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Journal of Neurology, Neurosurgery, and... Oct 2023Motivational symptoms such as apathy and anhedonia are common in Parkinson's disease (PD), respond poorly to treatment, and are hypothesised to share underlying neural...
BACKGROUND
Motivational symptoms such as apathy and anhedonia are common in Parkinson's disease (PD), respond poorly to treatment, and are hypothesised to share underlying neural mechanisms. Striatal dopaminergic dysfunction is considered central to motivational symptoms in PD but the association has never been examined longitudinally. We investigated whether progression of dopaminergic dysfunction was associated with emergent apathy and anhedonia symptoms in PD.
METHODS
Longitudinal cohort study of 412 newly diagnosed patients with PD followed over 5 years as part of the Parkinson's Progression Markers Initiative cohort.Apathy and anhedonia were measured using a composite score derived from relevant items of the 15-item Geriatric Depression Scale (GDS-15) and part I of the MDS-Unified Parkinson's Disease Rating Scale. Dopaminergic neurodegeneration was measured using repeated striatal dopamine transporter (DAT) imaging.
RESULTS
Linear mixed-effects modelling across all contemporaneous data points identified a significant negative relationship between striatal DAT specific binding ratio (SBR) and apathy/anhedonia symptoms, which emerged as PD progressed (interaction:β=-0.09, 95% CI (-0.15 to -0.03), p=0.002). Appearance and subsequent worsening of apathy/anhedonia symptoms began on average 2 years after diagnosis and below a threshold striatal DAT SBR level. The interaction between striatal DAT SBR and time was specific to apathy/anhedonia symptoms, with no evidence of a similar interaction for general depressive symptoms from the GDS-15 (excluding apathy/anhedonia items) (β=-0.06, 95% CI (-0.13 to 0.01)) or motor symptoms (β=0.20, 95% CI (-0.25 to 0.65)).
CONCLUSIONS
Our findings support a central role for dopaminergic dysfunction in motivational symptoms in PD. Striatal DAT imaging may be a useful indicator of apathy/anhedonia risk that could inform intervention strategies.
Topics: Humans; Aged; Apathy; Parkinson Disease; Anhedonia; Dopamine Plasma Membrane Transport Proteins; Longitudinal Studies; Dopamine
PubMed: 37221053
DOI: 10.1136/jnnp-2022-330790 -
Biomedicine & Pharmacotherapy =... Dec 2023Intracranial self-stimulation (ICSS) of the medial forebrain bundle in mice is an experimental model use to assess the relative potential of reward-seeking behaviors....
Abused drug-induced intracranial self-stimulation is correlated with the alteration of dopamine transporter availability in the medial prefrontal cortex and nucleus accumbens of mice.
Intracranial self-stimulation (ICSS) of the medial forebrain bundle in mice is an experimental model use to assess the relative potential of reward-seeking behaviors. Here, we used the ICSS model to evaluate the abuse potential of 18 abused drugs: 3-Fluoroethamphetamine (3-FEA); methylphenidate; cocaine; dextroamphetamine; alpha-Pyrrolidinobutyrophenone (α-PBT); 4'-Fluoro-4-methylaminorex (4-FPO); methamphetamine; larocaine; phentermine; paramethoxymethamphetamine (PMMA); phendimetrazine; N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide (AKB-48); Naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone (CB-13); 4-Ethylnaphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-210); Naphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-018); N-(ortho-methoxybenzyl)-4-ethylamphetamine (4-EA-NBOMe); N-[(2-Methoxyphenyl)methyl]-N-methyl-1-(4-methylphenyl)propan-2-amine (4-MMA-NBOMe); and 1-[1-(4-methoxyphenyl)cyclohexyl]piperidine (4-MeO-PCP). We determined dopamine transporter (DAT) availability in the medial prefrontal cortex (mPFC), striatum, and nucleus accumbens (NAc) after drug treatment. DAT availability in the mPFC and NAc significantly correlated with the ICSS threshold after drug treatment. Extracellular dopamine and calcium levels in PC-12 cells were measured following drug treatment. After drug treatment, Spearman rank and Pearson correlation analyses showed a significant difference between the extracellular dopamine level and the ICSS threshold. After drug treatment, Spearman rank correlation analysis showed a significant correlation between Ca signaling and the ICSS threshold. A positive correlation exists between the ICSS threshold and DAT availability in the mPFC and NAc provoked by abused drugs. The relative potential of drug-induced reward-seeking behavior may be related to DAT availability-mediated extracellular dopamine levels in the mPFC and NAc.
