RESUMO
BACKGROUND: Using 11C-(R)-PK11195-PET, we found increased microglia activation in isolated REM sleep behavior disorder (iRBD) patients. Their role remains to be clarified. OBJECTIVES: The objective is to assess relationships between activated microglia and progression of nigrostriatal dysfunction in iRBD. METHODS: Fifteen iRBD patients previously scanned with 11C-(R)-PK11195 and 18F-DOPA-PET underwent repeat 18F-DOPA-PET after 3 years. 18F-DOPA Ki changes from baseline were evaluated with volumes-of-interest and voxel-based analyses. RESULTS: Significant 18F-DOPA Ki reductions were found in putamen and caudate. Reductions were larger and more widespread in patients with increased nigral microglia activation at baseline. Left nigral 11C-(R)-PK11195 binding at baseline was a predictor of 18F-DOPA Ki reduction in left caudate (coef = -0.0426, P = 0.016). CONCLUSIONS: Subjects with increased baseline 11C-(R)-PK11195 binding have greater changes in nigrostriatal function, suggesting a detrimental rather than protective effect of microglial activation. Alternatively, both phenomena occur in patients with prominent nigrostriatal dysfunction without a causative link. The clinical and therapeutic implications of these findings need further elucidation. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Assuntos
Progressão da Doença , Microglia , Tomografia por Emissão de Pósitrons , Transtorno do Comportamento do Sono REM , Substância Negra , Humanos , Masculino , Transtorno do Comportamento do Sono REM/fisiopatologia , Microglia/metabolismo , Microglia/patologia , Feminino , Pessoa de Meia-Idade , Idoso , Substância Negra/diagnóstico por imagem , Substância Negra/patologia , Substância Negra/metabolismo , Substância Negra/fisiopatologia , Di-Hidroxifenilalanina/análogos & derivados , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/patologia , Corpo Estriado/metabolismo , Corpo Estriado/fisiopatologia , IsoquinolinasRESUMO
BACKGROUND: Reduced cortical acetylcholinesterase activity, as measured by 11 C-donepezil positron emission tomography (PET), has been reported in patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD). However, its progression and clinical implications have not been fully investigated. Here, we explored the relationship between longitudinal changes in brain acetylcholinesterase activity and cognitive function in iRBD. METHODS: Twelve iRBD patients underwent 11 C-donepezil PET at baseline and after 3 years. PET images were interrogated with statistical parametric mapping (SPM) and a regions of interest (ROI) approach. Clinical progression was assessed with the Movement Disorder Society-Unified Parkinson's Disease Rating Scale-Part III (MDS-UPDRS-III). Cognitive function was rated using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). RESULTS: From baseline to follow-up, the mean 11 C-donepezil distribution volume ratio (DVR) decreased in the cortex (p = 0.006), thalamus (p = 0.013), and caudate (p = 0.013) ROI. Despite no significant changes in the group mean MMSE or MoCA scores being observed, individually, seven patients showed a decline in their scores on these cognitive tests. Subgroup analysis showed that only the subgroup of patients with a decline in cognitive scores had a significant reduction in mean cortical 11 C-donepezil DVR. CONCLUSIONS: Our results show that severity of brain cholinergic dysfunction in iRBD patients increases significantly over 3 years, and those changes are more severe in those with a decline in cognitive test scores.
Assuntos
Doença de Parkinson , Transtorno do Comportamento do Sono REM , Humanos , Transtorno do Comportamento do Sono REM/psicologia , Acetilcolinesterase , Donepezila , Encéfalo/diagnóstico por imagemRESUMO
Synucleinopathies are neurodegenerative diseases with both central and peripheral immune responses. However, whether the peripheral immune changes occur early in disease and their relation to brain events is yet unclear. Isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD) can precede synucleinopathy-related parkinsonism and provides a prodromal phenotype to study early Parkinson's disease events. In this prospective case-control study, we describe monocytic markers in a cohort of iRBD patients that were associated with the brain-imaging markers of inflammation and neuronal dysfunction. Using 11C-PK11195 positron emission tomography (PET), we previously showed increased immune activation in the substantia nigra of iRBD patients, while 18F-DOPA PET detected reduced putaminal dopaminergic function. Here we describe that patients' blood monocytic cells showed increased expression of CD11b, while HLA-DR expression was decreased compared to healthy controls. The iRBD patients had increased classical monocytes and mature natural killer cells. Remarkably, the levels of expression of Toll-like receptor 4 (TLR4) on blood monocytes in iRBD patients were positively correlated with nigral immune activation measured by 11C-PK11195 PET and negatively correlated with putaminal 18F-DOPA uptake; the opposite was seen for the percentage of CD163+ myeloid cells. This suggesting a deleterious role for TLR4 and, conversely, a protective one for the CD163 expression. We show an association between peripheral blood monocytes and brain immune and dopaminergic changes in a synucleinopathy-related disorder, thus suggesting a cross-talk among periphery and brain during the disease.
