOI: 10.1039/d4fo00683f