Topics: Animals; Mice; Dopamine; Dopamine Plasma Membrane Transport Proteins; Nucleus Accumbens; Prefrontal Cortex; Self Stimulation
PubMed: 37948992
DOI: 10.1016/j.biopha.2023.115860 -
Rhode Island Medical Journal (2013) Sep 2023The Dopamine Transporter Scan (DaT) is a radionuclear imaging technique which was approved by the FDA to differentiate essential tremor (ET) from Parkinson's disease... (Review)
Review
The Dopamine Transporter Scan (DaT) is a radionuclear imaging technique which was approved by the FDA to differentiate essential tremor (ET) from Parkinson's disease (PD). The scan is a crude indicator of the number of dopamine-secreting cells and is abnormal in presynaptic parkinsonian syndromes. In this article we review this and other possible clinical situations in which a DaT scan may be useful.
Topics: Humans; Dopamine Plasma Membrane Transport Proteins; Parkinsonian Disorders; Parkinson Disease; Radionuclide Imaging
PubMed: 37643339
DOI: No ID Found -
Journal of Neuroimmune Pharmacology :... Sep 2023Impairment of specific cognitive domains in schizophrenia has been associated with prefrontal cortex (PFC) catecholaminergic deficits. Among other factors, prenatal...
BACKGROUND
Impairment of specific cognitive domains in schizophrenia has been associated with prefrontal cortex (PFC) catecholaminergic deficits. Among other factors, prenatal exposure to infections represents an environmental risk factor for schizophrenia development in adulthood. However, it remains largely unknown whether the prenatal infection-induced changes in the brain may be associated with concrete switches in a particular neurochemical circuit, and therefore, if they could alter behavioral functions.
METHODS
In vitro and in vivo neurochemical evaluation of the PFC catecholaminergic systems was performed in offspring from mice undergoing maternal immune activation (MIA). The cognitive status was also evaluated. Prenatal viral infection was mimicked by polyriboinosinic-polyribocytidylic acid (poly(I:C)) administration to pregnant dams (7.5 mg/kg i.p., gestational day 9.5) and consequences were evaluated in adult offspring.
RESULTS
MIA-treated offspring showed disrupted recognition memory in the novel object recognition task (t = 2.30, p = 0.031). This poly(I:C)-based group displayed decreased extracellular dopamine (DA) concentrations compared to controls (t = 3.17, p = 0.0068). Potassium-evoked release of DA and noradrenaline (NA) were impaired in the poly(I:C) group (DA: F[10,90] = 43.33, p < 0.0001; F[1,90] = 1.224, p = 0.2972; F[10,90] = 5.916, p < 0.0001; n = 11); (NA: F[10,90] = 36.27, p < 0.0001; F[1,90] = 1.841, p = 0.208; F[10,90] = 8.686, p < 0.0001; n = 11). In the same way, amphetamine-evoked release of DA and NA were also impaired in the poly(I:C) group (DA: F[8,328] = 22.01, p < 0.0001; F[1,328] = 4.507, p = 0.040; F[8,328] = 2.319, p = 0.020; n = 43); (NA: F[8,328] = 52.07; p < 0.0001; F[1,328] = 4.322; p = 0.044; F[8,398] = 5.727; p < 0.0001; n = 43). This catecholamine imbalance was accompanied by increased dopamine D and D receptor expression (t = 2.64, p = 0.011 and t = 3.55, p = 0.0009; respectively), whereas tyrosine hydroxylase, DA and NA tissue content, DA and NA transporter (DAT/NET) expression and function were unaltered.