Assuntos
Neurônios , Tomografia por Emissão de Pósitrons , Transtorno do Comportamento do Sono REM , Substância Negra , Idoso , Biomarcadores/sangue , Antígeno CD11b/sangue , Antígeno CD11b/imunologia , Feminino , Antígenos HLA-DR/sangue , Antígenos HLA-DR/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Neurônios/imunologia , Neurônios/metabolismo , Transtorno do Comportamento do Sono REM/sangue , Transtorno do Comportamento do Sono REM/diagnóstico por imagem , Transtorno do Comportamento do Sono REM/imunologia , Substância Negra/diagnóstico por imagem , Substância Negra/imunologia , Substância Negra/metabolismo , Receptor 4 Toll-Like/sangue , Receptor 4 Toll-Like/imunologiaRESUMO
BACKGROUND: Glutamatergic dysfunction has been implicated in sensory integration deficits in schizophrenia, yet how glutamatergic function contributes to behavioural impairments and neural activities of sensory integration remains unknown. METHODS: Fifty schizophrenia patients and 43 healthy controls completed behavioural assessments for sensory integration and underwent magnetic resonance spectroscopy (MRS) for measuring the anterior cingulate cortex (ACC) glutamate levels. The correlation between glutamate levels and behavioural sensory integration deficits was examined in each group. A subsample of 20 pairs of patients and controls further completed an audiovisual sensory integration functional magnetic resonance imaging (fMRI) task. Blood Oxygenation Level Dependent (BOLD) activation and task-dependent functional connectivity (FC) were assessed based on fMRI data. Full factorial analyses were performed to examine the Group-by-Glutamate Level interaction effects on fMRI measurements (group differences in correlation between glutamate levels and fMRI measurements) and the correlation between glutamate levels and fMRI measurements within each group. RESULTS: We found that schizophrenia patients exhibited impaired sensory integration which was positively correlated with ACC glutamate levels. Multimodal analyses showed significantly Group-by-Glutamate Level interaction effects on BOLD activation as well as task-dependent FC in a 'cortico-subcortical-cortical' network (including medial frontal gyrus, precuneus, ACC, middle cingulate gyrus, thalamus and caudate) with positive correlations in patients and negative in controls. CONCLUSIONS: Our findings indicate that ACC glutamate influences neural activities in a large-scale network during sensory integration, but the effects have opposite directionality between schizophrenia patients and healthy people. This implicates the crucial role of glutamatergic system in sensory integration processing in schizophrenia.
Assuntos
Imageamento por Ressonância Magnética , Esquizofrenia , Humanos , Imageamento por Ressonância Magnética/métodos , Giro do Cíngulo , Ácido Glutâmico , Espectroscopia de Prótons por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/métodos , Mapeamento EncefálicoRESUMO
Values of binding potentials (BPND) of dopamine D2/3 receptors differ in different regions of the brain, but we do not know with certainty how much of this difference is due either to different receptor numbers, or to different affinities of tracers to the receptors, or to both. We tested the claim that both striatal and extrastriatal dopamine D2/3 receptor availabilities vary with age in vivo in humans by determining the values of BPND of the specific radioligand [11C]raclopride. We determined values of BPND in striatal and extrastriatal volumes-of-interest (VOI) with the same specific receptor radioligand. We estimated values of BPND in individual voxels of brains of healthy volunteers in vivo, and we obtained regional averages of VOI by dynamic positron emission tomography (PET). We calculated average values of BPND in caudate nucleus and putamen of striatum, and in frontal, occipital, parietal, and temporal cortices of the forebrain, by means of four methods, including the ERLiBiRD (Estimation of Reversible Ligand Binding and Receptor Density) method, the tissue reference methods of Logan and Logan-Ichise, respectively, and the SRTM (Simplified Reference Tissue Method). Voxelwise generation of parametric maps of values of BPND used the multi-linear regression version of SRTM. Age-dependent changes of the binding potential presented with an inverted U-shape with peak binding potentials reached between the ages of 20 and 30. The estimates of BPND declined significantly with age after the peak in both striatal and extrastriatal regions, as determined by all four methods, with the greatest decline observed in posterior (occipital and parietal) cortices (14% per decade) and the lowest decline in caudate nucleus (3% per decade). The sites of the greatest declines are of particular interest because of the clinical implications.
