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European Journal of Neurology Oct 2023The correlates of motor parkinsonism in Alzheimer's disease (AD) remain controversial. The effects of nigrostriatal dopaminergic degeneration on parkinsonism and...
BACKGROUND AND PURPOSE
The correlates of motor parkinsonism in Alzheimer's disease (AD) remain controversial. The effects of nigrostriatal dopaminergic degeneration on parkinsonism and cognition in biomarker-validated patients with AD were evaluated.
METHODS
This study recruited 116 patients with AD who underwent dual-phase F-N-(3-fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) nortropane positron emission tomography, F-florbetaben positron emission tomography, 3 T brain magnetic resonance imaging, and Unified Parkinson's Disease Rating Scale (UPDRS) and neuropsychological tests. The mean cortical thickness in the frontal, temporal, parietal and occipital cortices, and the dopamine transporter (DAT) uptake in the caudate, anterior/posterior putamen and substantia nigra were quantified. The relationship between DAT uptake, mean lobar cortical thickness, UPDRS motor score and cognition was investigated using general linear models (GLMs) after controlling for age, sex, education, intracranial volume, and deep and periventricular white matter hyperintensities. A path analysis was performed for the UPDRS motor score with the same covariates.
RESULTS
Path analysis and multivariable GLMs for UPDRS motor score showed that lower caudate DAT uptake was directly associated with a higher UPDRS motor score, whereas caudate DAT uptake confounded the association between mean frontal/parietal thickness and UPDRS motor score. Multivariable GLMs for cognitive scores showed that lower caudate DAT uptake was associated with visuospatial/executive dysfunction independent of mean frontal or parietal thickness.
CONCLUSIONS
Nigrostriatal dopaminergic dysfunction is associated with parkinsonism and visuospatial/executive dysfunction in patients with AD.
Topics: Humans; Alzheimer Disease; Dopamine Plasma Membrane Transport Proteins; Parkinson Disease; Corpus Striatum; Parkinsonian Disorders; Cognition; Dopamine; Tomography, Emission-Computed, Single-Photon
PubMed: 37493955
DOI: 10.1111/ene.15995 -
CNS Neuroscience & Therapeutics Sep 2023Electroacupuncture (EA) shows advantages in both clinical practice and depression animal models. Dopaminergic-related dysfunction in the prefrontal cortex (PFC) may be a...
Electroacupuncture alleviated depression-like behaviors in ventromedial prefrontal cortex of chronic unpredictable mild stress-induced rats: Increasing synaptic transmission and phosphorylating dopamine transporter.
AIMS
Electroacupuncture (EA) shows advantages in both clinical practice and depression animal models. Dopaminergic-related dysfunction in the prefrontal cortex (PFC) may be a hidden antidepressant mechanism of EA, where dopamine transporter (DAT) plays an essential role. This study aimed to investigate the synaptic transmission and DAT-related changes of EA in depression.
METHODS
Male Sprague-Dawley rats were subjected to 3-week chronic unpredictable mild stress (CUMS). The successfully modeled rats were then randomly and equally assigned to CUMS, selective serotonin reuptake inhibitor (SSRI), and EA or SSRI + EA groups, followed by a 2-week treatment respectively. After monitoring body weight and behavioral tests of all rats, the ventromedial PFC (vmPFC) tissue was collected for electrophysiology and the expression detection of DAT, phosphorylated DAT (p-DAT), cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), and trace amine-associated receptor 1 (TAAR1).
RESULTS
Depressive-like behaviors induced by CUMS were alleviated by EA, SSRI, and SSRI + EA treatments through behavioral tests. Compared with CUMS group, EA improved synaptic transmission in vmPFC by upregulating spontaneous excitatory postsynaptic currents amplitude. Molecularly, EA reversed the increased total DAT and p-DAT expression as well as the decreased ratio of p-DAT/total DAT along with the activation of TAAR1, cAMP, and PKA in vmPFC.
CONCLUSION
We speculated that the antidepressant effect of EA was associated with enhanced synaptic transmission in vmPFC, and the upregulated phosphorylation of DAT relevant to TAAR1, cAMP, and PKA may be the potential mechanism.
Topics: Rats; Male; Animals; Rats, Sprague-Dawley; Depression; Electroacupuncture; Dopamine Plasma Membrane Transport Proteins; Hippocampus; Antidepressive Agents; Synaptic Transmission; Selective Serotonin Reuptake Inhibitors; Prefrontal Cortex; Disease Models, Animal
PubMed: 37002793
DOI: 10.1111/cns.14200 -
Movement Disorders : Official Journal... Nov 2023Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder characterized by motor and nonmotor symptoms. Several features have prognostic importance and have...