CONCLUSIONS
MIA induces in offspring a presynaptic catecholaminergic hypofunction in PFC with cognitive impairment. This poly(I:C)-based model reproduces catecholamine phenotypes reported in schizophrenia and represents an opportunity for the study of cognitive impairment associated to this disorder.
Topics: Pregnancy; Female; Mice; Animals; Humans; Dopamine; Brain; Prefrontal Cortex; Cognitive Dysfunction; Amphetamine; Norepinephrine; Prenatal Exposure Delayed Effects; Poly I-C; Disease Models, Animal
PubMed: 37208550
DOI: 10.1007/s11481-023-10070-1 -
BMC Biology Nov 2023Diets high in saturated fat and sugar, termed "Western diets," have been associated with several negative health outcomes, including increased risk for neurodegenerative...
BACKGROUND
Diets high in saturated fat and sugar, termed "Western diets," have been associated with several negative health outcomes, including increased risk for neurodegenerative disease. Parkinson's disease (PD) is the second most prevalent neurodegenerative disease and is characterized by the progressive death of dopaminergic neurons in the brain. We build upon previous work characterizing the impact of high-sugar diets in Caenorhabditis elegans to mechanistically evaluate the relationship between high-sugar diets and dopaminergic neurodegeneration.
RESULTS
Adult high-glucose and high-fructose diets, or exposure from day 1 to 5 of adulthood, led to increased lipid content, shorter lifespan, and decreased reproduction. However, in contrast to previous reports, we found that adult chronic high-glucose and high-fructose diets did not induce dopaminergic neurodegeneration alone and were protective from 6-hydroxydopamine (6-OHDA) induced degeneration. Neither sugar altered baseline electron transport chain function and both increased vulnerability to organism-wide ATP depletion when the electron transport chain was inhibited, arguing against energetic rescue as a basis for neuroprotection. The induction of oxidative stress by 6-OHDA is hypothesized to contribute to its pathology, and high-sugar diets prevented this increase in the soma of the dopaminergic neurons. However, we did not find increased expression of antioxidant enzymes or glutathione levels. Instead, we found evidence suggesting downregulation of the dopamine reuptake transporter dat-1 that could result in decreased 6-OHDA uptake.
CONCLUSIONS
Our work uncovers a neuroprotective role for high-sugar diets, despite concomitant decreases in lifespan and reproduction. Our results support the broader finding that ATP depletion alone is insufficient to induce dopaminergic neurodegeneration, whereas increased neuronal oxidative stress may drive degeneration. Finally, our work highlights the importance of evaluating lifestyle by toxicant interactions.
Topics: Animals; Humans; Caenorhabditis elegans; Oxidopamine; Dopamine; Neurodegenerative Diseases; Nerve Degeneration; Dopaminergic Neurons; Adenosine Triphosphate; Sugars; Fructose; Glucose; Disease Models, Animal
PubMed: 37950228
DOI: 10.1186/s12915-023-01733-9 -
NPJ Parkinson's Disease Feb 2024Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons. Exercise has been reported to slow the clinical progression of PD. We evaluated...
Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons. Exercise has been reported to slow the clinical progression of PD. We evaluated the dopaminergic system of patients with mild and early PD before and after a six-month program of intense exercise. Using F-FE-PE2I PET imaging, we measured dopamine transporter (DAT) availability in the striatum and substantia nigra. Using NM-MRI, we evaluated the neuromelanin content in the substantia nigra. Exercise reversed the expected decrease in DAT availability into a significant increase in both the substantia nigra and putamen. Exercise also reversed the expected decrease in neuromelanin concentration in the substantia nigra into a significant increase. These findings suggest improved functionality in the remaining dopaminergic neurons after exercise. Further research is needed to validate our findings and to pinpoint the source of any true neuromodulatory and neuroprotective effects of exercise in PD in large clinical trials.
PubMed: 38336768
DOI: 10.1038/s41531-024-00641-1 -
Journal of Psychiatry & Neuroscience :... 2023Interhemispheric cooperation is one of the most prominent functional architectures of the human brain. In patients with schizophrenia, interhemispheric cooperation...