Assuntos
Dopamina , Receptores de Dopamina D2 , Humanos , Adulto , Adulto Jovem , Dopamina/metabolismo , Receptores de Dopamina D2/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Racloprida , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Receptores de Dopamina D3/metabolismoRESUMO
During the prodromal period of Parkinson's disease and other α-synucleinopathy-related parkinsonisms, neurodegeneration is thought to progressively affect deep brain nuclei, such as the locus coeruleus, caudal raphe nucleus, substantia nigra, and the forebrain nucleus basalis of Meynert. Besides their involvement in the regulation of mood, sleep, behaviour, and memory functions, these nuclei also innervate parenchymal arterioles and capillaries throughout the cortex, possibly to ensure that oxygen supplies are adjusted according to the needs of neural activity. The aim of this study was to examine whether patients with isolated REM sleep behaviour disorder, a parasomnia considered to be a prodromal phenotype of α-synucleinopathies, reveal microvascular flow disturbances consistent with disrupted central blood flow control. We applied dynamic susceptibility contrast MRI to characterize the microscopic distribution of cerebral blood flow in the cortex of 20 polysomnographic-confirmed patients with isolated REM sleep behaviour disorder (17 males, age range: 54-77 years) and 25 healthy matched controls (25 males, age range: 58-76 years). Patients and controls were cognitively tested by Montreal Cognitive Assessment and Mini Mental State Examination. Results revealed profound hypoperfusion and microvascular flow disturbances throughout the cortex in patients compared to controls. In patients, the microvascular flow disturbances were seen in cortical areas associated with language comprehension, visual processing and recognition and were associated with impaired cognitive performance. We conclude that cortical blood flow abnormalities, possibly related to impaired neurogenic control, are present in patients with isolated REM sleep behaviour disorder and associated with cognitive dysfunction. We hypothesize that pharmacological restoration of perivascular neurotransmitter levels could help maintain cognitive function in patients with this prodromal phenotype of parkinsonism.
Assuntos
Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/patologia , Transtorno do Comportamento do Sono REM/patologia , Idoso , Circulação Cerebrovascular , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Microcirculação , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: Imaging activated glutamate N-methyl-D-aspartate receptor ion channels (NMDAR-ICs) using positron emission tomography (PET) has proved challenging due to low brain uptake, poor affinity and selectivity, and high metabolism and dissociation rates of candidate radioligands. The radioligand [18 F]GE-179 is a known use-dependent marker of NMDAR-ICs. We studied whether interictal [18 F]GE-179 PET would detect foci of abnormal NMDAR-IC activation in patients with refractory focal epilepsy. METHODS: Ten patients with refractory focal epilepsy and 18 healthy controls had structural magnetic resonance imaging (MRI) followed by a 90-min dynamic [18 F]GE-179 PET scan with simultaneous electroencephalography (EEG). PET and EEG findings were compared with MRI and previous EEGs. Standard uptake value (SUV) images of [18 F]GE-179 were generated and global gray matter uptake was measured for each individual. To localize focal increases in uptake of [18 F]GE-179, the individual SUV images were interrogated with statistical parametric mapping in comparison to a normal database. Additionally, individual healthy control SUV images were compared with the rest of the control database to determine their prevalence of increased focal [18 F]GE-179 uptake. RESULTS: Interictal [18 F]GE-179 PET detected clusters of significantly increased binding in eight of 10 patients with focal epilepsy but none of the controls. The number of clusters of raised [18 F]GE-179 uptake in the patients with epilepsy exceeded the focal abnormalities revealed by the simultaneously recorded EEG. Patients with extensive clusters of raised [18 F]GE-179 uptake showed the most abnormal EEGs. SIGNIFICANCE: Detection of multiple foci of abnormal NMDAR-IC activation in 80% of our patients with refractory focal epilepsy using interictal [18 F]GE-179 PET could reflect enhanced neuronal excitability due to chronic seizure activity. This indicates that chronic epileptic activity is associated with abnormal NMDAR ion channel activation beyond the initial irritative zones. [18 F]GE-179 PET could be a candidate marker for identifying pathological brain areas in patients with treatment-resistant focal epilepsy.