BACKGROUND
Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder characterized by motor and nonmotor symptoms. Several features have prognostic importance and have been used as key indicators for identifying clinical subtypes. However, the symptom-based classification approach has limitations with respect to the stability of the obtained subtypes.
OBJECTIVES
The purpose of this study was to identify subtypes of PD using nuclear imaging biomarkers targeting the cardiac sympathetic nervous and nigro-striatal systems and to compare patterns of cortical morphological change among obtained subtypes.
METHODS
We performed unbiased hierarchical cluster analysis using I-metaiodobenzylguanidine cardiac scintigraphy and I-N-(3-fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl) nortropane single photon emission computed tomography data for 56 patients with PD. We compared clinical characteristics and the patterns of cortical atrophy in the obtained clusters.
RESULTS
Three clusters were identified and showed distinct characteristics in onset ages and dopamine-replacement therapy and deep brain stimulation requirements. According to the characteristics, clusters were classified into two subtypes, namely, "cardio-cortical impairment (CC)" and "dopaminergic-dominant dysfunction (DD)" subtype. The three clusters were named according to subtype and time since onset in which 14 patients were classified as "early DD," 25 as "advanced DD," and 17 as "early CC." Compared with the early DD subtype, the early CC subtype showed parietal-dominant diffuse cortical atrophy and the advanced DD subtype showed left-side predominant mild cortical atrophy.
CONCLUSIONS
Nuclear imaging biomarker-based classification can be used to identify clinically and pathologically relevant PD subtypes with distinct disease trajectories. © 2023 International Parkinson and Movement Disorder Society.
Topics: Humans; Parkinson Disease; Radionuclide Imaging; Tomography, Emission-Computed, Single-Photon; Corpus Striatum; Atrophy; Tropanes; Dopamine Plasma Membrane Transport Proteins
PubMed: 37638533
DOI: 10.1002/mds.29582 -
Nature Cancer Mar 2024Cancer stem cells (CSCs), functionally characterized by self-renewal and tumor-initiating activity, contribute to decreased tumor immunogenicity, while fostering tumor...
Cancer stem cells (CSCs), functionally characterized by self-renewal and tumor-initiating activity, contribute to decreased tumor immunogenicity, while fostering tumor growth and metastasis. Targeting G9a histone methyltransferase (HMTase) effectively blocks CSC functions in colorectal tumors by altering pluripotent-like molecular networks; however, existing molecules directly targeting G9a HMTase activity failed to reach clinical stages due to safety concerns. Using a stem cell-based phenotypic drug-screening pipeline, we identified the dopamine transporter (DAT) antagonist vanoxerine, a compound with previously demonstrated clinical safety, as a cancer-specific downregulator of G9a expression. Here we show that gene silencing and chemical antagonism of DAT impede colorectal CSC functions by repressing G9a expression. Antagonizing DAT also enhanced tumor lymphocytic infiltration by activating endogenous transposable elements and type-I interferon response. Our study unveils the direct implication of the DAT-G9a axis in the maintenance of CSC populations and an approach to improve antitumor immune response in colon tumors.
Topics: Humans; Histone-Lysine N-Methyltransferase; Dopamine Plasma Membrane Transport Proteins; Colonic Neoplasms; Neoplastic Stem Cells; Piperazines
PubMed: 38351181
DOI: 10.1038/s43018-024-00727-y -
Parkinsonism & Related Disorders Oct 2023Parkinsonism is now recognized as an additional feature in RFC1/CANVAS syndrome; however, no systematic evaluation of nigrostriatal dopaminergic function has been...
INTRODUCTION
Parkinsonism is now recognized as an additional feature in RFC1/CANVAS syndrome; however, no systematic evaluation of nigrostriatal dopaminergic function has been published so far.
METHODS
This is an observational, single-center study, which analyzed 13 patients with molecular confirmation of RFC1/CANVAS. Disease severity was assessed with the SARA scale. Each subject was carefully evaluated for the presence of parkinsonian features. Dopamine transporter (DAT) imaging was acquired and reconstructed in the transverse, coronal and sagittal planes 4 h after venous injection of 99mTc-TRODAT-1. An experienced nuclear physician performed the visual analysis of all images.