BACKGROUND
Interhemispheric cooperation is one of the most prominent functional architectures of the human brain. In patients with schizophrenia, interhemispheric cooperation deficits have been reported using increasingly powerful neurobehavioural and neuroimaging measures. However, these methods rely in part on the assumption of anatomic symmetry between hemispheres. In the present study, we explored interhemispheric cooperation deficits in schizophrenia using a newly developed index, connectivity between functionally homotopic voxels (CFH), which is unbiased by hemispheric asymmetry.
METHODS
Patients with schizophrenia and age- and sexmatched healthy controls underwent multimodal MRI, and whole-brain CFH maps were constructed for comparison between groups. We examined the correlations of differing CFH values between the schizophrenia and control groups using various neurotransmitter receptor and transporter densities.
RESULTS
We included 86 patients with schizophrenia and 86 matched controls in our analysis. Patients with schizophrenia showed significantly lower CFH values in the frontal lobes, left postcentral gyrus and right inferior temporal gyrus, and significantly greater CFH values in the right caudate nucleus than healthy controls. Moreover, the differing CFH values in patients with schizophrenia were significantly correlated with positive symptom score and illness duration. Functional connectivity within frontal lobes was significantly reduced at the voxel cluster level compared with healthy controls. Finally, the abnormal CFH map of patients with schizophrenia was spatially associated with the densities of the dopamine D and D receptors, fluorodopa, dopamine transporter, serotonin transporter and acetylcholine transporter.
CONCLUSION
Regional abnormalities in interhemispheric cooperation may contribute to the clinical symptoms of schizophrenia. These CFH abnormalities may be associated with dysfunction in neurotransmitter systems strongly implicated in schizophrenia.
Topics: Humans; Schizophrenia; Brain; Brain Mapping; Magnetic Resonance Imaging; Caudate Nucleus
PubMed: 38123242
DOI: 10.1503/jpn.230037 -
BMC Medicine Jul 2023Coffee is the most widely consumed psychostimulant worldwide. Emerging evidence indicates that coffee consumption habit significantly reduces the risk of developing...
BACKGROUND
Coffee is the most widely consumed psychostimulant worldwide. Emerging evidence indicates that coffee consumption habit significantly reduces the risk of developing Parkinson's disease (PD). However, the effect of coffee consumption on nigrostriatal dopaminergic neurodegeneration is still largely unknown. We therefore aim to investigate the role of coffee consumption in nigrostriatal dopaminergic neurodegeneration using dopamine transporter (DAT) imaging in PD and healthy controls (HC).
METHODS
A total of 138 PD patients and 75 HC with questionnaires about coffee consumption, and DAT scans were recruited from the Parkinson's Progression Markers Initiative cohort. Demographic, clinical, and striatal DAT characteristics were compared across subgroups of current, former, and never coffee consumers in PD and HC, respectively. Furthermore, partial correlation analyses were performed to determine whether there was a relationship between coffee cups consumed per day and striatal DAT characteristics in each striatal region. In addition, the factors that may have influenced the loss of nigrostriatal dopaminergic neurons were included in multiple linear regression analyses to identify significant contributing factors to DAT availability in each striatal region.
RESULTS
PD patients had lower DAT availability in each striatal region than HC (p < 0.001). In PD patients, there were significant differences in DAT availability in the caudate (p = 0.008, Bonferroni corrected) across three PD subgroups. Specifically, post hoc tests showed that current coffee consumers had significantly lower DAT availability in the caudate than former coffee consumers (p = 0.01) and never coffee consumers (p = 0.022). In HC, there were significant differences in DAT availability in the caudate (p = 0.031, Bonferroni uncorrected) across three HC subgroups. Specifically, post hoc tests showed that current coffee consumers had significantly lower DAT availability in the caudate than former coffee consumers (p = 0.022). Moreover, correlation analysis revealed that cups per day were negatively correlated with DAT availability in the caudate in current consumers of PD patients (r = - 0.219, p = 0.047). In addition, multiple linear regression analyses showed that current coffee consumption remained an independent predictor of decreased DAT availability in the caudate in PD patients and HC.