Assuntos
Epilepsia Resistente a Medicamentos , Epilepsias Parciais , Epilepsia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Epilepsia Resistente a Medicamentos/diagnóstico por imagem , Epilepsia Resistente a Medicamentos/metabolismo , Eletroencefalografia , Epilepsias Parciais/diagnóstico por imagem , Epilepsias Parciais/metabolismo , Epilepsia/metabolismo , Fluordesoxiglucose F18/metabolismo , Humanos , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons/métodos , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
Machine learning has increasingly been applied to classification of schizophrenia in neuroimaging research. However, direct replication studies and studies seeking to investigate generalizability are scarce. To address these issues, we assessed within-site and between-site generalizability of a machine learning classification framework which achieved excellent performance in a previous study using two independent resting-state functional magnetic resonance imaging data sets collected from different sites and scanners. We established within-site generalizability of the classification framework in the main data set using cross-validation. Then, we trained a model in the main data set and investigated between-site generalization in the validated data set using external validation. Finally, recognizing the poor between-site generalization performance, we updated the unsupervised algorithm to investigate if transfer learning using additional unlabeled data were able to improve between-site classification performance. Cross-validation showed that the published classification procedure achieved an accuracy of 0.73 using majority voting across all selected components. External validation found a classification accuracy of 0.55 (not significant) and 0.70 (significant) using the direct and transfer learning procedures, respectively. The failure of direct generalization from one site to another demonstrates the limitation of within-site cross-validation and points toward the need to incorporate efforts to facilitate application of machine learning across multiple data sets. The improvement in performance with transfer learning highlights the importance of taking into account the properties of data when constructing predictive models across samples and sites. Our findings suggest that machine learning classification result based on a single study should be interpreted cautiously.
Assuntos
Conectoma/métodos , Imageamento por Ressonância Magnética/métodos , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/fisiopatologia , Aprendizado de Máquina não Supervisionado , Adulto , Conectoma/normas , Feminino , Humanos , Imageamento por Ressonância Magnética/normas , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Aprendizado de Máquina não Supervisionado/normasRESUMO
INTRODUCTION: Investigating obsessive-compulsive symptoms in subclinical populations provides a useful framework for understanding the early development of obsessive-compulsive spectrum disorders. The present study aimed to apply searchlight classification analysis on resting-state functional magnetic resonance imaging data to identify potential brain markers in subclinical individuals with obsessive-compulsive symptoms. METHODS: In this observational study, 40 college students with high obsessive-compulsive symptom scores and 40 with low obsessive-compulsive symptom scores were recruited from universities in China. We conducted searchlight classification and comparison analysis between the two groups based on Amplitude of Low Frequency Fluctuation (ALFF), fraction ALFF (fALFF) and resting-state functional connectivity using searchlight classification. RESULTS: We found that the highest accuracy rate in differentiating between the two groups was 85.00%. Significant discriminating features included the ALFF of the left medial superior frontal gyrus and the functional connectivity between the right thalamus and the bilateral medial superior frontal gyrus, and the right putamen, as well as the functional connectivity between the left caudate and the right insula. CONCLUSIONS: These findings highlight the specific and distinguishing brain functional abnormalities associated with obsessive-compulsive symptoms.