RESULTS
Patients had a mean age of 62.3 ± 8.8 years, and there were 9 women. The mean SARA score was 15.5 ± 5.8. Nine patients had abnormal DAT imaging results. The putamen was more frequently affected than the caudate nucleus on both sides. Considering all regions, uptake of 99mTc-TRODAT-1 did not correlate with disease duration or SARA scores. Parkinsonism was noticed in 3/13 patients, all of which had abnormal DAT scans. Interestingly, six subjects had reduced DAT imaging uptake, but no clinical signs of parkinsonism.
CONCLUSION
Nigrostriatal dysfunction is frequent in RFC1/CANVAS even in the absence of clinical parkinsonism and may occur early in the disease course.
PubMed: 37729670
DOI: 10.1016/j.parkreldis.2023.105854 -
Movement Disorders : Official Journal... Nov 2023Preliminary studies suggested seasonality of dopaminergic functioning, but it is unknown whether dopamine transporter (DAT) expression in humans is also dependent on the...
BACKGROUND
Preliminary studies suggested seasonality of dopaminergic functioning, but it is unknown whether dopamine transporter (DAT) expression in humans is also dependent on the seasons. We, therefore, investigated seasonal and sunlight-dependent effects on DAT availability in early Parkinson's disease (PD) patients and healthy controls.
METHODS
DAT single-photon emission computed tomography scans (n = 730) were gathered from the Parkinson's Progression Marker Initiative (PPMI) database. We used global horizontal irradiance (GHI) as proxy for sun exposure/month and assessed associations between striatal DAT availability and season (autumn/winter versus spring/summer), GHI and latitude of the PPMI site.
RESULTS
In PD patients, DAT availability in the left caudate nucleus was higher in spring/summer (B [standard error (SE)] = 0.05 [0.02], P = 0.03) and positively associated with higher sun exposure (B [SE] = 0.59 [0.22] × 10 , P = 0.007). Latitude (in degrees north) of the PPMI site was negatively associated with DAT availability in both PD and healthy controls.
CONCLUSION
Striatal DAT availability may be influenced by daylight exposure. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Humans; Corpus Striatum; Dopamine Plasma Membrane Transport Proteins; Parkinson Disease; Sunlight; Tomography, Emission-Computed, Single-Photon
PubMed: 37670567
DOI: 10.1002/mds.29597 -
PLCγ1 in dopamine neurons critically regulates striatal dopamine release via VMAT2 and synapsin III.Experimental & Molecular Medicine Nov 2023Dopamine neurons are essential for voluntary movement, reward learning, and motivation, and their dysfunction is closely linked to various psychological and...
Dopamine neurons are essential for voluntary movement, reward learning, and motivation, and their dysfunction is closely linked to various psychological and neurodegenerative diseases. Hence, understanding the detailed signaling mechanisms that functionally modulate dopamine neurons is crucial for the development of better therapeutic strategies against dopamine-related disorders. Phospholipase Cγ1 (PLCγ1) is a key enzyme in intracellular signaling that regulates diverse neuronal functions in the brain. It was proposed that PLCγ1 is implicated in the development of dopaminergic neurons, while the physiological function of PLCγ1 remains to be determined. In this study, we investigated the physiological role of PLCγ1, one of the key effector enzymes in intracellular signaling, in regulating dopaminergic function in vivo. We found that cell type-specific deletion of PLCγ1 does not adversely affect the development and cellular morphology of midbrain dopamine neurons but does facilitate dopamine release from dopaminergic axon terminals in the striatum. The enhancement of dopamine release was accompanied by increased colocalization of vesicular monoamine transporter 2 (VMAT2) at dopaminergic axon terminals. Notably, dopamine neuron-specific knockout of PLCγ1 also led to heightened expression and colocalization of synapsin III, which controls the trafficking of synaptic vesicles. Furthermore, the knockdown of VMAT2 and synapsin III in dopamine neurons resulted in a significant attenuation of dopamine release, while this attenuation was less severe in PLCγ1 cKO mice. Our findings suggest that PLCγ1 in dopamine neurons could critically modulate dopamine release at axon terminals by directly or indirectly interacting with synaptic machinery, including VMAT2 and synapsin III.