CONCLUSIONS
This study demonstrates that current coffee consumption is associated with decreased striatal DAT availability in the caudate. However, the effects of caffeine on striatal DAT may fade and disappear after quitting coffee consumption.
TRIAL REGISTRATION
ClinicalTrials.gov, NCT01141023.
Topics: Humans; Parkinson Disease; Coffee; Dopamine Plasma Membrane Transport Proteins; Tomography, Emission-Computed, Single-Photon; Corpus Striatum
PubMed: 37491235
DOI: 10.1186/s12916-023-02994-5 -
EJNMMI Research Aug 2023Atypical parkinsonism (AP) often presents with Parkinson's symptoms but has a much worse long-term prognosis. The diagnosis is presently based on clinical criteria, but...
BACKGROUND
Atypical parkinsonism (AP) often presents with Parkinson's symptoms but has a much worse long-term prognosis. The diagnosis is presently based on clinical criteria, but a cerebral positron emission tomography (PET) scan with [F]fluoro-2-deoxy-2-D-glucose ([F]FDG) may assist in the diagnosis of AP such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Lewy body dementia (DLB). Only few studies have evaluated the sensitivity and specificity of [F]FDG PET for separating the diseases in a mixed patient population, which we aim to assess in a retrospective material.
RESULTS
We identified 156 patients referred for a cerebral [F]FDG PET for suspicion of AP during 2017-2019. The [F]FDG PET was analysed by a nuclear medicine specialist blinded to clinical information but with access to dopamine transporter imaging. The reference standard was the follow-up clinical diagnosis (follow-up: 6-72 months). The overall accuracy for correct classification was 74%. Classification sensitivity (95% confidence interval, CI) and specificity (95% CI) for MSA (n = 20) were 1.00 (0.83-1.00) and 0.91 (0.85-0.95), for DLB/Parkinson with dementia (PDD) (n = 26) were 0.81 (0.61-0.93) and 0.97 (0.92-0.99) and for CBD/PSP (n = 68) were 0.62 (0.49-0.73) and 0.97 (0.90-0.99).
CONCLUSIONS
Our results support the additional use of [F]FDG PET for the clinical diagnosis of AP with moderate to high sensitivity and specificity. Use of [F]FDG PET may be beneficial for prognosis and supportive treatment of the patients and useful for future clinical treatment trials.
PubMed: 37572162
DOI: 10.1186/s13550-023-01025-x -
Experimental and Molecular Pathology Dec 2023An increasing number of patients experiences prolonged symptoms, whose profile and timeline remain uncertain, a condition that has been defined as post COVID. The...
An increasing number of patients experiences prolonged symptoms, whose profile and timeline remain uncertain, a condition that has been defined as post COVID. The majority of recovered hospitalized patients manifests at least one persistent symptom even sixty days after the first clinical manifestation's onset. Particularly, in light of the COVID-19-related symptomatology, it has been hypothesized that SARS-CoV-2 might affect the dopamine pathway. However, no scientific evidence has been produced so far. To this end, human iPSC-derived dopaminergic neurons were infected with EU, Delta and Omicron SARS-CoV-2 variants. The infection with EU and Delta variants, but not with Omicron, results in a reduced intracellular content and extracellular release of dopamine. Indeed, the tyrosine hydroxylase was found to be significantly upregulated at the mRNA level, while being greatly reduced at the protein level. The major downstream synthetic enzyme DOPA-decarboxylase and the dopamine transporter were significantly downregulated both at the mRNA and protein level. Notably, in vitro SARS-CoV-2 infection was also associated with an altered MAP2 and TAU expression and with an increased presence of neuronal stress markers. These preliminary observations suggest that the dopamine metabolism and production are affected by SARS-CoV-2, partially explaining some of the neurological symptoms manifested.
Topics: Humans; SARS-CoV-2; Dopaminergic Neurons; COVID-19; Dopamine; Induced Pluripotent Stem Cells; RNA, Messenger
PubMed: 37775022
DOI: 10.1016/j.yexmp.2023.104874