Assuntos
Encéfalo/fisiopatologia , Conectoma/métodos , Transtorno Obsessivo-Compulsivo/fisiopatologia , Adulto , Encéfalo/diagnóstico por imagem , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Transtorno Obsessivo-Compulsivo/diagnóstico por imagem , Adulto JovemRESUMO
AIMS/HYPOTHESIS: The aim of this randomised, crossover trial was to compare cognitive functioning and associated brain activation patterns during hypoglycaemia (plasma glucose [PG] just below 3.1 mmol/l) and euglycaemia in individuals with type 1 diabetes mellitus. METHODS: In this patient-blinded, crossover study, 26 participants with type 1 diabetes mellitus attended two randomised experimental visits: one hypoglycaemic clamp (PG 2.8 ± 0.2 mmol/l, approximate duration 55 min) and one euglycaemic clamp (PG 5.5 mmol/l ± 10%). PG levels were maintained by hyperinsulinaemic glucose clamping. Cognitive functioning was assessed during hypoglycaemia and euglycaemia conditions using a modified version of the digit symbol substitution test (mDSST) and control DSST (cDSST). Simultaneously, regional cerebral blood flow (rCBF) was measured in pre-specified brain regions by six H215O-positron emission tomographies (PET) per session. RESULTS: Working memory was impaired during hypoglycaemia as indicated by a statistically significantly lower mDSST score (estimated treatment difference [ETD] -0.63 [95% CI -1.13, -0.14], p = 0.014) and a statistically significantly longer response time (ETD 2.86 s [7%] [95% CI 0.67, 5.05], p = 0.013) compared with euglycaemia. During hypoglycaemia, mDSST task performance was associated with increased activity in the frontal lobe regions, superior parietal lobe and thalamus, and decreased activity in the temporal lobe regions (p < 0.05). Working memory activation (mDSST - cDSST) statistically significantly increased blood flow in the striatum during hypoglycaemia (ETD 0.0374% [95% CI 0.0157, 0.0590], p = 0.002). CONCLUSIONS/INTERPRETATION: During hypoglycaemia (mean PG 2.9 mmol/l), working memory performance was impaired. Altered performance was associated with significantly increased blood flow in the striatum, a part of the basal ganglia implicated in regulating motor functions, memory, language and emotion. TRIAL REGISTRATION: NCT01789593, clinicaltrials.gov FUNDING: This study was funded by Novo Nordisk.
Assuntos
Circulação Cerebrovascular/fisiologia , Diabetes Mellitus Tipo 1/fisiopatologia , Hipoglicemia/fisiopatologia , Memória de Curto Prazo/fisiologia , Adulto , Cognição/fisiologia , Estudos Cross-Over , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: The majority of patients diagnosed with idiopathic rapid eye movement sleep behaviour disorder (iRBD) progress over time to a Lewy-type α-synucleinopathy such as Parkinson's disease or dementia with Lewy bodies. This in vivo molecular imaging study aimed to investigate if extrastriatal monoaminergic systems are affected in iRBD patients and if this coincides with neuroinflammation. METHODS: We studied twenty-one polysomnography-confirmed iRBD patients with 18F-DOPA and 11C-PK11195 positron emission tomography (PET) to investigate extrastriatal monoaminergic function and microglial activation. Twenty-nine healthy controls (nâ¯=â¯9 18F-DOPA and nâ¯=â¯20 11C-PK11195) were also investigated. Analyses were performed within predefined regions of interest and at voxel-level with Statistical Parametric Mapping. RESULTS: Regions of interest analysis detected monoaminergic dysfunction in iRBD thalamus with a 15% mean reduction of 18F-DOPA Ki values compared to controls (mean differenceâ¯=â¯-0.00026, 95% confidence interval [-0.00050 to -0.00002], p-valueâ¯=â¯0.03). No associated thalamic changes in 11C-PK11195 binding were observed. Other regions sampled showed no 18F-DOPA or 11C-PK11195 PET differences between groups. Voxel-level interrogation of 11C-PK11195 binding identified areas with significantly increased binding within the occipital lobe of iRBD patients. CONCLUSION: Thalamic monoaminergic dysfunction in iRBD patients may reflect terminal dysfunction of projecting neurons from the locus coeruleus and dorsal raphe nucleus, two structures that regulate REM sleep and are known to be involved in the early phase of PD. The observation of significantly raised microglial activation in the occipital lobe of these patients might suggest early local Lewy-type α-synuclein pathology and possibly an increased risk for later cognitive dysfunction.