Topics: Animals; Mice; Dopamine; Dopaminergic Neurons; Presynaptic Terminals; Synapsins; Vesicular Monoamine Transport Proteins
PubMed: 37907739
DOI: 10.1038/s12276-023-01104-y -
Frontiers in Cellular Neuroscience 2023Alzheimer's disease (AD) is characterized by the pathologic deposition of amyloid and neurofibrillary tangles in the brain, leading to neuronal damage and defective... (Review)
Review
Alzheimer's disease (AD) is characterized by the pathologic deposition of amyloid and neurofibrillary tangles in the brain, leading to neuronal damage and defective synapses. These changes manifest as abnormalities in cognition and behavior. The functional deficits are also attributed to abnormalities in multiple neurotransmitter systems contributing to neuronal dysfunction. One such important system is the dopaminergic system. It plays a crucial role in modulating movement, cognition, and behavior while connecting various brain areas and influencing other neurotransmitter systems, making it relevant in neurodegenerative disorders like AD and Parkinson's disease (PD). Considering its significance, the dopaminergic system has emerged as a promising target for alleviating movement and cognitive deficits in PD and AD, respectively. Extensive research has been conducted on dopaminergic neurons, receptors, and dopamine levels as critical factors in cognition and memory in AD. However, the exact nature of movement abnormalities and other features of extrapyramidal symptoms are not fully understood yet in AD. Recently, a previously overlooked element of the dopaminergic system, the dopamine transporter, has shown significant promise as a more effective target for enhancing cognition while addressing dopaminergic system dysfunction in AD.
PubMed: 38026688
DOI: 10.3389/fncel.2023.1292858 -
Molecular Psychiatry Jul 2023Concurrent cocaine and alcohol use is among the most frequent drug combination, and among the most dangerous in terms of deleterious outcomes. Cocaine increases...
Concurrent cocaine and alcohol use is among the most frequent drug combination, and among the most dangerous in terms of deleterious outcomes. Cocaine increases extracellular monoamines by blocking dopamine (DA), norepinephrine (NE) and serotonin (5-HT) transporters (DAT, NET and SERT, respectively). Likewise, ethanol also increases extracellular monoamines, however evidence suggests that ethanol does so independently of DAT, NET and SERT. Organic cation transporter 3 (OCT3) is an emergent key player in the regulation of monoamine signaling. Using a battery of in vitro, in vivo electrochemical, and behavioral approaches, as well as wild-type and constitutive OCT3 knockout mice, we show that ethanol's actions to inhibit monoamine uptake are dependent on OCT3. These findings provide a novel mechanistic basis whereby ethanol enhances the neurochemical and behavioral effects of cocaine and encourage further research into OCT3 as a target for therapeutic intervention in the treatment of ethanol and ethanol/cocaine use disorders.
Topics: Mice; Animals; Dopamine; Ethanol; Carrier Proteins; Cocaine-Related Disorders; Cocaine; Serotonin; Mice, Knockout; Cations; Dopamine Plasma Membrane Transport Proteins; Serotonin Plasma Membrane Transport Proteins
PubMed: 37308680
DOI: 10.1038/s41380-023-02064-5 -
International Journal of Geriatric... Sep 2023Neuropsychiatric symptom could be useful for detecting patients with prodromal dementia. Similarities and differences in the NPSs between preclinical/prodromal...
OBJECTIVES
Neuropsychiatric symptom could be useful for detecting patients with prodromal dementia. Similarities and differences in the NPSs between preclinical/prodromal Alzheimer's disease (AD) and prodromal Parkinson's disease dementia (PDD)/Dementia with Lewy bodies (DLB) may exist. This study aimed to compare the NPSs between preclinical/prodromal AD and prodromal PDD/DLB.
METHODS
One hundred and three participants without dementia aged ≥50 years were included in this study. The mild behavioral impairment (MBI) total score and the MBI scores for each domain were calculated using the neuropsychiatric inventory questionnaire score. Participants were divided into five groups based on the clinical diagnosis by neurologists or psychiatrists in each institution based on the results of the amyloid positron emission tomography and dopamine transporter single photon emission computed tomography (DAT-SPECT): Group 1: amyloid-positive and abnormal DAT-SPECT, Group 2: amyloid-negative and abnormal DAT-SPECT, Group 3: amyloid-positive and normal DAT-SPECT, Group 4: mild cognitive impairment unlikely due to AD with normal DAT-SPECT, and Group 5: cognitively normal with amyloid-negative and normal DAT-SPECT.
RESULTS
The MBI abnormal perception or thought content scores were significantly higher in Group 1 than Group 5 (Bonferroni-corrected p = 0.012). The MBI total score (Bonferroni-corrected p = 0.011) and MBI impulse dyscontrol score (Bonferroni-corrected p = 0.033) in Group 4 were significantly higher than those in Group 5.
CONCLUSION
The presence of both amyloid and putative Lewy body pathologies may be associated with psychotic symptoms.
Topics: Humans; Lewy Bodies; Dementia; Parkinson Disease; Alzheimer Disease; Cognitive Dysfunction
PubMed: 37655505
DOI: 10.1002/gps.5993