Assuntos
Monoaminas Biogênicas/metabolismo , Núcleo Dorsal da Rafe/metabolismo , Locus Cerúleo/metabolismo , Microglia/metabolismo , Transtorno do Comportamento do Sono REM/metabolismo , Tálamo/metabolismo , Idoso , Di-Hidroxifenilalanina/metabolismo , Núcleo Dorsal da Rafe/diagnóstico por imagem , Feminino , Humanos , Locus Cerúleo/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Polissonografia/métodos , Tomografia por Emissão de Pósitrons/métodos , Transtorno do Comportamento do Sono REM/diagnóstico por imagem , Transtorno do Comportamento do Sono REM/fisiopatologia , Tálamo/diagnóstico por imagemRESUMO
To better understand the role of the neuropeptide oxytocin in autism spectrum disorder (ASD), we investigated potential deficits in social play behaviour and oxytocin receptor (OXTR) density alterations in the amygdala in a rodent model of ASD. Pregnant rats were injected daily with 20 or 100 mg/kg valproic acid (VPA) or saline from day 12 until the end of pregnancy. The number of pinning and pouncing events was assessed at postnatal days 29-34. Brains from male offspring (n=7/group) were removed at postnatal day 50. We performed quantitative autoradiography with an OXTR radioligand, the [I]-ornithine vasotocin analogue, in brain slices from the amygdala and other limbic brain regions involved in rat social behaviour. The results demonstrated a significant reduction in pinning behaviour and decreased OXTR density in the central nucleus of the amygdala in the 20 mg/kg VPA group. However, the 100 mg/kg VPA group had no significant changes in the number of play behaviour-related events or OXTR binding in the central nucleus of the amygdala. The reduction in OXTR density in the amygdala may be a critical disrupting mechanism affecting social behaviour in pervasive disorders such as ASD.
Assuntos
Ocitocina/efeitos dos fármacos , Ácido Valproico/efeitos adversos , Ácido Valproico/farmacologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Feminino , Masculino , Ocitocina/metabolismo , Jogos e Brinquedos/psicologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ratos , Ratos Wistar , Receptores de Ocitocina/efeitos dos fármacos , Comportamento SocialRESUMO
INTRODUCTION: We examined whether cortical microvascular blood volume and hemodynamics in Alzheimer's disease (AD) are consistent with tissue hypoxia and whether they correlate with cognitive performance and the degree of cortical thinning. METHODS: Thirty-two AD patients underwent cognitive testing, structural magnetic resonance imaging (MRI), and perfusion MRI at baseline and after 6 months. We measured cortical thickness, microvascular cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time (MTT), and capillary transit time heterogeneity (CTH) and estimated tissue oxygen tension (PtO2). RESULTS: At baseline, poor cognitive performance and regional cortical thinning correlated with lower CBF and CBV, with higher MTT and CTH and with low PtO2 across the cortex. Cognitive decline over time was associated with increasing whole brain relative transit time heterogeneity (RTH = CTH/MTT). DISCUSSION: Our results confirm the importance of microvascular pathology in AD. Deteriorating microvascular hemodynamics may cause hypoxia, which is known to precipitate amyloid retention.
Assuntos
Doença de Alzheimer/complicações , Circulação Cerebrovascular/fisiologia , Disfunção Cognitiva/etiologia , Hemodinâmica/fisiologia , Doenças Neurodegenerativas/etiologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Disfunção Cognitiva/diagnóstico por imagem , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Microvasos/patologia , Microvasos/fisiopatologia , Pessoa de Meia-Idade , Doenças Neurodegenerativas/diagnóstico , Testes Neuropsicológicos , PerfusãoRESUMO
OBJECTIVE: Prenatal exposure to valproic acid (VPA) enhances the risk for later development of autism spectrum disorders (ASD). An altered gamma-aminobutyric acid (GABA) system may be a key factor in ASD. Here we investigated possible changes in the GABA system in rats exposed to a low dose of prenatal VPA. METHOD: We performed autoradiography with [3H]muscimol, (a GABAA receptor agonist), and [11C]Ro15-4513 (a partial agonist of the GABAA α1+5 receptor subtypes), in brain sections containing amygdala, thalamus and hippocampus of rats treated prenatally with 20 mg/kg VPA or saline from the 12th day of gestation. Result Prenatal VPA significantly increased [11C]Ro15-4513 binding in the left amygdala compared with controls (p<0.05). This difference was not observed in the hippocampus, thalamus or right amygdala. No differences were observed in [3H]muscimol binding. CONCLUSION: We observed an asymmetric increase in GABAA receptor binding. Disturbances in the GABAA receptor system have also been detected in human autism with [11C]Ro15-4513.
Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Transtorno do Espectro Autista/induzido quimicamente , GABAérgicos/administração & dosagem , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Receptores de GABA-A/metabolismo , Ácido Valproico/administração & dosagem , Animais , Transtorno do Espectro Autista/metabolismo , Autorradiografia , Azidas/farmacocinética , Benzodiazepinas/farmacocinética , Radioisótopos de Carbono , Modelos Animais de Doenças , Feminino , Agonistas de Receptores de GABA-A/farmacocinética , Masculino , Muscimol/farmacocinética , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , RatosRESUMO
The introduction of magnetoencephalography has made it possible to study electromagnetic signaling in deeper, paralimbic cortical structures such as the medial prefrontal/anterior cingulate (ACC) and medial parietal/posterior cingulate (PCC) cortices. Self-awareness and self-control have been attributed to these regions. To test the hypothesis that they are dysfunctional in pathological gambling with poor self-control, we studied gamblers with and without previous stimulant abuse and age- and sex-matched controls. We found that pathological gamblers were more impulsive than controls in a stop-signal task and attributed this to changes in the activity of the paralimbic network: Pathological gamblers had reduced synchronization at rest in the high gamma range (55-100 Hz) compared with controls and failed to show an increase in gamma synchronization during rest compared with the task, as observed in controls. Subgroup analysis revealed that pathological gamblers without a history of stimulant abuse had lower PCC power during the stop-signal task compared with controls and gamblers with previous stimulant abuse. Furthermore, gamblers with a history of stimulant abuse had up to four times higher power at the ACC site during rest and the task compared with controls. In conclusion, pathological gamblers had higher impulsivity and functional paralimbic abnormalities, which could not be explained by a history of stimulant abuse. In addition, previous stimulant abuse had a marked effect on the amplitude of oscillatory brain activity in the ACC and PCC, suggesting long-term deleterious effects of repeated dopaminergic drug exposure. These consequences should be investigated in more detail in longitudinal studies.
Assuntos
Jogo de Azar/fisiopatologia , Sistema Límbico/fisiopatologia , Magnetoencefalografia , Adulto , Dopaminérgicos/administração & dosagem , Dopaminérgicos/efeitos adversos , Feminino , Jogo de Azar/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Depression and a specific personality profile are often outlined as premorbid characteristics of Parkinson's disease (PD). However, few studies have explored possible relations between personality and depression in PD despite research in non-parkinsonian samples identifying specific personality traits as risk factors for depression. The personality profiles of 290 non-depressed and 119 depressed patients with PD were compared. The depressed patients were characterized by elevated neuroticism, reduced extroversion, and reduced conscientiousness and less convincing findings of reduced openness and agreeableness. The largest unique contribution to a regression analysis predicting depression was greater number of motor symptoms, increased neuroticism, and reduced extroversion.
Assuntos
Depressão/etiologia , Depressão/psicologia , Doença de Parkinson/complicações , Personalidade , Idoso , Idoso de 80 Anos ou mais , Distribuição de Qui-Quadrado , Dinamarca , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Inventário de Personalidade , Escalas de Graduação PsiquiátricaRESUMO
Here we describe the cryo-electron microscopy structure of the human histamine 2 receptor (H2R) in an active conformation with bound histamine and in complex with Gs heterotrimeric protein at an overall resolution of 3.4 Å. The complex was generated by cotranslational insertion of the receptor into preformed nanodisc membranes using cell-free synthesis in E. coli lysates. Structural comparison with the inactive conformation of H2R and the inactive and Gq-coupled active state of H1R together with structure-guided functional experiments reveal molecular insights into the specificity of ligand binding and G protein coupling for this receptor family. We demonstrate lipid-modulated folding of cell-free synthesized H2R, its agonist-dependent internalization and its interaction with endogenously synthesized H1R and H2R in HEK293 cells by applying a recently developed nanotransfer technique.
Assuntos
Escherichia coli , Histamina , Humanos , Histamina/metabolismo , Microscopia Crioeletrônica , Células HEK293 , Escherichia coli/metabolismo , Receptores Histamínicos H2/metabolismoRESUMO
Methylphenidate (MPH) is a stimulant that increases extracellular levels of dopamine and noradrenaline. It can diminish risky decision-making tendencies in certain clinical populations. MPH is also used, without license, by healthy adults, but the impact on their decision-making is not well established. Previous work has found that dopamine receptor activity of healthy adults can modulate the influence of stake magnitude on decisions to persistently gamble after incurring a loss. In this study, we tested for modulation of this effect by MPH in 40 healthy human adults. In a double-blind experiment, 20 subjects received 20 mg of MPH, while 20 matched controls received a placebo. All were provided with 30 rounds of opportunities to accept an incurred loss from their assets or opt for a "double-or-nothing" gamble that would either avoid or double it. Rounds began with a variable loss that would double with every failed gamble until it was accepted, recovered, or reached a specified maximum. Probability of recovery on any gamble was low and ambiguous. Subjects receiving placebo gambled less as the magnitude of the stake was raised and as the magnitude of accumulated loss escalated over the course of the task. In contrast, subjects treated with MPH gambled at a consistent rate, well above chance, across all stakes and trials. Trait reward responsiveness also reduced the impact of high stakes. The findings suggest that elevated catecholamine activity by MPH can disrupt inhibitory influences on persistent risky choice in healthy adults.
Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Tomada de Decisões/efeitos dos fármacos , Inibição Psicológica , Metilfenidato/farmacologia , Assunção de Riscos , Adulto , Estudos de Casos e Controles , Método Duplo-Cego , Feminino , Jogos Experimentais , Humanos , Masculino , Motivação/efeitos dos fármacos , Personalidade/efeitos dos fármacos , Probabilidade , Tempo de Reação/efeitos dos fármacos , Recompensa , Análise e Desempenho de Tarefas , Adulto JovemRESUMO
Neurovascular coupling links neuronal activity to vasodilation. Nitric oxide (NO) is a potent vasodilator, and in neurovascular coupling NO production from NO synthases plays an important role. However, another pathway for NO production also exists, namely the nitrate-nitrite-NO pathway. On this basis, we hypothesized that dietary nitrate (NO3-) could influence the brain's hemodynamic response to neuronal stimulation. In the present study, 20 healthy male participants were given either sodium nitrate (NaNO3) or sodium chloride (NaCl) (saline placebo) in a crossover study and were shown visual stimuli based on the retinotopic characteristics of the visual cortex. Our primary measure of the hemodynamic response was the blood oxygenation level dependent (BOLD) response measured with high-resolution functional magnetic resonance imaging (0.64×0.64×1.8 mm) in the visual cortex. From this response, we made a direct estimate of key parameters characterizing the shape of the BOLD response (i.e. lag and amplitude). During elevated nitrate intake, corresponding to the nitrate content of a large plate of salad, both the hemodynamic lag and the BOLD amplitude decreased significantly (7.0±2% and 7.9±4%, respectively), and the variation across activated voxels of both measures decreased (12.3±4% and 15.3±7%, respectively). The baseline cerebral blood flow was not affected by nitrate. Our experiments demonstrate, for the first time, that dietary nitrate may modulate the local cerebral hemodynamic response to stimuli. A faster and smaller BOLD response, with less variation across local cortex, is consistent with an enhanced hemodynamic coupling during elevated nitrate intake. These findings suggest that dietary patterns, via the nitrate-nitrite-NO pathway, may be a potential way to affect key properties of neurovascular coupling. This could have major clinical implications, which remain to be explored.
Assuntos
Mapeamento Encefálico/métodos , Circulação Cerebrovascular/fisiologia , Nitratos/administração & dosagem , Óxido Nítrico/metabolismo , Nitritos/metabolismo , Estimulação Luminosa/métodos , Percepção Visual/fisiologia , Administração Oral , Adulto , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Velocidade do Fluxo Sanguíneo/fisiologia , Circulação Cerebrovascular/efeitos dos fármacos , Estudos Cross-Over , Método Duplo-Cego , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Efeito Placebo , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Sensation seeking is a core personality trait that declines with age in both men and women, as do also both density and availability of the dopamine D(2/3) receptors in striatum and cortical regions. In contrast, novelty seeking at a given age relates inversely to dopamine receptor availability. The simplest explanation of these findings is an inverted-U-shaped correlation between ratings of sensation seeking on the Zuckerman scale and dopamine D(2/3) receptor availability. To test the claim of an inverted-U-shaped relation between ratings of the sensation-seeking personality and measures of dopamine receptor availability, we used PET to record [(11)C]raclopride binding in striatum of 18 healthy men. Here we report that an inverted-U shape significantly matched the receptor availability as a function of the Zuckerman score, with maximum binding potentials observed in the midrange of the scale. The inverted-U shape is consistent with a negative correlation between sensation seeking and the reactivity ("gain") of dopaminergic neurotransmission to dopamine. The correlation reflects Zuckerman scores that are linearly linked to dopamine receptor densities in the striatum but nonlinearly linked to dopamine concentrations. Higher dopamine occupancy and dopamine concentrations explain the motivation that drives afflicted individuals to seek sensations, in agreement with reduced protection against addictive behavior that is characteristic of individuals with low binding potentials.